Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Leptin: a review of its peripheral actions and interactions


Following the discovery of leptin in 1994, the scientific and clinical communities have held great hope that manipulation of the leptin axis may lead to the successful treatment of obesity. This hope is not yet dashed; however the role of the leptin axis is now being shown to be ever more complex than was first envisaged. It is now well established that leptin interacts with pathways in the central nervous system and through direct peripheral mechanisms. In this review, we consider the tissues in which leptin is synthesized and the mechanisms which mediate leptin synthesis, the structure of leptin and the knowledge gained from cloning leptin genes in aiding our understanding of the role of leptin in the periphery. The discoveries of expression of leptin receptor isotypes in a wide range of tissues in the body have encouraged investigation of leptin interactions in the periphery. Many of these interactions appear to be direct, however many are also centrally mediated. Discovery of the relative importance of the centrally mediated and peripheral interactions of leptin under different physiological states and the variations between species is beginning to show the complexity of the leptin axis. Leptin appears to have a range of roles as a growth factor in a range of cell types: as be a mediator of energy expenditure; as a permissive factor for puberty; as a signal of metabolic status and modulation between the foetus and the maternal metabolism; and perhaps importantly in all of these interactions, to also interact with other hormonal mediators and regulators of energy status and metabolism such as insulin, glucagon, the insulin-like growth factors, growth hormone and glucocorticoids. Surely, more interactions are yet to be discovered. Leptin appears to act as an endocrine and a paracrine factor and perhaps also as an autocrine factor. Although the complexity of the leptin axis indicates that it is unlikely that effective treatments for obesity will be simply derived, our improving knowledge and understanding of these complex interactions may point the way to the underlying physiology which predisposes some individuals to apparently unregulated weight gain.


Obesity is a major health issue in much of the human population. In the UK over 16% of men and 17.5% of women are obese and a further 45% of men and 35% of women are overweight,1 representing a doubling since 1980. In the USA, it is estimated that over one-third of the population are overweight by at least 20%, and this proportion is increasing.2,3 Recently, a survey by Brown et al4 showed that 48% of Australian women aged 45–49 were overweight. Increasingly, obesity has become a serious medical problem in developing nations, with the incidence correlating with urbanization and a more plentiful food supply. The morbidities associated with obesity, including type 2 diabetes, cardiovascular disease, osteoarthritis and several forms of cancer, represent a major health risk to the obese population.

Physiologically, obesity is a disorder of energy balance; excess energy is stored as fat whenever energy intake exceeds energy expenditure. Thus, the optimal treatment for obesity would be one that both suppresses food intake and increases energy expenditure. Energy intake and energy expenditure are closely regulated processes, as reflected in the relative stability of body weight in the presence of large daily fluctuations in energy intake.5 Complex interactions between hormone axes in the periphery are integral in maintaining homeostasis of a diverse range of functions. Feedback from these complex interactions is ultimately integrated at the level of the central nervous system (CNS) by a similarly complex array of neurotransmitter signals.

An important regulator in both the CNS and the periphery is leptin. It is now over 8 y since the mouse and human ob genes were cloned,6 leading to the discovery that their expression encoded a 16 kDa protein, which was termed ob protein or leptin (from the Greek leptos, meaning thin). Although it was demonstrated that correction of leptin deficiency in the ob/ob mouse caused a marked reduction in food intake and a normalization of its obesity syndrome,7,8,9 the role of leptin in mediating short-term food intake is still a matter for debate. Both leptin deficiency (in ob/ob mice) and leptin resistance (in db/db mice, having a defective leptin receptor10,11) are characterized by hyperphagia and decreased energy expenditure, leading to an obese phenotype that is notable in animals less than 1 month old.12 The weight of the animals stabilizes at 60–70 g, compared with 25–35 g in control littermates (Figure 1). Both ob/ob and db/db mice manifest numerous other abnormalities, such as non-insulin-dependent diabetes mellitus with severe insulin resistance, hypothermia and cold intolerance, infertility and decrease in lean body mass.12 Studies of both mouse models have provided valuable understanding of many aspects of obesity and the role of the leptin axis. However, these pathologies are not always instructive in the understanding of normal leptin biology and the data presented throughout this review should be considered with this in mind.

Figure 1

Mutations in the mouse obese (ob) gene. The ob/ob mouse (left) is massively obese as compared with the control (right). (Adapted from Glick.331)

This review will focus upon the peripheral interactions of leptin, and will address the aspects of leptin biology which are germane to our understanding of these roles, including the sites and regulation of both leptin and leptin receptor (Ob-R) synthesis, the mechanisms of leptin signalling, and its interaction with other regulatory signalling pathways from the level of the whole body, to the intracellular and molecular levels. These complex interactions will be illustrated using examples from in vitro models, and studies conducted in vivo in animals and in humans. Where there is species variation, we have attempted to clarify the known differences, especially between animal and human studies. However, there are many examples illustrated here in which leptin interactions are highly consistent across the species studied, and add great interpretive value to leptin biology and the factors contributing to obesity in humans.

Leptin synthesis

Transcription of the leptin gene in mice yields a mRNA of 3.5 kb that is expressed primarily in adipose tissues, but recent studies have confirmed that some other tissues also express leptin, including placenta, ovaries, skeletal muscle and stomach.13,14,15,16,17 In humans, leptin is encoded by a gene located in human chromosome 7q31.3, and is similar to that in rodents.18

Leptin is translated as a 167 amino acid protein with an amino-terminal secretory signal sequence of 21 amino acids. The signal sequence is functional, and results in the trans-location of leptin into microsomes with the subsequent removal of the signal peptide.6 Therefore, leptin circulates in the blood as protein of 146 amino acid residues.

Tissue sites of leptin synthesis

White adipose tissue (WAT) is the main site of leptin synthesis, but it is now evident that the hormone is also produced in other tissues as well. There is some evidence that brown adipose tissue (BAT) is also a site of leptin production.19,20,21,22,23,24,25,26 A major issue is the physiological role of leptin produced by brown fat. One possibility is that it simply adds to the pool of circulating hormone, thus its contribution would be small relative to that of white fat in mature animals and man.27 Other reports suggest that the expression that is observed may be a reflection of contamination or infiltration of brown fat with white adipocytes.28 However, Moinat et al19 reported that the level of mRNA in interscapular brown fat was about 40% of that in the epididymal white fat depot, a result that is unlikely to be explained by infiltration or contamination. If the ob gene is expressed by brown adipocytes, then there are important implications for the physiological role of leptin. The interaction of the leptin axis and thermogenesis is discussed below.

Comparison of the levels of ob mRNA in different adipose tissue depots suggests that there are site-specific variations in the expression of the ob gene in both rodents,28,29,30 and humans.31,32 In humans leptin expression appears to be greater in subcutaneous than in omental adipose tissue.31,33,34 The differences in mRNA level between various adipose tissue sites may reflect differences in fat cell size; the larger the adipocytes, the greater the expression of the ob gene.28,29,30,34 However, Lonnqvist et al35 using in situ hybridization, found no differences in leptin expression between subcutaneous and omental fat in a small group of four obese humans.

In rodents the opposite is apparent as leptin expression may be lower in subcutaneous fat than in the internal depots, and the highest level of expression is generally evident in the epididymal (males) and perirenal adipose tissues.29,31 However, site-specific leptin expression also varies with maturation as in adult rodents; the ob mRNA level is much higher in the gonadal and perirenal sites than in subcutaneous depots,28 but in suckling rats during the first 1–2 weeks after birth, the subcutaneous fat is the main site of ob gene expression.36

Sexual dimorphism in humans is evident in both ob mRNA expression,33,37 and in the correlation between leptin concentrations and fat mass.38,39 Kennedy and co-workers39 proposed that the observed gender differences in leptin synthesis are because of the stimulating roles of oestrogens and/or a suppressive effect of circulating androgens, while other authors have been unable to find a correlation between sexual dimorphism and sex hormones.40

An important new dimension to leptin biology has emerged with the recognition that the placenta and ovary express the leptin gene and that they are sites of production of the hormone. This has been demonstrated in mice, rats and humans.13,15,41,42,43 Two hypotheses about the role of placental synthesis of leptin are that it may either be a new growth factor, or act as a signal of energy status between the mother and the foetus. The placenta also expresses the leptin receptor gene, implying that the organ is a target for the action of leptin as well as being a source of the hormone.13 These observations suggest that leptin may act in an autocrine manner. The expression of leptin by syncytiotrophoblasts13,44,45 has added support to the hypothesis of the importance of leptin in nutrient transfer. In situ hybridization and immunohistochemical studies on pregnant mice have demonstrated leptin synthesis in several regions of the foetus, including the heart, bone and cartilage, choroid plexus of the foetal brain, lung, kidney, heart and liver, and cells of the hair follicle.46

Leptin has also been detected in rat stomach.16 Leptin mRNA was identified after screening of total RNA extracted from fundic epithelium scrapings using the polymerase chain reaction after reverse transcription of RNA. Leptin mRNA was not detected in any other gastrointestinal tissue, including the liver and pancreas. Subsequent studies demonstrated that leptin immunoreactive cells were localized in the lower half of the fundic glands, a site similar to that of the pepsinogen secreting chief cells.16,47 Recent studies have also shown leptin synthesis by other tissues, including rat skeletal muscle,17 rat and mouse pituitary gland,48,49 human mammary epithelial cells,50 human and newborn mouse bone marrow51,52 and mouse liver.53

Taouis et al,54 reported that leptin gene expression in chicken was not only localized in adipose tissue, as in mammals, but also was present in liver. The expression of leptin in liver may be associated with a key role of this organ in avian species in controlling lipogenesis. The diverse picture of where leptin is produced in the body indicates that the functions of the hormone may extend beyond the basic lipostatic model originally envisaged.

Regulation of leptin synthesis

The level of ob mRNA in white adipose tissue and the circulating leptin concentration are increased markedly in obesity, as shown in both human studies and in studies of several types of obese animal.30,55,56,57 Indeed, in human subjects there is a high correlation between body mass index (BMI) and circulating leptin.30 Thus, the greater the amount of adipose tissue, the higher the level of the hormone. In addition, as previously mentioned, adipocyte size appears to be another major determinant of leptin mRNA expression.58 Hormonal factors have also been studied in relation to leptin and are discussed below.

Exercise training induces an increase in metabolic rate and overall energy expenditure.59 The mechanisms which regulate leptin mRNA expression and circulation levels during exercise are still unknown. Controversy exists over whether exercise has any effect on leptin levels. Landt et al60 demonstrated that prolonged endurance exercise, such as marathon running, decreased leptin concentrations. Hypoleptinemia was also detected in female and male elite gymnastics of pubertal age.61 Leptin gene expression was also decreased in Sprague–Dawley rats after 4 weeks of exercise training.62 However, other studies63,64,65,66 have shown that moderate-intensity aerobic exercise and acute and chronic exercise in men and women do not affect leptin levels. In contrast, Hickey et al67 reported that moderate intensity aerobic exercise in women reduced leptin levels by 17.5% after 12 weeks. Pasman and co-workers68 investigated the effect of 4 month moderate-intensity training on leptin levels in obese males and found that serum leptin levels were reduced by 23%. Hickey and co-workers67 have suggested that the gender-specific responses to training reflects differences in insulin-resistance between males and females; males, being the more insulin-resistant, may need more time and a greater stimulus to respond with lower leptin levels. There are a number of potential mechanisms by which exercise might regulate leptin production, such as via changes in insulin sensitivity to fatty acid concentrations or by alterations in sympathoadrenal activity.69 As leptin concentrations are determined by energy balance, it is conceivable that energy expenditure may also be a regulatory signal for leptin production.

It has been shown that cold exposure reduces circulating leptin levels and leptin expression,19,28,70,71,72 suggesting that leptin may participate in the adaptive mechanism triggered by variations in external temperature. Trayhurn and co-workers28,73 hypothesized that the inhibitory effect of low temperature on leptin results from an increase in the adrenergic tone induced by exposure to cold temperatures, which would in turn act through the β3-adrenoceptor (β3-AR) present in adipose tissue, inducing a reduction in the expression of leptin mRNA. It has been reported that this was the case for mice19 and rats.28 Hardie et al70 also found that acute cold exposure decreased the level of circulating leptin in lean Zucker rats. However, it appears that this is not so for other rodents, such as the Djungarian hamster.21 For animals living in areas with large seasonal temperature variations, a decrease in serum leptin may represent an adaptive mechanism for maximising the size of fat deposits when environment temperature is low. Trayhurn et al28 showed that the leptin mRNA observed in brown adipose tissue was further reduced on cold exposure, paralleling the response observed in mouse white adipose tissue. These authors postulated that these findings may suggest the existence of a feedback loop between the hypothalamus and BAT, that would result in an inhibition of leptin gene expression when the sympathetic system is activated. Interestingly, Trayhurn et al28 reported contrasting results to those reported by Moinat et al,19 who showed no change in leptin expression in the white adipose tissue of rats which were acutely cold-exposed (6°C for 24 h).

Changes in physiological state induced by fasting result in reduced ob gene expression and a subsequent fall in circulating leptin.28,74,75 Rapid decreases in leptin levels in response to energy restriction or fasting appear to be greater than the decrease in fat mass in both rodents55 and humans.76 Thus, leptin may serve as a sensor of short-term changes in energy stores. Another study in mice has shown that re-feeding after fasting led to a rapid restoration of gene expression and plasma leptin.77 The inhibitory effect of fasting on leptin expression might also be mediated by the sympathetic nervous system and the β3-AR. Leptin is involved in increased energy utilization, possibly through enhanced thermogenesis mediated by tissue uncoupling proteins (UCPs). Studies on UCP subtype expression in rodents have shown that UCP-1 is expressed at higher levels during cold exposure and decreased by fasting78 and that leptin treatment enhances79 or does not alter80 BAT UCP-1 mRNA, compared with untreated ad libitum fed controls. These contrasting findings indicate that the interaction between cold exposure, thermogenesis and leptin production requires further investigation.

The role of leptin has been investigated in the pathogenesis of eating disorders. In most studies, serum leptin concentrations in patients with anorexia nervosa, bulimia, non-specific eating disorders81 and depression82 are similar to those of healthy persons with comparable BMI. In contrast, Haluzik et al83 found that serum leptin levels in patients with anorexia nervosa were significantly lower than those in the control group. However, Mantzoros et al84 found that patients with anorexia nervosa have relatively higher transport of leptin to the cerebrospinal fluid at lower serum leptin concentrations, which may explain both the symptoms of anorexia nervosa and the difficulty that these patients have in regaining weight.

The sympathetic nervous system, especially the β-AR axis, has been implicated in the regulation of leptin gene expression. For example, the β-AR agonists, noradrenaline and isoprenaline decreased leptin gene expression in WAT in mice73 and decreased serum leptin.85 It has been shown, both in vivo and in vitro, that β3-agonists induce a decrease in the expression of leptin in WAT and BAT and decrease serum leptin.27,73,86,87,88 The significance of β3-AR in the control of leptin production in human subjects is uncertain, although there is evidence that the receptor may play an important role in the control of lipolysis in human omental and subcutaneous adipose tissue.89,90 Mantzoros et al86 reported that acute treatment of mice with the β3-agonist, CL 316,243 suppressed leptin expression in WAT. Inhibition of leptin expression was observed only in normal (control) mice, while the effect of β3-AR agonist was absent in knockout mice (with targeted disruption of the β3-AR gene). Also, despite the falling leptin levels, β3-agonist administration acutely suppressed food intake. Li et al87 showed that another β3-agonist, CGP-12177, also caused reduction in food consumption in F-344 rats. In another study,19 β3-AR stimulation by Ro 16-8714 decreased leptin mRNA in WAT of lean (Fa/Fa), but not obese (fa/fa) Zucker rats. Thus it appears that the leptin response to specific β3-AR activation is analogous to classical adrenergic activation. Thus, it appears that the body's response to a stressor such as low temperature conserves triacyl-glycerol (TAG) from mobilization for use by muscle and promotes its use for thermogenesis. In addition, leptin has been shown to increase noradrenaline turnover in thermogenic interscapular BAT91 and to also increase the sympathetic outflow to other tissues,92,93 consistent with this hypothesis.

Leptin-treated mice lose more weight than pair-fed vehicle-treated animals, implying that leptin also increases energy expenditure.8 Furthermore, Campfield et al7 showed that leptin-treated animals have higher core temperatures and metabolic rates than controls. These observations are consistent with the peripheral interaction of leptin with insulin, mobilizing fuels and inhibiting energy storage mechanisms as outlined in more detail below. It is also possible that leptin increases overall sympathetic nerve activity, thereby leading to a significant increase in energy expenditure. Summaries of variables that appear to regulate leptin production are shown in Tables 1 and 2.

Table 1 Variables that increase serum leptin levels
Table 2 Variables that decrease serum leptin levels

The leptin gene promoter is also positively regulated by the functional binding site for CCAAT/enhancer binding protein α (C/EBP-α), a transcription factor important in adipocyte differentiation.94,95 In contrast, thiazolidinediones, a class of new antidiabetic agents which activate another transcription factor involved in adipocyte differentiation, peroxisome proliferator-activated receptor γ(PPARγ), suppress leptin expression in adipocytes.96,97 Thus, the relationships between the control of leptin expression and adipocyte differentiation are not well understood.

Leptin receptors (Ob-R)

Ob-R cloning

The identification of the leptin receptor (Ob-R) was realised through an expression cloning strategy.10 Tartaglia and co-workers10 constructed a cDNA library from mouse choroid plexus. A cDNA that encoded the Ob-R was found by expression cloning using an alkaline phosphatase-Ob fusion protein as a probe. Expression of the Ob-R in COS cells was achieved, and displaceable binding of mouse and human leptin was observed. Scatchard analysis revealed a high affinity receptor with a binding constant of about 0.7 nM. The human homologue of the mouse leptin receptor was cloned using a human infant total brain library.10 The murine and human leptin receptors are highly similar in amino acid sequences for both the extracellular (78% identity) and intracellular domains (71% identity).98In situ analysis with probes generated from the extracellular domain (common to all Ob-R forms), RNase protection or polymerase chain reaction (PCR) revealed expression of Ob-R in multiple tissues. Ob-R exhibit a widespread distribution including liver, heart, kidneys, lungs, small intestine, testes, ovaries, spleen, pancreas and adipose tissue.11,13,52,99,100,101,102 However, analysis has shown that the majority of transcripts detected are those encoding short intracellular domain forms.52,99 Within the hypothalamus, the long form leptin receptor has been found in several hypothalamic nuclei, including the arcuate nucleus, ventromedial, dorsomedial and lateral hypothalamic nuclei, and the paraventricular nucleus.103,104

Alternative splicing

Previous data suggest that the diabetes (db) gene encodes the receptor for the obese (ob) gene product, leptin.6,105 Leptin receptor maps to the same 300 kb interval as db, and has at least six alternatively spliced forms.11 Lee and co-workers11 isolated candidate genes for db from two bacterial artificial chromosomes, 43 and 242, and complementary DNA selection from mouse hypothalamus. Mouse cDNAs predicted proteins with differing cytoplasmic portions, designated Ob-Ra, Ob-Rb, Ob-Rc (also known as B219) and Ob-Rd. Ob-Re has a different predicted amino-acid sequence after His 796.11

All isoforms of the murine leptin receptor share an identical extracellular, ligand-binding domain of 816 amino acids, while the intracellular domain at the C-terminus is different.10,11 Ob-Ra, Ob-Rb, Ob-Rc, Ob-Rd and Ob-Rf contain transmembrane domains of 34 amino acids, whereas Ob-Re is truncated before the membrane-spanning domain and is therefore likely to be secreted.11 Secreted extracellular domains of other cytokine receptors are also known to function as specific binding proteins.106 Ob-Rb (the human form of which is also referred to as Ob-RL; L=long) has a long cytoplasmic domain of 320 amino acids. Recently, another splice variant of leptin receptor, B219, was cloned from murine foetal liver.107

Ob-R structure

Sequencing of the original murine cDNA revealed a single membrane-spanning receptor, which belongs to the gp 130 family of cytokine receptors.10 The extracellular region of these receptors is characterized by the presence of multiple domains. Each of these domains is characterized by unique consensus residues.108,109,110 For cytokine receptors, the CK-F3 domain seems to form the ligand binding site. In contrast to the growth hormone receptor, the extracellular region of the leptin receptor contains two repeating CK-F3 domains. Such repeating CK-F3 domains are not commonly found in cytokine receptors, and localization of the ligand binding site was not described until recently. Fong et al111 found that the first CK-F3 domain of Ob-R is not required for leptin binding and receptor activation, whereas the second CK-F3 domain is the most likely leptin binding site.

Ob-R-induced signal transduction

Class I cytokine receptors are known to act through cytoplasmic tyrosine kinases of the Janus kinase family (JAKs) and signal transducers and activators of transcription (STAT). The intracellular domain of the truncated leptin receptor variant, in the db/db mouse, contains the Box 1 motif, but lacks the Box 2 and 3 motifs, required for activation of JAK.11,112 In the db/db mouse, the short form of the leptin receptor, appears to be unable to activate the JAK/STAT pathway.99,113 Zucker fatty (fa/fa) rats have a full-length, but dysfunctional leptin receptor. The study of Yamashita et al114 showed that transformed Chinese hamster ovary cells (CHO) which expressed fa-type Ob-Rb exhibited slightly reduced leptin binding activities and reduced signal transduction, in comparison to CHO cells which expressed wild-type Ob-Rb. The affinity values obtained by Yamashita et al114 were 0.4 nM for normal rat Ob-R and 1.2 nM for fa rat Ob-R. These data illustrate that only a relatively minor decrease in the affinity of the leptin-Ob-R interaction results in a loss of receptor function. It is unknown whether this single amino acid substitution in the extracellular domain has any direct effect on second messenger signalling.

Upon leptin binding to its receptor, receptor dimerisation occurs, which seems to be necessary for signalling activity.115,116,117 After leptin binding and receptor homodimerization, the long form of the receptor (Ob-Rb) activates JAK/STAT pathways. The activated JAKs phosphorylate tyrosine sites on the intracellular domain of the receptor, which serve as docking sites for the Src-homology domains (SH2, SH3) that occur in all of the STATs.108,110 The phosphorylated intracellular domain then provides a binding site for a STAT protein. The activated STAT proteins dimerise and translocate to the nucleus, where they bind DNA and activate transcription. Ob-Rb activation may also phosphorylate JAK leading to the activation of insulin receptor substrate (IRS-1) and mitogen-activated protein kinase (MAPK). Upon leptin binding, the short form of the leptin receptor (OB-Ra) phosphorylates IRS-1 and consequently activates MAPK. The activation of MAPK leads to the activation of pp90 S6-K.118,119 Thus, as described above, leptin receptors share, at least in part, some of the signalling pathways characteristic for the class I cytokine receptor family.

The intracellular domains of Ob-Ra–Ob-Rd contain a Box 1 motif, which is highly conserved among most members of the cytokine family.110 A less conserved Box 2 motif is also found in a number of receptors of this family. Mutational analyses of the conserved regions in several receptors suggested that these two domains are required for activation of the JAK/STAT pathway. Since short isoforms of leptin receptor do not contain Box 2, it has been predicted that they are signalling inactive.10,11,120 However, in some cases, cytokine receptors of the GH receptor subfamily with a mutation in Box 2 motif and/or with only short intracellular domains have been shown to have signalling capability.113,121,122 Bjorbaek and co-workers118 have found that Ob-Ra was able to activate JAK and IRS-1 tyrosine phosphorylation in a leptin-dependant manner in transfected COS cells. Their results showed that Ob-Ra has signalling capability, and that these required Box 1, but not Box 2, as was predicted before.

The activation of STAT proteins in response to leptin was assayed in a variety of mouse tissues or cells known to express Ob-R. In vivo, in mice, administration of recombinant leptin caused activation of STAT3 in the hypothalamus of wild-type and ob/ob mice.123,124,125 However, in vitro, binding of leptin to leptin receptors activates STAT1, STAT3 and STAT5.99,113,120,124,126,127 Recently, a new family of cytokine-inducible inhibitors of signalling has been identified, including cytokine-inducible sequence (CIS) and suppressor-of-cytokine-signalling-3 (SOCS3).125,128,129,130,131,132,133 CIS and SOCS3 may function as part of an intracellular negative-feedback loop, inhibiting JAK activity, and thereby switching off or dampening cytokine signal transduction.131,132

Leptin receptor function

The reasons why several distinct short intracellular forms of leptin receptors are produced and their respective roles are still not clear. It has been suggested that the short intracellular domain form in the choroid plexus plays a role in transporting leptin from the blood into the cerebrospinal fluid,11,98 where it can move by diffusion to the brain centres that regulate body weight. It has been shown that leptin enters the brain by a specific and saturable mechanism,133,134 but the role of Ob-Ra in this process has not yet been fully demonstrated. However, the recent study by Kastin et al135 showed that the transport of leptin across the blood–brain barrier in rats lacking the Ob-Ra was decreased, indicating that Ob-Ra may have a functional role in leptin transport. As mentioned before, it has been shown that Ob-Ra may perform signal transduction, although different from that induced by the long form.118,136 Murakami and co-workers136 have found that expression of mRNA for the immediate-early genes c-fos, c-jun and jun-B, which are induced by addition of leptin, is observed in both CHO cells expressing Ob-Rb and also in cells expressing Ob-Ra. Thus, it appears that short and long isoforms of the leptin receptors have the potential to mediate signal transduction. Although the short forms have an attenuated signal, their relative abundance in peripheral tissues may mediate specific effects of leptin on those tissues.

It has been implied that Ob-Rc and Ob-Rd isoforms may play a role in clearance of leptin from the circulation.11 Two of the leptin receptor isoforms have been described in only one species: Ob-Rd in the mouse11 and Ob-Rf in the rat.137 It has been proposed that the soluble isoform Ob-Re functions as a binding protein. Fei et al,104 using RT-PCR, found that Ob-Re was not expressed significantly in mouse tissues, while the study of Chua et al138 showed that Ob-Re was not expressed at all in human tissues (brain, skeletal muscle, heart, liver and lung). The exception to this is during pregnancy,139 which is covered in greater detail below. There are, however, reports of an Ob-R mutation in humans.140,141 A consanguineous family with both homozygous and heterozygous members had higher plasma leptin concentrations than expected given their BMIs: 526, 600 and 670 ng/ml and 145, 212, 240, 294 and 362 ng/ml, respectively. The mutated Ob-R had no transmembrane or intracellular domains and >80% of circulating leptin was in a high molecular weight associated form, compared with 7.5% bound in a non-mutated sibling. However, Lollmann et al,142 using RNase protection assay, found that in mice Ob-Re expression was ubiquitous and occurred in rather large amounts. These authors142 concluded that Ob-Re is produced at a level that is sufficiently high to act as a buffering system for free circulating leptin.

Another splice variant of the leptin receptor was cloned from murine foetal liver, B219.107 Results from the Northern analysis and PCR analysis of ObR/B219 mRNA showed that the B219 isoform was associated with haemopoietic stem cells, thus these authors proposed a possible role of leptin in haemopoiesis.

Expression of Ob-R in peripheral tissues

There are numerous reports of the expression of leptin receptors in peripheral tissues, including liver, heart, kidneys, lungs, small intestine, pituitary cells, testes, ovaries, spleen, pancreas, adrenal gland and adipose tissue.11,13,14,49,52,99,100,101,102,107,143 Furthermore, a number of studies have now reported partial characterisation of Ob-R using radioligand binding, confirming the presence of high- affinity leptin binding sites in rodent kidney144 (and Margetic et al, submitted) as well as in the CNS.105,145,146,147 These studies are supported by binding analysis in a range of transformed cells expressing particular isoforms of Ob-R.10,113,114,126,148,149 These findings suggest that leptin may have more complex roles than initially thought, raising the question of additional physiological functions of leptin in different tissues (Figure 2).

Figure 2

Schematic representation of pathways in which leptin plays an important role (Gal, galanin; NT, neurotensin; POMC, proopiomelanocortin; IGF-1, insulin-like growth factor-1; GH, growth hormone; BAT, brown adipose tissue; UCP, uncoupling protein; FFA, free fatty acid).

Hoggard et al14 examined expression of leptin receptor splice variants in murine peripheral tissues. Reverse transcriptase-polymerase chain reaction indicated that the leptin receptor, Ob-R, in particular the short splice variant of the leptin receptor, Ob-Ra, was expressed in a wide range of tissues. Expression of Ob-R was localized by in situ hybridization to specific sites in the spleen, testes, intestine, heart, lung, liver skeletal muscle and adrenal gland. However, the long form of the leptin receptor, Ob-Rb, was only detected at significant levels in the medulla of the adrenal gland and in the inner zone of the medulla of the kidney.

Chen et al52 investigated tissue localization of Ob-R mRNA in brain and peripheral tissues of adult and newborn mice using in situ hybridization. This study confirmed previously published reports99,103,150,151 that the long isoform of leptin receptor was predominantly expressed in hypothalamic nuclei, while low levels were observed in choroid plexus. Chen and co-workers52 further described the expression of Ob-Rb in peripheral tissues of adult mice as either very low or undetectable. In newborn mice, the expression of Ob-Rb was similar to that of adult mice, although bone marrow was the site of highest Ob-R expression.

Cao et al152 demonstrated the presence of Ob-Ra on adrenaline-secreting chromaffin cells in rat adrenal medulla, suggesting that leptin may directly affect the adrenal medulla. In addition, Hoggard et al14 and Takekoshi et al143 showed that Ob-Rb was highly expressed in the mouse and porcine adrenal medulla, respectively.

Recently, Tsuchiya et al153 found that the leptin receptor expressed in human lungs is the long isoform, Ob-Rb, suggesting that leptin may be involved in the peripheral regulation of respiratory function in humans. However, several studies10,14,104 have shown the presence of only Ob-Ra in lung, or both Ob-Ra and Ob-Rb.101,142 Thus, it appears that there may be a further unidentified role for leptin in the lungs.

De Matteis et al101 studied localization of leptin receptor splice variants in mouse peripheral tissues by immunohistochemistry. Their results indicate that most of the organs expressing Ob-Ra (adrenal gland, adipose tissue, heart, liver, lung, ovary, endocrine pancreas, skeletal muscle and testis) also express Ob-Rb in the same cell type, although in some (adrenal gland, liver, endocrine pancreas and testis) staining for Ob-Rb was weaker. Thus, many tissues may contain a heterologous mix of Ob-R subtypes.

Characterization of Ob-R in peripheral tissues by radioligand binding analysis

Excluding studies of binding analysis of Ob-R in the CNS, binding has also been characterized in mouse lung, intestine, kidney, liver, skin, stomach, heart and spleen.154 Additionally, we have characterized leptin binding in the bovine kidney (Margetic et al, submitted) and leptin binding in rat kidney has been characterized by other workers.144

The study of Serradiel-Le Gal et al144 found the affinity of the leptin binding site to be 0.5–0.7 nM, which appears to be low in comparison to other studies in which the affinity of leptin for the Ob-R was accurately determined.114,145,149,154

The study of Dal Farra et al154 appears to be thorough, the binding affinity being characterized in a range of tissues, Kd=0.1–0.3 nM. However, of concern is that the highest concentration of radioligand used was not stated, but appears to be only 0.6 nM. Given the experimentally determined affinity (0.2 nM), saturation analysis would require a total radioligand concentration of at least 4 nM. Thus, this study has not fulfilled the underlying criteria for saturation analysis, and their results must be regarded with caution. Despite this, the affinity is in close agreement with that found in studies in our own laboratory (Margetic et al, submitted), in which leptin binding affinity to bovine kidney membranes was 0.1 nM. However, the number of binding sites characterized in our study, 46 fmol/mg protein, and in the study of Serradiel-Le Gal et al144 in rat kidney, 45 fmol/mg protein, may have been underestimated in the study of Dal Farra et al,154 which found a Bmax=6 fmol/mg protein in mouse kidney membranes.

Tissue distribution studies and leptin pharmacokinetics

The authors155 and others156 have demonstrated in pharmacokinetic studies in normal rats that the loss of leptin from the circulation is best described by a two-pool model, consistent with the occurrence of leptin in two forms: free and bound to other proteins. The biological forms which constitute the bound pool of leptin include the hormone bound to tissue receptors, to non-specific sites in the tissues, and to a carrier molecule(s) in plasma155 (and Margetic et al, submitted). The rapid removal of the free form of leptin from plasma (half-life, 3.4 min) is consistent with data for other peptide hormones which occur in the free form such as insulin (half-life, 4 min157) or insulin-like growth factor-1 (IGF-1) in which the free form is cleared rapidly (half-life, 12–15 min158,159). Furthermore, clearance of the bound form of leptin which is retained in the plasma for a much longer period (half-life, 71 min155) is consistent with the values obtained for IGF-1, which is known to also occur bound to one of several specific binding proteins (half-life, 148–264 min158,159), suggesting that a specific binding molecule for leptin may also be important in the rat.

Van Heek et al100 determined brain and whole body localization and distribution of 125I-leptin after intraperitoneal (i.p.) administration to ob/ob and db/db mice. After a single injection of 125I-leptin, radioactivity was detected at early time points in all tissues sampled in both ob/ob and db/db mice. Analysis of the tissue distribution of 125I-leptin revealed that leptin rapidly appears in the serum and accumulates in the fat, intestines, liver and kidneys in both ob/ob and db/db mice. These similarities may be unexpected, as these two models are at the ‘extremities’ in terms of leptin biology (ob/ob, non-functional leptin with up-regulated receptors; db/db, high circulating leptin with non-functional receptors). Thus, leptin distribution may be affected by its hydrophobic character, as non-specific interactions with abundant lower affinity binding sites, independent of binding to specific Ob-R, may have a large effect on its tissue distribution. Alternatively, it must be remembered that these results were obtained in animals which received very high doses (0.3 mg/kg) of exogenous leptin. Thus, it is likely that receptors were saturated and that non-specific binding sites were disproportionately represented in this study, possibly obscuring differences between ob/ob and db/db mice.

Klein et al160 used an arteriovenous balance method in humans and found that the rate of clearance of plasma leptin was 1.50 ml/kg/min. This lower rate of clearance may indicate that leptin in humans remains biologically active for a longer period than in rodents. These results were recently supported by a study in another primate, Rhesus monkeys,161 which found a similar clearance rate (1.82 ml/min/kg). It is likely that leptin association with carrier molecules which appear to be different across the species investigated to date162,163 is an important factor affecting leptin clearance.

Pharmacokinetics studies also provide evidence on the relative tissue distribution of leptin.155 The high abundance of leptin distributed throughout the peripheral tissues compared with brain is consistent with data from studies of Ob-R mRNA expression in both rodents and humans.11,14,99,107,150 Using Northern blot analysis Cioffi et al107 showed that the mouse tissues with the highest abundance of Ob-RNA were lung and kidney, with less in heart, liver, spleen, muscle and brain, and none in testis. The distribution of tissue expression may be quite species-specific, as in human tissues the highest expression was found in heart, liver, small intestine, prostate and ovary, whereas levels were relatively lower in lung and kidney. Ghilardi et al99 quantified the results of RNase protection assays using densitometry. In normal mouse tissues, mRNA from both the long and the short isoforms of the receptor were detected, and the relative abundance of the long isoform expressed as a percentage of the total Ob-R mRNA. Interestingly, stomach (11%), small intestine (7%), pancreas (11%), skeletal muscle (8%), and heart (10%) had comparable abundance to that in the brain (18%). However, the level in hypothalamus was higher (36%).

In addition to providing corroborating evidence of Ob-R mRNA expression in defining the tissue distribution of Ob-R, pharmacokinetics studies provide evidence for the relative importance of rate of synthesis of leptin, and may indicate that short-term changes in rate of leptin synthesis and thus, minor changes in circulating plasma leptin concentrations, may be of little biological significance owing to the prolonged half-life of leptin in plasma and the presence of a substantial pool of non-specific tissue and plasma binding sites, providing a large buffering capacity for circulating plasma leptin concentrations. If this is so, the role of leptin, particularly in satiety, requires further clarification, and suggests a more complex interaction between leptin, its transport across the blood–brain barrier and CNS-specific hormones such as neuropeptide Y.

Major peripheral interactions

The role of leptin in the circulatory system

Leptin and haemopoiesis

It has recently been shown that Ob-R is expressed in haemopoietic cells and that leptin may be linked to the proliferation and differentiation of haemopoietic precursors.107,164 This topic was recently reviewed by Gainsford and Alexander165 and will only be briefly reviewed here. It is perhaps not surprising that leptin appears to have a role in haemopoiesis. Leptin structure is similar to the cytokines, containing four alpha helices. Furthermore, the Ob-R is a member of the type I cytokine receptor superfamily. In cell culture studies, it appears that leptin has a mediation role, at least in murine myelocytic cells from bone marrow, in cell proliferation.166 However, at least one study using human bone marrow cells was unable to demonstrate clonal proliferation.164 Rather, in this study differentiation of transformed myelocytic cells expressing Ob-R was evoked by leptin.

Of particular interest, the study of Umemoto et al166 provided data describing the colony formation of granulocyte macrophage cells from bone marrow derived from both normal and db/db mice. The dose–response relationship for leptin was rightward shifted in db/db cells compared to normal cells. Thus, there was a significant response in normal cells at a leptin concentration of 10 ng/ml (physiological concentration), while in db/db cells (which have a dysfunctional Ob-R), a leptin concentration of 100 ng/ml evoked a similar response. This evidence suggests that intracellular events (at least in these cell types) may be evoked by supraphysiological concentrations of leptin, which are independent of the Ob-R.

Furthermore, this concentration of leptin is typical of that observed in obese individuals and poses an intriguing question: if leptin at this concentration has intracellular effects independent of the Ob-R, is obesity a ‘pathological state’ in which some of the peripheral actions of leptin are dysfunctional, and independent of Ob-R binding?

Nakata et al167 reported that relatively high concentrations (50–100 ng/ml) of human leptin corresponding to plasma leptin levels in obese individuals, promoted platelet aggregation. At lower concentrations (<10 ng/ml), leptin failed to potentiate agonist-induced platelet aggregation. This suggests that the leptin effect of potentiating platelet aggregation operates specifically in obese individuals, and it may be a key coupling factor between obesity and the cardiovascular disease associated with syndrome X (which includes glucose intolerance, insulin insensitivity and abnormal fat distribution) and diabetes. Alternatively, these data may indicate that leptin action in platelets functions via an Ob-R-independent mechanism, as suggested above.

Leptin, other roles in the circulatory system—angiogenesis

Further roles for leptin have been proposed in the circulatory system, including stimulation of endothelial cell growth and angiogenesis.168,169 Several studies have demonstrated that vascular endothelium expresses the long form of the receptor146,167,168,169,170,171 (in rodents and humans170) and short131,171,172 forms of the leptin receptor in rodents.

Sierra-Honigmann et al168 demonstrated that the leptin receptors are expressed in human vasculature and in primary cultures of human umbilical vein endothelial cells (HUVEC). Ob-Rb was detected in HUVEC using immunofluorescence microscopy and rabbit polyclonal antibodies specific for the intracellular domain of the Ob-Rb isoform, as a 170 kDa protein. The proliferative effects of human leptin on HUVEC have also been reported by Bouloumie et al.169 RT-PCR analysis revealed the expression of both short and long isoforms of Ob-R in endothelial cells. Moreover, human leptin evoked a time-dependent tyrosine phosphorylation of a number of endothelial proteins, the most prominent of which were the mitogen-activated protein kinases, Erk 1/2. Treatment of HUVECs with leptin led to a concentration-dependent increase in cell number that was maximal at a leptin concentration of 10 ng/ml. This effect was associated with enhanced formation of capillary-like tubes in an in vitro angiogenesis assay and neovascularization in an in vivo chick allantoic membrane (CAM) model of angiogenesis. We have found similar effects of leptin on angiogenesis using the CAM model.173 Of particular interest in this study was the dose–response relationship of leptin with angiogenic activity. At 0.1, 0.5 and 1 µg/disc applied to CAM, leptin had increasing angiogenic activity. However, at higher concentrations (3 and 10 µg/disc), not only was angiogenic activity increased, but there were also pronounced toxic effects including capillary leakage, and marked avascular zones. These data appear to be consistent with findings in other systems such as the colony formation induced in granulocyte macrophage cells from db/db mice166 (cited above), and may suggest that some actions of leptin, when present in high concentrations, are associated with pathophysiological effects independent of the Ob-R.

In a recent study, Ring and co-workers171 studied leptin's effect on wound repair in ob/ob and db/db mice. Systemic administration of leptin at doses ranging from 0.1 to 10 mg/kg/day induced a highly significant acceleration in wound repair in ob/ob mice, but not in db/db mice, indicating that leptin effects on wound repair were at least partially due to a direct interaction of leptin with its receptors at the wound site. Topical application of leptin also induced dose-dependent acceleration in wound repair. However, these authors also found in ob/ob mice that neither systemic nor topical leptin application changed wound haemoglobin or wound vessel density. These data may suggest that leptin is acting via a mechanism independent of angiogenesis, however further studies are required to clarify this point.

Leptin and reproduction

Recently, it was found that leptin plays an unexpected role in reproduction.41,174,175 Human ovary and prostate and murine ovary and embryo express mRNA for the leptin receptor.10,107,176 Although much of the evidence suggests a central site for the effects of leptin on the reproductive axis, a direct effect on the ovary has also been demonstrated as leptin at physiological concentrations inhibits insulin-induced oestradiol production by granulosa cells from both small and large bovine follicles.15,43,177 This is an example of non-competitive antagonism between leptin and insulin, demonstrated in a range of tissues (examined in greater detail below).

Expression of Ob-R has also been demonstrated in human granulosa cells.178 Furthermore, Lindheim et al179 showed that a significant increase in circulating leptin levels occurred during controlled ovarian hyperstimulation, suggesting that leptin plays a role in follicular growth and maturation.

To date, human and animal studies suggest that placental leptin is likely to affect maternal, placental and foetal function through both autocrine and paracrine mechanisms. It is possible that placental leptin may have physiological effects on the placenta including angiogenesis, growth and immunomodulation.175 Leptin may also be involved in regulation of foetal and uterine metabolism.

Leptin in fertility

The sterility of male and female ob/ob mice is a recognized feature of this mutation.12 Hoggard and co-workers46 found that reproductive hormone levels are reduced in ob/ob females, suggesting a functional defect in the hypothalamic–pituitary axis. Several independent reports have demonstrated that correction of leptin deficiency in ob/ob mice by peripheral injections of recombinant leptin activates the reproductive axis and restores fertility in both sexes. Barash and co-workers180 dosed ob/ob mice with human leptin (50 µg, i.p, twice daily) for 14 days. Leptin-treated females had significantly elevated serum levels of LH, increased ovarian and uterine weight, and stimulated aspects of ovarian and uterine histology compared to controls. Leptin-treated males had significantly elevated serum levels of FSH, increased testicular and seminal vesicle weights, greater seminal vesicle epithelial width, and elevated sperm counts compared with controls. The study of Chehab et al176 also showed that repeated administration of human leptin to female ob/ob mice corrected their infertility, thus restoring ovulation, pregnancy, parturition and lactation. The stimulatory effect of leptin on reproductive organs appears to have functional significance, as leptin-treated male and female ob/ob mice were able to mate successfully with their wild-type counterparts.176,181 Thus, leptin has an essential permissive role in the endocrinological processes which control fertility.

Furthermore, in vitro studies have revealed that oestrogens increase leptin mRNA expression.37,182 Testosterone, in contrast, inhibits leptin gene expression in vivo and in vitro,37,183 possibly through a direct suppressive effect. These findings suggest that androgens and oestrogens modulate leptin expression at the mRNA level through sex steroid receptor-dependent transcriptional mechanisms.37 Thus, there appear to be some counter-regulatory mechanisms between leptin and, particularly, the oestrogens. The study of Jockenhovel et al184 indicated that testosterone substitution normalized elevated serum leptin levels in hypogonadal men. These investigators have concluded that interaction of testosterone and leptin might be part of a hypothalamic–pituitary–gonadal–adipose tissue axis that is involved in body weight maintenance and reproductive function.

Role of leptin in pregnancy

This topic was recently reviewed by Henson and Castracane.185 Readers will find that the treatment of this topic in the present review has a different emphasis.

In females of most mammalian species, high leptin levels may signal the attainment of the sufficient long-term energy stores that are crucial for successful reproduction.174 During human pregnancy, leptin levels were elevated throughout compared with the non-pregnant state.42,186,187 Furthermore, in both humans42 and mice,174 serum leptin was particularly elevated during the second and third trimesters.

Both Ob-Ra and Ob-Rb were found in mouse, rat and human placenta using RT-PCR, in situ hybridization, Western blotting or immunohistochemistry.13,42,44,45,188 However, expression of leptin mRNA in rat placenta was much lower than that in the human placenta.13,189 Both the short and the long forms of leptin receptor were detected in the human placenta in early and in the full-term stages of gestation, using quantitative RT-PCR.190 Cioffi et al107 also detected transcription of the leptin receptor isoform termed Ob-R/B219 in human placenta using Northern blot and RT-PCR. In a recent study by Bodner et al45 Ob-R/B219 was not detected in human placenta cells, but was detected in blood cells of the intervillous space and foetal vessels. Using in situ hybridization and immunohistochemistry, they also found that Ob-Rb was expressed by the apical membrane of the syncytiotrophoblasts.

At present there appears to be a number of possible explanations for the increase in leptin levels in pregnancy: increased production by maternal fat; increased expression by the placenta; and increased levels of binding protein(s) (also of placental origin in the case of the mouse191), in the maternal circulation.46 However, hyperleptinaemia during pregnancy is not associated with decreased food intake or a decline in metabolic efficiency, as might be expected given one of the roles of leptin is as a satiety factor. Explanations for this may be a possible pregnancy-induced state of leptin resistance, or a change in leptin bioavailability.192,193 It is interesting to note that some authors believe that the increase in leptin concentration during pregnancy is counter-intuitive as this is a period of increased nutritional demands, and not one in which the actions of a satiety factor are expected to increase.185 Others have hypothesized that the soluble form of the leptin receptor mediates leptin actions during pregnancy as the circulating concentrations of this protein are increased, especially in the mouse,191,194 although much less so in humans.139 Given the range of interactions between leptin and other hormone axes, and the complex pattern of central and peripheral pathways invoked, we hypothesize that, if leptin does in fact have a role as a satiety factor, this role is centrally mediated and may not be significantly modulated by the soluble leptin receptor. Interactions such as those between leptin and insulin, which modulate oxidation of FFA and lipogenesis (see below) as part of the process which mobilizes energy reserves during pregnancy, are peripherally modulated and more influenced by the balance of energy reserve status and the demands of the foetus. Studies on the interaction of leptin binding protein status with plane of nutrition and energy reserve status during pregnancy will be required to confirm or refute this.

Holness et al193 suggest the possibility that leptin may be important for optimizing pregnancy outcome. Potential roles of leptin may include facilitation of endocrine responses to pregnancy, maintenance of maternal fuel homeostasis during a period of increased nutrient intake and requirement and/or optimization of foetal growth and development.

The relative contributions of foetal-derived leptin and maternal leptin to maternal total leptin has recently been described by Linnemann et al195 using an in vitro perfusion technique. This study suggests that only 1–2% of placental leptin enters the foetal circulation, while approximately 98% enters the maternal circulation. Although not yet determined, the interaction of leptin with insulin may also be important in pregnancy. Leptin appears to act as a permissive factor with respect to its effects on insulin-mediated fuel storage in muscle and in the liver and on insulin-mediated fuel utilization by muscle (see below). Thus, one of the actions of foetal- and placental-derived leptin may be to act on maternal liver and muscle, changing the dynamics of fuel utilization. Particularly in the case where maternal nutrition may become limiting, and thus maternal leptin reduced; foetal- and placental-derived leptin would act on the maternal metabolism to ensure that fuel is preferentially utilized by the foetus, rather than rebuilding maternal stores. This hypothesis is consistent with the observation that leptin concentration is higher in arterial than in venous cord blood (see below), and suggests that both foetal- and placental-derived leptin targets maternal metabolism.

To consider this interaction further, we hypothesize that, following parturition, and the accompanying sudden decrease in leptin in the maternal circulation, insulin-mediated fuel storage undergoes a rebound phase, in which maternal fuel stores are rapidly rebuilt. In some women, it may be that this rapid phase of increasing fuel storage is not counter-regulated, and thus begins a phase in which adipocyte number increases, predisposing the subject to increased fat-to-lean ratio and, in the longer-term, in the case of repeated pregnancies, obesity. These factors are also likely to be intricately linked with lactation as serum leptin concentrations in lactating women are lower post-partum, but somewhat higher than in non-lactating women, further demonstrating a role for leptin in mobilizing fuel reserves.196

Leptin expression in the foetus

The finding that leptin levels are increased in pregnancy42,174,186,187 has raised the possibility that leptin may play an important role in nutritional signalling between mother and the foetus during pregnancy. The expression of leptin by syncytiotrophoblasts13,44,45 suggests a role for leptin in nutrient transfer. Hoggard and co-workers13 studied leptin gene expression and localization of leptin protein in a number of tissues in the 14.5-day-old murine foetus by in situ hybridization and immunohistochemistry. High levels of leptin and its receptor expressed in foetal bone and cartilage suggested a role for leptin in bone or cartilage development. Leptin receptor mRNA and leptin receptor protein were also identified in leptomeninges and the choroid plexus of the foetal brain, and in lung, kidney, heart and liver.

Schubring and co-workers197 found that maternal serum leptin concentrations do not correlate with birth weight. In contrast, leptin concentrations in umbilical cord blood correlated positively with birth weight and placental weight in humans.197,198,199 Schubring et al197 demonstrated that leptin concentrations were higher in arterial cord blood than in venous cord blood, leading to the suggestion that leptin synthesis by foetal tissue may be greater than by placental tissue. However, evidence from Linnemann et al195 now suggests that foetal and placentally derived leptin may target maternal metabolism as outlined above. The high levels of expression of both leptin and leptin receptors in the placenta and foetus suggest that leptin plays a key role in foetal development. One possible role is that of a foetal growth factor, ie a signal to the foetus of the maternal energy status. Alternatively, as the concentration of leptin in arterial cord blood is higher than in venous cord blood, leptin may signal to the placenta the energy status of the foetus, and may have further actions on maternal metabolism, particularly if maternal energy stores become limiting.

Leptin and the onset of puberty

The weight hypothesis of the development of puberty states that, when body weight reaches a certain level, puberty occurs. If rats are underfed, puberty is delayed, but with access to food rapid weight gain leads to onset of puberty.200 It has been shown that exogenous leptin accelerates the onset of puberty in normal female mice174,201 and normal prepubertal female rats.202 From this evidence it may be speculated that puberty is induced when fat stores reach a certain level, increasing the release of leptin from adipocytes into the bloodstream. Leptin may then act on hypothalamic cells to stimulate release of LHRH, thereby triggering gonadotropin release. The subsequent release of follicle-stimulating hormone (FSH) and LH stimulates gonadal steroid secretion, leading to development of the reproductive tract and induction of puberty.

However, several studies203,204,205 have demonstrated contrasting data which indicate that the timing of the onset of puberty in male Rhesus monkeys is not triggered by rising circulating leptin concentrations. Given the conflicting reports in the literature,174,205,206 it is likely that leptin is a factor permissive to the onset of puberty, and that, although some minimal threshold level of leptin is necessary to pubertal development, leptin is more likely not sufficient to initiate puberty. The interactions between leptin and oestrogens and androgens outlined above indicate that leptin's role in the onset of puberty is mediated by different mechanisms in males and females and that further work is required to elucidate these differences. The notion that leptin is a permissive factor is supported by data which show that leptin is also expressed in skeletal muscle tissue.10,17,99,107 Thus, leptin may act as an indicator of general well-being: that sufficient muscle mass has developed (and is in a phase of anabolic growth) and that a commensurate level of body fat has been deposited, such that it is favourable for puberty (and its consequences, such as pregnancy) to proceed.

Leptin and insulin

Insulin is an important regulator of energy homeostasis. It stimulates glucose, free fatty acid and amino acid uptake by tissues and tissue anabolism. It is not surprising that a link between leptin and insulin should exist in the regulation of energy homeostasis.

Insulin effects on leptin

Current knowledge suggests that insulin plays a chronic role in the regulation of leptin gene expression and production by WAT. Some studies have shown that hyperinsulinaemia increased plasma leptin concentrations and gene expression in WAT in both rodents and humans.207,208,209,210,211,212,213,214,215,216 Recent studies have shown that humans and rodents with insulinoma also have increased plasma leptin and leptin mRNA, and plasma leptin concentrations returned to normal after removal of the insulinoma.217,218,219 Streptozotocin-induced insulin deficiency results in reduced circulating concentrations of leptin and mRNA, and that suppression was rapidly reversed by treatment with insulin.71,220 Insulin appears to act directly at the level of the adipocyte by increasing leptin secretion and gene expression, perhaps due to increased glucose transport and metabolism.221 An in vivo study222 has shown that fa/fa rats have 40-fold higher leptin concentration compared with lean littermates, but euglycaemic hyperinsulinaema increased plasma leptin only in lean rats. The authors suggested that insulin may be a regulator of in vivo leptin secretion by adipose tissue of lean rats, whereas it is inactive in increasing plasma leptin in obese fa/fa rats. However, this lack of sensitivity may simply be a consequence of peripheral insulin resistance, a characteristic of this phenotype.

Leptin effects on insulin secretion and tissue sensitivity to insulin

In 1996, Kieffer et al102 reported that leptin receptors are expressed in the insulin producing β-cells within the pancreatic islets, suggesting that leptin might influence insulin secretion through a direct action on these cells. This hypothesis was investigated by several others,223,224,225,226,227 with apparently conflicting results.

Leptin has been shown to inhibit insulin secretion from isolated rodent217,225,227,228,229 and human217,230 islets, perfused rodent pancreas224,228 and in vivo in mice217 (Table 3). Emilsson et al228 demonstrated that supraphysiological concentrations of recombinant leptin (100 nM) inhibited insulin secretion either in perfused pancreas preparations with 5.6 mM glucose, or in isolated β-cells from ob/ob mice incubated in the presence of a high concentration (16.7 mM) of glucose. In contrast, Ceddia et al231 also indicated that in the presence of low (2.8 mM) or physiological (5.6 mM) glucose concentrations, leptin (50 nM) increased insulin secretion by perfused isolated islets. Similarly, Tanizawa231,232 showed that leptin stimulated insulin secretion in islets. However, there are also conflicting reports in the literature. Some studies using an isolated perfused rat pancreas model233,234 and isolated rodent islets217,235 found that leptin did not affect insulin secretion (Table 3). According to Leclercq-Meyer and co-workers234 normal physiological concentrations of leptin (1 nM) failed to influence the release of either insulin or glucagon in the isolated perfused rat pancreas.

Table 3 Experimental conditions and outcome evaluating the effects of leptin on insulin secretiona

It is important to note that the normal physiological range of plasma leptin concentrations is of the order of 1–10 ng/ml or approximately 0.06–0.6 nM. Furthermore, most of the in vitro studies reviewed here have found effects only at supraphysiological concentrations of leptin and thus these results should be considered with this caution. However, we have shown in saturation binding studies that leptin binds to abundant hydrophobic sites (Margetic et al, submitted), and it may be that, to obtain a biologically relevant concentration of leptin, sufficient leptin must be added to the system to saturate hydrophobic sites on the apparatus and in the tissues in the in vitro system. Furthermore, Cawthorne et al236 and LA Campfield (op. cit.) have suggested that recombinant leptin may be less potent than the native form. Thus, further investigation will be required to confirm or refute the effects of these factors.

In isolated rat adipocytes, (Table 4) Walder et al237 found that 125I-insulin binding was dose-dependently inhibited by leptin (1 nM to 2.5 µM). The study of Muller et al238 shows a range of effects in isolated rat adipocytes consistent with leptin inhibition of insulin binding. Leptin clearly impaired insulin-mediated stimulation of glucose transport, glycogen synthase activity, lipogenesis, inhibition of isoprenaline-induced lipolysis, protein kinase A activation and protein synthesis in a dose-dependent manner. These effects appeared to require preincubation with leptin for at least 2 h. Thus, in another study using a short leptin incubation (30 min), no leptin effects on insulin-mediated glucose uptake were observed.239 Similarly, Ranganathan et al240 found a negative result; however, this study incubated adipocytes at a sub-physiological glucose concentration, making interpretation of their findings more difficult. Thus, leptin inhibition of insulin-mediated glucose transport appears to be a direct (peripheral) relationship in adipocytes, however it appears to be centrally controlled in muscle tissue (see below).

Table 4 Peripheral pathways and interactions of leptin with insulin and glucagon: in vitro models of normal physiology

Other studies have found a direct link between plasma leptin concentration and measures of insulin sensitivity independent of the degree of body fatness.223,241,242 High levels of leptin were associated with insulin resistance independent of BMI. In humans, it is still not clear whether the hyperinsulinaemia that accompanies insulin resistance is associated with the higher leptin levels observed in some obese subjects with non-insulin-dependent diabetes mellitus (NIDDM)243 or polycystic ovary syndrome (PCOS).244

Whether leptin plays a role in the short-term response to food ingestion and/or macronutritient composition remains a matter for debate. It appears, however, that in ruminants in which nutrient flux from the rumen and small intestine (into the circulation) remains much more constant than in monogastrics, that leptin is not involved in signalling short-term changes to food intake.245 Furthermore, the mechanism underlying the contribution of leptin to insulin secretion as well as the physiological impact of leptin's nutrient stimulation effect remains to be studied in more detail.

Several studies have suggested that glucose is also an important regulator of leptin expression and secretion.246,247 Kamohara et al248 have demonstrated that i.v. (1 µg/h) and i.c.v. (5 ng/h) administered leptin into wild-type mice increased glucose turnover and glucose uptake, independent of increases in plasma insulin. However, given that leptin modifies insulin sensitivity of muscle and liver to glucose uptake (see below), probably via CNS control, it appears likely that glucose is regulated and is not a regulator.

Leptin and insulin sensitivity of skeletal muscle

It is worthy of note that skeletal muscle accounts for a large proportion of insulin-stimulated glucose uptake and whole body lipid oxidation and is the major contributing tissue to resting metabolic rate. Thus, muscle may be an important tissue for the expression of the juxtaposed interactions of leptin and insulin.

The recent study by Wang and co-workers17 found that leptin mRNA was expressed in skeletal muscle in Sprague–Dawley rats. The presence of Ob-Ra and Ob-Rb in mouse skeletal muscle has been reported previously.10,99,107 Although only 8% of total leptin receptor mRNA expression in skeletal muscle is the long form, both isoforms Ob-Ra and Ob-Rb appear to be able to mediate signal transduction.99,136

At the intracellular level, evidence for the intersection of the leptin and insulin pathways is supported as the effects of leptin treatment on muscle may be partially attenuated by synthetic blockade of phoshphatidylinositol (PI) 3-kinase activity.249 Furthermore, in hepatic cell models, leptin had profound effects on tyrosine phosphorylation of IRS-1, with no associated effect on insulin receptor phosphorylation;250 and, in addition, leptin-mediated recruitment of PI-3 kinase to IRS-2 has been shown. However, in this study the activity at PI-3 kinase did not translate to increased tyrosine phosphorylation of IRS-2.148 Most recently it was reported that leptin directly stimulates fatty-acid oxidation in muscle by activating the 5′-AMP-activated protein kinase, an enzyme that phosphorylates and subsequently inactivates CoA carboxylase.251 Thus a direct mechanism for the action of leptin on fatty acid oxidation consistent with the work of Muoio et al249,252 has now been defined.

Effect on glucose transport

Muoio et al252 showed that leptin (10 µg/ml) did not change insulin-stimulated metabolism in isolated mouse (female C57BL/6J mice) soleus and exterior digitorum longus (EDL) muscle. In agreement with this finding Ranganathan et al240 showed that leptin (0.5 µg/ml, for 24 h) had no effect on basal and insulin (10 nM)-stimulated glucose transport in cultured rat and human skeletal muscle cells. However, Burcelini et al253 found that i.v administration of leptin (40 ng/g/h) for 6 h to ob/ob mice (which are insulin-resistant) increased glucose turnover and stimulated glucose uptake in BAT, brain and heart. No increase in glucose turnover was observed in skeletal muscle or WAT. Kamohara et al248 suggested that leptin may acutely increase skeletal muscle glucose uptake by an insulin-independent mechanism. Infusion of murine leptin (1 µg/h) for 5 h into the femoral vein of conscious C57BL/6J wild-type mice led to an increase in glucose turnover and 2-deoxyglucose uptake into skeletal muscle and BAT increased whole-body glucose turnover and increased glucose oxidation, despite no change in plasma insulin or glucose concentrations. Furthermore, the leptin-induced increase in glucose uptake into edl and soleus muscles was attenuated by denervation. Taken together, all of these data indicate that the effects of acute leptin administration on glucose metabolism in muscle are mediated centrally.

Effect on lipid partitioning

Muscle plays an important role in clearance of serum free fatty acids (FFA) and triacylglycerol (TAG) and in whole-body FFA oxidation. In contrast to their findings of a lack of leptin-mediated glucose uptake by isolated skeletal muscle, Muoio et al252 found that leptin (10 µg/ml) increased FFA oxidation in isolated mouse soleus muscle by 42%, whereas insulin (10 mU/ml) decreased soleus muscle FFA oxidation by 40%. When both hormones were administered, leptin attenuated both the antioxidative and the lipogenic effects of insulin by 50%. Less pronounced hormonal effects were observed in mouse edl. Also, their study showed that the effect of leptin on lipid partitioning was dose-dependent in both soleus and edl (Table 4). These data are consistent with the findings of Solini et al,254 who showed that, during euglycaemic, hyperinsulinaemic clamp, lipid oxidation was higher in obese than in lean subjects. However, this study also found that during the clamp glucose turnover was lower in obese subjects. One interpretation of these data links the apparent differing responses of muscle and adipose tissue to the interaction between leptin and insulin: obese subjects, having proportionately greater fat mass, may show a direct peripheral effect of leptin suppressing insulin-mediated glucose transport in adipose tissue, while the lipid oxidation effects are mostly manifested in muscle tissue. On the other hand, in lean subjects, having much lower fat mass, most of the effects on turnover are manifested in muscle tissue, and the relativity of the circulating concentrations of leptin and insulin, being lower, would favour lower FFA oxidation in muscle of lean compared to obese subjects. This relationship would be further complicated by the generally increased insulin resistance of obese subjects.

Muoio et al249 also studied the acute (60–90 min) effects of leptin and insulin on glucose and oleate metabolism in muscles isolated from lean and obese ob/ob mice with insulin resistance. In ob/ob soleus, leptin decreased glycogen synthesis by 36–46%, increased oleate oxidation by 26%, decreased oleate incorporation into TAG by 32%, and decreased the oleate partitioning ratio by 44%. Insulin decreased oleate oxidation by 31%, increased oleate incorporation into TAG by 46%, and increased the partitioning ratio by 125%. Addition of leptin (10 µg/ml) diminished insulin's antioxidative, lipogenic effects, recapitulating this group's earlier findings in isolated, normal mouse muscle.252 Thus, leptin opposes insulin's promotion of TAG accumulation in lean and ob/ob muscle, and indicates that skeletal muscle is critical in mediating leptin's effects on fuel homeostasis, weight regulation and adiposity. Importantly, these studies indicate that leptin attenuates insulin's antioxidative, lipogenic actions on muscle FFA metabolism via a peripheral mechanism, while leptin mediation of insulin-stimulated glucose disposal appears to occur via a central mechanism. Furthermore, as skeletal muscle represents approximately 40% of the total body weight,255 leptin-stimulated FFA oxidation in skeletal muscle may represent a very important anti-obesity mechanism independent of the central nervous system.

Leptin interaction with insulin-mediated glycogen synthesis

Defective glycogen synthesis in muscle is one of the earliest manifestations of insulin resistance. Liu et al256 found that recombinant mouse leptin at 10 and 100 nM inhibited glycogen synthesis by 35 and 45%, respectively, in soleus muscle of ob/ob mice in the presence of insulin (100 µU/ml). Leptin did not have an inhibitory effect on glycogen synthesis in soleus muscle from either wild-type (Table 4) or db/db mice. Ob-Rb was expressed in soleus muscle of both ob/ob and wild-type mice with no detectable difference in expression level, suggesting that the ob/ob leptin receptor may be linked to a more sensitive down-stream pathway. In contrast, two other studies have shown that leptin increased glycogen synthesis in cultured C2C12 muscle cells.257,258 A possible factor contributing to these contradictory results may be the difference between muscle cell lines and freshly isolated skeletal muscle. C2C12 cells represent an homogeneous cell population, whereas skeletal muscle is heterogeneous with respect to fibre and cell composition. Thus, the effect in C2C12 cells may not be truly representative of leptin effects on muscle in vivo.

In contrast, leptin actions on insulin binding in rat liver (a major storage depot for glycogen) were studied by Nowak et al.259 These workers found that administration of a single dose of mouse leptin (1 and 2 nM) to rats decreased Bmax but did not change the affinity of insulin for its high affinity binding sites in the liver. These results show that leptin may antagonize some functions of insulin by the attenuation of insulin receptor capacity. Furthermore, this action of leptin is consistent with the hypothesis that leptin tends to mobilize body fuel reserves and increase energy expenditure. However, Zhao and co-workers260 showed that leptin, like insulin, induced an intracellular signalling pathway in primary rat hepatocytes, probably mediated through the short forms of the leptin receptor. This pathway involves stimulation of phosphatidylinositol 3-kinase (PI3K) binding to insulin receptor substrate-1 and insulin receptor substrate-2, activation of PI3K and protein kinase B, and PI3K-dependent activation of cyclic nucleotide phosphodiesterase 3B, a cAMP-degrading enzyme. Leptin also suppressed glucagon-induced cAMP elevation in a PI3K-dependent manner. Indeed, Ahren and Havel261 suggested that cAMP-protein kinase A signal transduction pathway is a target for leptin to inhibit insulin secretion in insulin-producing cells.

Leptin interaction with insulin-mediated hexosamine synthesis

Several studies have demonstrated a clear interaction between intracellular hexosamine concentrations (in muscle and in fat) and insulin resistance, in the rodent model, using in vivo17,262,263,264,265 and in vitro17,266 methods. This interaction has also been demonstrated in vitro in both human myogenic cells267 and adipocytes.262 Importantly, in the rodent model, an increase in leptin gene expression was associated with insulin resistance and intracellular glucosamine concentrations.17,266,268

The hexosamine biosynthetic pathway is the primary source of the substrates for the glycosylation of (glyco-) proteins,269 and is hypothesized to be a cellular ‘sensor’ of energy availability.17,262,263 However, quantitatively, only 1–3% of incoming glucose ultimately enters the hexosamine pathway.264,269 An alternative perspective to this proposed model is that, in vivo, it is increased leptin which signals excess energy stores and that leptin-mediated damping of insulin actions (particularly in muscle) on both glucose and in this case hexosamines reduces the activity in these storage pathways. In this alternative model, as leptin concentration increases in response to increasing fat mass (muscle has already become loaded with glycogen and hexosamines), the actions of insulin on glucose and hexosamine storage become increasingly damped. Simultaneously, TAG and thus, fatty acids are preferentially utilized as an energy source. This leads to a brief discussion of leptin interaction with insulin resistance.

Leptin and insulin resistance in muscle

A vast majority of studies of insulin resistance concentrate upon insulin interactions with glucose, while less attention is paid to insulin-mediated fatty acid uptake, for which mechanisms are now becoming clarified.270,271,272 However, the inter-relationship of the classes of substrate utilized for energy, as first proposed by Randle,273 has been long established. Although insulin actively increases free fatty acid uptake by muscle,270,271,272 it clearly inhibits oxidation of free fatty acids, an action which is suppressed by leptin.249,252,274,275 This partitioning of insulin actions, some of which appear to be synergistic with leptin actions, such as increased uptake of free fatty acids by a direct mechanism and uptake of glucose possibly via a CNS-mediated mechanism (above), and others of which may appear to be antagonistic to leptin actions, such as inhibition of insulin-mediated suppression of fatty acid oxidation,249,252,274,275 are difficult to resolve into a single model. However, it may be stated in broad terms that insulin is anabolic and tends to increase storage of fuels and amino acids, while leptin appears to mobilize TAG and modulate preferential utilization of fatty acids. Simultaneously, leptin inhibits insulin-mediated mechanisms of long-term glucose storage and oxidation. It is this sub-set of insulin actions upon which many investigations of insulin resistance have focussed, and it may be that the typical, many-fold increases in circulating leptin concentrations observed in obesity have profound effects only upon glucose-metabolism-linked peripheral insulin resistance through the mechanisms proposed here. Thus, more thorough investigations of the interaction of leptin and insulin in regulating both glucose and fatty acid oxidation are of paramount importance in clarifying the progression of obesity and the development of peripheral insulin resistance.

Leptin and glucocorticoids

Adipocyte culture studies have shown that glucocorticoids stimulate leptin gene expression.276,277 Glucocorticoid secretion is linked with meal times in normal humans and rodents,278 and is increased in Cushing's disease or by glucocorticoid administration to normal volunteers.279 In humans, glucocorticoids stimulate leptin gene expression and secretion independently of effects on food intake, although increases in insulin or lipogenesis associated with food intake may contribute to leptin production.280,281 The recent study of Solano and Jacobson282 indicated that leptin infusion (0.5 µg/h) significantly decreased food intake and body weight in adrenalectomized mice. Glucocorticoid replacement increased food intake without reversing leptin inhibition of hypothalamic neuropeptide Y (NPY) mRNA levels. These investigators have concluded that glucocorticoid levels within the physiological range interfere with leptin action and that glucocorticoid effects are at least partly independent of NPY. Dexamethasone administration (10 mg/day) in obese humans caused increases in leptin levels from 16.3 ng/ml at baseline to 27.6 ng/ml after 5 days of treatment.280 Similar stimulatory effects were also obtained in obese children with a lower dose (1 mg), although the effects were less pronounced.283

The mechanism(s) of glucocorticoid stimulation of plasma leptin is still unknown. Wabitsch and co-workers277 have postulated that glucocorticoids may influence leptin gene expression directly and independently of their differentiation-promoting effects on adipocytes, or they can induce changes in plasma insulin sensitivity. De Vos et al have shown similar effects on leptin expression in rats,284 however, a later study by the same group285 indicates that the leptin gene promoter region does not contain a binding site for the glucocorticoid receptor, thus the effect does not rely on the classical molecular mechanism of glucocorticoid receptor action. However, another possible mechanism includes modulation via the CNS, mediated by NPY.286

Leptin interaction with the growth hormone axis and with other cytokines

Although most of the interactions of leptin with growth hormone are likely to be centrally mediated, interactions of leptin with major components of the growth hormone axis, such as insulin-like growth factor-1 (IGF-1), appear to be more direct (see below).

Leptin and growth hormone

Several groups have reported that leptin regulates growth hormone (GH) secretion in humans,287,288 rodents,289,290,291 sheep,292,293,294 and pigs.295 However, when isolated rat adipocytes were incubated with either GH or insulin-like growth factor-1 (IGF-1) alone, there was no effect on leptin secretion.74 Recently, Houseknecht et al296 have extended the work of Hardie et al74 to include incubation of bovine adipose tissue explants with insulin, dexamethasone and GH alone and in combination. After 24 h incubation, GH alone had no effect on leptin expression in bovine subcutaneous adipose tissue. However, when incubated in combination, GH attenuated the insulin or dexamethasone stimulation of leptin expression. In addition, the same investigators reported apparently contrasting results in an in vivo experiment as part of the same study. This study used young castrated male cattle treated with GH for 3 days, and found that GH treatment increased adipose tissue leptin and IGF-1 mRNA concentrations. Furthermore, leptin levels were highly correlated with adipose tissue IGF-1 mRNA in GH-treated animals. In contrast, other in vivo studies have shown an inhibitory effect of GH on leptin gene expression.297,298 Each of these studies was conducted in a growth hormone-deficient model, growth hormone-deficient children and fatty Zucker rats, respectively. These results are consistent with the in vitro studies cited above.296,299,300

Leptin and IGF-1

Studies of the effects of IGF-1 on serum leptin and leptin expression are also contradictory. Isozaki et al298 showed that IGF-1 did not change the percentage body fat or leptin mRNA in visceral fat tissue in Zucker rats, while Boni-Schnetzler and co-workers301 found that IGF-1 decreased leptin mRNA in epidydimal fat tissue of hypophysectomized rats. Boni-Schnetzler et al302 in a recent study showed that 6 days subcutaneous (s.c.) administration of human IGF-1 (1 mg/day) decreased leptin mRNA in epididymal fat pads in normal rats (by 38.8%) and reduced serum leptin (by 51.6%) in comparison to control rats. Fat pad weight was also reduced (by 60.3%). These authors concluded that the effect of IGF-1 on the reduction of fat pad mass is most likely due to a suppression of insulin secretion, and thus enhancement of fat mobilization and fatty acid (FA) oxidation. As a consequence, adipose tissue leptin mRNA and serum leptin concentrations decrease as well.

Leptin and other cytokines

The influence of cytokines on leptin mRNA expression and circulating concentrations has been investigated in human subjects.303,304,305,306 Interleukin-1 (IL-1) was found to induce leptin levels directly or indirectly, by increasing the activity of the hypothalamic–pituitary axis.303,307 Mantzoros and co-workers306 reported a positive and independent association between tumour necrosis factor-α (TNF-α) levels and circulating leptin concentrations, suggesting that TNF-α may directly induce leptin gene expression in humans, as it does in rodents.307,308 These studies may implicate a role for leptin in the pathogenesis of cachexia that is accompanied by increased levels of cytokine in advanced stages of AIDS and cancer.309

Interaction of leptin with other metabolites and hormones

Recent studies have shown that free fatty acids (FFA) decrease leptin mRNA levels in adipocytes,22,310 suggesting that FFA are involved in the regulation of leptin production in adipocytes. However, regulation of FFA in vivo involves complex mechanisms mediated by a range of hormones including insulin, growth hormone and leptin. Thus, it is likely that hormones mediating FFA are the drivers of this interaction.

Stumvoll et al85 showed that, in humans, isoprenoline acutely suppressed leptin levels independently of increased FFA, indicating a direct effect via β-adrenergic receptors on leptin secretion. These authors concluded that a signalling mechanism other than that mediated by cAMP must be involved in modulating leptin secretion.

There is conflicting evidence as to the effects of thyroid hormone on leptin production, with suggestions that tri-iodothyronine (T3) has inhibitory,311 stimulatory312 or no effect313,314 on leptin levels. The study of Fain et al311 showed that administration of T3 to hypothyroid male rats resulted in a 40% decrease in leptin mRNA at 8 h. This decrease in leptin mRNA was associated with a parallel decline in circulating leptin levels of about 50% at 24 h. In contrast, Sesmilo et al314 investigated patients with hypothyroidism and hyperthyroidism returning to normal thyroid function. Hypothyroid patients were treated with L-T4 and hyperthyroid patients with methimazole. This study showed that there appeared to be no correlation between serum leptin and thyroid hormone (free thyroxine, thyrotrophin and T3) levels at any stage during the study.


Although the proposed roles of leptin in satiety and energy expenditure were originally thought to be centrally focussed, more recent studies have begun to reveal direct effects of leptin in the periphery and via interactions with other peripherally acting hormones, one of the most important of which is insulin.

It is clear that one of the principal roles of leptin is as a lipostat, signalling to other systems the energy reserves available to the body, mediating fuel utilization and mobilization and, consequently, energy expenditure. In some cases, this extends to signalling that the (juvenile) body has sufficient reserves to move into a potentially more metabolically demanding phase—puberty. Puberty in both humans and animals potentially leads to secondary consequences which are metabolically demanding. In the female, pregnancy, lactation and nurture and, in the male, competitive behaviours in the quest for a suitable mate(s) and paternal duties. In this context leptin's actions are complex and mediated both centrally and peripherally.

During pregnancy, leptin production by the foetus and the placenta may signal foetal nutrient status. However, it may also provide a mechanism whereby maternal fuel reserves are more readily mobilized, favouring utilization by the foetus rather than building maternal reserves such as glycogen in muscle and in the liver. In the case where maternal leptin concentrations are low owing to limiting nutrition, the proportional importance of foetal and placental leptin in mobilizing fuel for use by the foetus may be greater.

Obesity is a state characterized by hyperleptinaemia. Although plasma leptin concentration is correlated with level of obesity, many other factors interact. These include developmental stage, sex, pregnancy, multiple hormonal factors, present nutritional status and nutritional history of the individual. Thus, leptin is not simply an indicator of proportional body fat or lean mass. In some in vitro studies, in which leptin has been used at concentrations typical of plasma concentrations in obese subjects, leptin has had some unexpected effects which may be mediated through a mechanism independent of the Ob-R. This observation may suggest a pathophysiological effect of hyperleptinaemia associated with obesity. Clearly, this mechanism is not at work in all cell types, as many studies using supraphysiological concentrations of leptin have reported no aberrant effects.

Leptin is still only a newly discovered hormone. Despite extensive investigations, worldwide since 1994, we have much to learn about the leptin axis and its interactions both centrally and in the periphery.


  1. 1

    Jebb SA . Obesity: from molecules to man Proc Nutr Soc 1999 58: 1–14.

    Article  CAS  Google Scholar 

  2. 2

    Vanltallie TB . Worldwide epidemiology of obesity PharmacoEconom 1994 5 (Supp 1): 1–7.

    Article  Google Scholar 

  3. 3

    Kuczmarski RJ, Fiegal KM, Campbell SM, Johnson CL . Increasing prevalence of overweight among US adults JAMA 1994 272: 205–211.

    CAS  Article  Google Scholar 

  4. 4

    Brown W, Dobson A, Mishra G . What is a healthy range for middle aged women? Int J Obes Relat Metab Disord 1998 22: 520–528.

    Article  CAS  Google Scholar 

  5. 5

    Strader CD, Hwa JJ, Van Heek M, Parker EM . Novel molecular targets for the treatment of obesity Drug Discov Today 1998 3: 250–256.

    Article  CAS  Google Scholar 

  6. 6

    Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM . Positional cloning of the mouse obese gene and its human homologue Nature 1994 372: 425–432.

    Article  CAS  Google Scholar 

  7. 7

    Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P . Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks Science 1995 269: 546–549.

    CAS  Article  Google Scholar 

  8. 8

    Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Robinowitz D, Lollone RL, Burley SK, Friedman JM . Weight-reducing effects of the plasma protein encoded by the obese gene Science 1995 269: 543–546.

    CAS  Article  Google Scholar 

  9. 9

    Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, Boone T, Collins F . Effects of the obese gene product on body weight regulation in ob/ob mice Science 1995 269: 540–543.

    Article  CAS  Google Scholar 

  10. 10

    Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards JG, Campfield LA, Clark FT, Deeds J, Muir C, Sanker S, Moriarty A, Moore KJ, Smutko JS, Mays GG, Woolf EA, Monroe CA, Tepper RI . Identification and expression cloning of a leptin receptor, OB-R Cell 1995 83: 1263–1271.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Lee G-H, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, Friedman JM . Abnormal splicing of the leptin receptor in mice Nature 1996 379: 632–635.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Bray GA, York DA . Hypothalamic and genetic obesity in experimental animals: an autonomic and endocrine hypothesis Physiol Rev 1979 59: 719–809.

    Article  CAS  Google Scholar 

  13. 13

    Hoggard N, Hunter L, Duncan JS, Williams LM, Trayhurn P, Mercer JG . Leptin and leptin receptor mRNA and protein expression in the murine fetus and placenta Proc Natl Acad Sci USA 1997 94: 11073–11078.

    Article  CAS  Google Scholar 

  14. 14

    Hoggard N, Mercer JG, Rayner DV, Moar K, Trayhurn P, Williams LM . Localization of leptin receptor mRNA splice variants in murine peripheral tissues by RT-PCR and in situ hybridisation Biochem Biophys Res Commun 1997 232: 383–387.

    CAS  Google Scholar 

  15. 15

    Spicer LJ, Francisco CC . The adipose obese gene product, leptin: evidence of direct inhibitory role in ovarian function Endocrinology 1997 138: 3374–3379.

    Article  CAS  Google Scholar 

  16. 16

    Bado A, Levasseur S, Attoub S, Kermorgant S, Laigneau J-P, Bortoluzzi M-N, Moizo L, Lehy T, Buerre-Millo M, Le Marchand-Brustel Y, Lewin MJM . The stomach is a source of leptin Nature 1998 394: 790–793.

    Article  CAS  Google Scholar 

  17. 17

    Wang J, Liu R, Hawkins M, Barzilai N, Rossetti L . A nutrient-sensing pathway regulates leptin gene expression in muscle and fat Nature 1998 393: 684–688.

    Article  CAS  Google Scholar 

  18. 18

    Considine RV, Caro JF . Leptin and the regulation of body weight Int J Biochem Cell Biol 1997 11: 1255–1272.

    Article  Google Scholar 

  19. 19

    Moinat M, Deng C, Muzzin P, Assimocopoulos-Jeannet F, Seydoux J, Dulloo AG, Giacobino JP . Modulation of obese gene expression in rat brown and white adipose tissues FEBS Lett 1995 373: 131–134.

    Article  CAS  Google Scholar 

  20. 20

    Tsuro Y, Sato I, Iida M, Murakami T, Ishimura K, Shima K . Immunohistochemical detection of the ob gene product (leptin) in rat white and brown adipocytes Horm Metab Res 1996 28: 753–755.

    Article  Google Scholar 

  21. 21

    Klingenspor M, Dickopp A, Heldmaier G, Klaus S . Short photoperiod reduces leptin gene expression in white and brown adipose tissue of Djungarian hamsters FEBS Lett 1996 399: 290–294.

    Article  CAS  Google Scholar 

  22. 22

    Deng C, Moinat M, Curtis L, Nadakal A, Preinter F, Boss O, Assimacopoulos-Jeannet F, Sedoux J, Giacobino J-P . Effects of b-adrenoceptor subtype stimulation on obese gene mRNA and on leptin secretion in mouse brown adipocytes differentiated in culture Endocrinology 1997 138: 548–552.

    Article  CAS  Google Scholar 

  23. 23

    Dessolin S, Schalling M, Champigny O, Lonnqvist F, Alhaud G, Dani C, Ricquier D . Leptin gene is expressed in rat brown adipose tissue at birth FASEB J 1997 11: 382–387.

    Article  CAS  Google Scholar 

  24. 24

    Cinti S, Frederich RC, Zingaretti MC, De Matteis R, Flier JS, Lowell BB . Immunohistochemical localisation of leptin and uncoupling protein in white and brown adipose tissue Endocrinology 1997 138: 797–804.

    Article  CAS  Google Scholar 

  25. 25

    Siegrist-Kaiser CA, Pauli V, Juge-Aubry CE, Boss O, Pernin A, Chin WW, Cusin I, Rohner-Jeanrenaud C, Burger AG, Zapf J, Meier CA . Direct effects of leptin on brown and white tissues J Clin Invest 1997 100: 2858–2864.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Kutoh E, Boss O, Levasseur F, Giacobino J-P . Quantification of the full length leptin receptor (OB-Rb) in human brown and white adiposse tissue Life Sci 1998 62: 445–451.

    Article  CAS  Google Scholar 

  27. 27

    Giacobino JP . Role of β3-adrenoceptor in the control of leptin expression Horm Metab Res 1996 28: 633–637.

    Article  CAS  Google Scholar 

  28. 28

    Trayhurn P, Duncan JS, Rayner DV . Acute cold-induced suppression of ob (obese) gene expression in white adipose tissue of mice; mediation by the sympathetic system Biochem J 1995 311: 729–733.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, Fei H, Kim S, Lallone R, Ranganathan S, Kern PA, Friedman JM . Leptin levels in human and rodents measurement of plasma leptin and ob RNA in obese and weight-reduced subjects Nat Med 1995 1: 1155–1161.

    CAS  Article  Google Scholar 

  30. 30

    Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL, Caro JF . Serum immunoreactive-leptin concentrations in normal-weight and obese humans New J Engl Med 1996 334: 292–295.

    Article  CAS  Google Scholar 

  31. 31

    Hube F, Lietz U, Igel M, Jensen PB, Tornqvist H, Joost H-G, Hauner H . Difference in leptin mRNA levels between omental and subcutaneous abdominal adipose tissue from obese humans Horm Metab Res 1996 28: 690–693.

    Article  CAS  Google Scholar 

  32. 32

    Masuzaki H, Ogawa Y, Isse N, Satoh N, Okazaki T, Shigemoto M, Mori K, Tamura N, Hosoda K, Yoshimasa Y, Jingami H, Kawada T, Nakao K . Human obese gene expression: adipocyte-specific expression and regional differences in the adipose tissue Diabetes 1995 44: 855–858.

    CAS  Article  Google Scholar 

  33. 33

    Montague CT, Prins JB, Sanders L, Digby JE, O'Rahilly S . Depot- and sex-specific differences in human leptin mRNA expression: implications for the control of regional fat distribution Diabetes 1997 46: 342–347.

    Article  CAS  Google Scholar 

  34. 34

    Van Harmelen V, Reynisdottir S, Eriksson P, Thorne A, Hoffstedt J, Lonnqvist F, Arner P . Leptin secretion from subcutaneous and visceral adipose tissue in women Diabetes 1998 47: 913–917.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Lonnqvist F, Arner P, Nordfors L, Schalling M . Overexpression of the obese (ob) gene in adipose tissue of human obese subjects Nat Med 1995 1: 950–953.

    Article  CAS  Google Scholar 

  36. 36

    Rayner DV, Dalgliesh GD, Duncan JS, Hardie LJ, Hoggard N, Trayhurn P . Postnatal development of the ob gene system: elevated leptin levels in suckling fa/fa rats Am J Physiol 1997 42: R446–R450.

    Google Scholar 

  37. 37

    Machinal F, Dieudonne M-N, Leneveu M-C, Pecquery R, Giudicelli Y . In vivo and in vitro ob gene expression and leptin secretion in rat adipocytes: evidence for a regional specific regulation by sex steroid hormones Endocrinology 1999 140: 1567–1574.

    Article  CAS  Google Scholar 

  38. 38

    Rosenbaum M, Nicolson M, Hirsch J, Heymsfield SB, Gallagher D, Chu F, Leibel RL . Effects of gender, body composition, and menopause on plasma concentrations of leptin J Clin Endocrinol Metab 1996 81: 3424–3427.

    CAS  Google Scholar 

  39. 39

    Kennedy A, Gettys TW, Watson, Wallace P, Ganaway E, Pan Q, Garvey WT . The metabolic significance of leptin in humans; gender-based differences in relationship to adiposity, insulin sensitivity, and energy expenditure J Clin Endocrinol Metab 1997 82: 1293–1300.

    CAS  Google Scholar 

  40. 40

    Saad MF, Damani S, Gingerich RL . Sexual dimorphism in plasma leptin concentration J Clin Endocrinol Metab 1997 82: 579–584.

    CAS  Google Scholar 

  41. 41

    Hassink WG, de Lancey E, Sheslow DV, Smith-Kirwin SM, O'Connor, Considine RVOI, Dostal K, Spear ML, Leef K, Ash M, Spitzer AR, Funange VL . Placental leptin: an important new growth factor in intrauterine and neonatal development? Pediatrics 1997 100: 1–6.

    Article  Google Scholar 

  42. 42

    Masuzaki H, Ogava Y, Sagawa N, Hosoda K, Matsumoto T, Mise H, Nishimura H, Yoshimasa Y, Tanaka I, Mori T, Nakao K . Nonadipose tissue production of leptin; leptin as a novel placenta-derived hormone in humans Nat Med 1997 3: 1029–1033.

    Article  CAS  Google Scholar 

  43. 43

    Bennett PA, Lindell K, Wilson C, Carlsson LMS, Carlsson B, Robinson CAF . Cyclical variations in the abundance of leptin receptors, but not in circulating leptin, correlate with NPY expression during the oestrus cycle Neuroendocrinology 1999 69: 417–423.

    Article  CAS  Google Scholar 

  44. 44

    Senaris R, Garcia-Caballero T, Casabiell X, Gallego R, Castro R, Considine RV, Dieguez C, Casanueva FF . Synthesis of leptin inhuman placenta Endocrinology 1997 138: 4501–4504.

    Article  CAS  Google Scholar 

  45. 45

    Bodner J, Ebenbichler CF, Wolf HJ, Muller-Holzner E, Stanzi U, Gander R, Huter O, Patsch JR . Leptin receptor in human term placenta: in situ hybridisation and immunohistochemical localisation Placenta 1999 20: 677–682.

    Article  CAS  Google Scholar 

  46. 46

    Hoggard N, Hunter L, Trayhurn P, Williams LM, Mercer KG . Leptin and reproduction Proc Nutr Soc 1998 57: 421–427.

    Article  CAS  Google Scholar 

  47. 47

    Lostao MP, Urdaneta E, Martinez-Anso E, Barber A, Martinez JA . Presence of leptin receptors in rat small intestine and leptin effect on sugar absorption FEBS Lett 1998 423: 302–306.

    Article  CAS  Google Scholar 

  48. 48

    Morash B, Li A, Murphy PR, Wilkinson M, Ur E . Leptin gene expression in the brain and pituitary gland Endocrinology 1999 140: 5995–5998.

    Article  CAS  Google Scholar 

  49. 49

    Jin L, Zhang S, Burguera BG, Couce ME, Osamura RY, Kulig E, Lloyd RV . Leptin and leptin receptors expression in rat and mouse pituitary cells Endocrinology 2000 141: 333–339.

    Article  CAS  Google Scholar 

  50. 50

    Smith-Kirwin SM, O'Connor DM, De Fohnston J, DeLancey ED, Hassink SG, Funanage VL . Leptin expression in human mammary epithelial cells and breast milk J Clin Endocrinol Metab 1998 83: 1810–1813.

    Article  CAS  Google Scholar 

  51. 51

    Laharrague P, Larroy D, Fontanilles A-M, Truel N, Campfield A, Tenenbaum R, Galitzky J, Corberand JX, Penicaud L, Casteilla L . High expression of leptin by human bone marrow adipocytes in primary culture FASEB J 1998 12: 747–752.

    Article  CAS  Google Scholar 

  52. 52

    Chen S-C, Kochan JP, Campfield A, Burn P, Smeyne RJ . Splice variants of the ob receptor gene are differentially expressed in brain and peripheral tissues of mice J Recept Signal Transm R 1999 19: 245–266.

    Article  CAS  Google Scholar 

  53. 53

    Soukas A, Cohen P, Friedman JM . Gene expression profile induced by leptin in white adipose tissue and liver Nat Gen 1999 23: 75.

    Article  Google Scholar 

  54. 54

    Taouis M, Chen J-W, Daviaud C, Dupont J, Derouet M, Simon J . Cloning the chicken leptin gene Gene 1998 208: 239–242.

    Article  CAS  Google Scholar 

  55. 55

    Frederich RC, Lollmann B, Hamann A, Napolitano-Rosen A, Kahn BB, Lowell BB, Flier JS . Expression of ob mRNA and its encoded protein in rodents: impact of nutrition and obesity J Clin Invest 1995 96: 1659–1663.

    Article  Google Scholar 

  56. 56

    Fruhbeck G, Aguardo M, Martinez JA . In vitro lipolytic effect of leptin on mouse adipocytes; evidence for a possible autocrine-paracrine role of leptin Biochem Biophys Res Commun 1997 240: 590–594.

    Article  CAS  Google Scholar 

  57. 57

    Maffei M, Fei H, Lee G-H, Dani C, Leroy P, Zhang Y, Proenca R, Nagrel R, Ailhaud G, Friedman J . Increased expression in adipocytes of ob RNA in mice with lesions of the hypothalamus and with mutations at the db locus Proc Natl Acad Sci USA 1995 92: 6957–6960.

    Article  CAS  Google Scholar 

  58. 58

    Masuzaki H, Ogawa Y, Isse N, Satoh N, Okazaki T, Shigemoto M, Mori K, Tamura N, Hosoda K, Yoshimasa Y, Jingami H, Kawada T, Nakao K . Human obese gene expression: Adipocyte-specific expression and regional differences in the adipose tissue Diabetes 1995 44: 855–858.

    Article  CAS  Google Scholar 

  59. 59

    Arner P . Impact of exercise on adipose tissue metabolism in humans Int J Obes Relat Metab Disord 1995 19: S18–S21.

    CAS  Google Scholar 

  60. 60

    Landt M, Lawson GM, Helgeson JM, Davila-Roman VG, Laderson JH, Jaffe AS, Hickner RC . Prolonged exercise decreases serum leptin concentrations Metabolism 1997 46: 1109–1112.

    Article  CAS  Google Scholar 

  61. 61

    Weimann E, Blum WF, Witzel C, Schwidergall S, Bohles HJ . Hypoleptinemia in female and male elite gymnasts Eur J Clin Invest 1999 29: 853–860.

    Article  CAS  Google Scholar 

  62. 62

    Zheng D, Wooter MH, Zhou Q, Dahm GL . The effect of exercise on ob gene expression Biochem Biophys Res Commun 1996 225: 747–750.

    Article  CAS  Google Scholar 

  63. 63

    Kohrt W, Landt M, Birge SJJ . Serum leptin levels are reduced in response to exercise training, but not hormone replacement therapy, in older women J Clin Endocrinol Metab 1996 81: 3980–3985.

    CAS  Google Scholar 

  64. 64

    Racette SB, Coppack SW, Landt M, Klein S . Leptin production during moderate-intensity aerobic exercise J Clin Endocrinol Metab 1997 82: 2275–2277.

    CAS  Google Scholar 

  65. 65

    Hickey MS, Considine RV, Israel RG, Mahar TL, McCammon MR, Tyndall GL, Houmard JA, Caro JF . Leptin is related to body fat content in male distance runners Am J Physiol 1996 271: E938–E940.

    CAS  PubMed  Google Scholar 

  66. 66

    Perusse L, Collier G, Gagnon J, Leon A, Rao DC, Skinner JS, Wilmore JH, Nadeau A, Zimmet PZ, Bouchard C . Acute and chronic effects of exercise on leptin levels in humans J Appl Physiol 1997 83: 5–10.

    Article  CAS  Google Scholar 

  67. 67

    Hickey MS, Houmard JA, Considine RV, Tyndall GL, Midgette JB, Gavigan KE, Weidner ML, McCammon MR, Israel RG, Caro JF . Gender dependent effects of exercise training on serum leptin levels in humans Am J Physiol 1997 272: E562–E566.

    CAS  Google Scholar 

  68. 68

    Pasman WJ, Westerterp-Plantenga MS, Saris WHM . The effect of exercise training on leptin levels in obese males Am J Physiol 1998 274: E280–E286.

    CAS  Google Scholar 

  69. 69

    Fruhbeck G, Jebb SA, Prentice AM . Leptin; physiology and pathophysiology Clin Physiol 1998 18: 399–419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Hardie LJ, Rayner DV, Holmes S, Trayhurn P . Circulating leptin levels are modulated by fasting, cold exposure and insulin administration in lean but Zucker (fa/fa) rats as measured by ELISA Biochem Biophys Res Commun 1996 223: 660–665.

    Article  CAS  Google Scholar 

  71. 71

    MacDougald OA, Hwang CS, Fan H, Lane MD . Regulated expression of the obese gene product (leptin) in white adipose tissue and 3T3-L1 adipocytes Proc Natl Acad Sci USA 1995 92: 9034–9037.

    Article  CAS  Google Scholar 

  72. 72

    Peino R, Pineiro V, Gualillo O, Menendez C, Brenlla J, Casabiell X, Dieguez C, Casanueva FF . Cold exposure inhibits leptin secretion in vitro by a direct and non-specific action on adipose tissue Eur J Endocrinol 2000 142: 195–199.

    Article  CAS  Google Scholar 

  73. 73

    Trayhurn P, Duncan JS, Rayner DV, Hardie LJ . Rapid inhibition of ob gene expression and circulating leptin levels in lean mice by the b3-adrenoceptor agonists BRL 35135A and ZD2079 Biochem Biophys Res Commun 1996 228: 605–610.

    Article  CAS  Google Scholar 

  74. 74

    Hardie LJ, Guilhot N, Trayhurn P . Regulation of leptin production in cultured mature white adipocytes Horm Metab Res 1996 28: 685–689.

    Article  CAS  Google Scholar 

  75. 75

    Leininger MT, Portocarrero CP, Schinckel AP, Spurlock ME, Bidwell CA, Nielsen JN, Houseknecht KL . Physiological response to acute endotoxemia in swine: effect of genotype on energy metabolites and leptin Domest Anim Endocrinol 2000 18: 71–82.

    Article  CAS  Google Scholar 

  76. 76

    Boden G, Chen X, Mazzoli M, Ryan I . Effect of fasting on serum leptin in normal human subjects J Clin Endocrinol Metab 1996 81: 2419–3423.

    Google Scholar 

  77. 77

    Trayhurn P, Thomas MEA, Duncan JS, Rayner DV . Effects of fasting and refeeding on ob gene expression in white adipose tissue of lean and obese (ob/ob) mice FEBS Lett 1995 368: 488–490.

    Article  CAS  Google Scholar 

  78. 78

    Champigny O, Ricquier D . Effects of fasting and refeeding on the level of uncoupling protein mRNA in rat brown adipose tissue; evidence for diet-induced and cold-induced responses J Nutr 1990 120: 1730–1736.

    Article  CAS  Google Scholar 

  79. 79

    Scarpace PJ, Matheny M . Leptin induction of UCP1 gene expression is dependent on sympathetic innervation Am J Physiol 1998 275: E259–E264.

    CAS  Google Scholar 

  80. 80

    Sivitz WI, Fink BD, Donohoue PA . Fasting and leptin modulate adipose and muscle uncoupling protein: divergent effects between messenger ribonucleic acid and protein expression Endocrinology 1999 140: 1511–1519.

    Article  CAS  Google Scholar 

  81. 81

    Grinspoon S, Gulick T, Askari H, Landt M, Lee K, Anderson E, Ma Z, Vignati L, Bowsher R, Herzog D, Klibanski A . Serum leptin levels in women with anorexia nervosa J Clin Endocrinol Metab 1996 81: 3861–3863.

    CAS  Google Scholar 

  82. 82

    Deuschle M, Blum WF, Englaro P, Schweiger U, Weber B, Pflaum C-D, Heuser I . Plasma leptin in depressed patients and healthy controls Horm Metab Res 1996 28: 714–717.

    Article  CAS  Google Scholar 

  83. 83

    Haluzik M, Kabrt J, Nedvidkova J, Svoboda J, Kotrlikova E, Papezova H . Relationship of serum leptin levels and selected nutritional parameters in patients with protein-caloric malnutrition Nutrition 1999 15: 829–833.

    Article  CAS  Google Scholar 

  84. 84

    Mantzoros CS, Flier JS, Lesem MD, Brewerton TD, Jimerson DC . Cerebrospinal fluid leptin in anorexia nervosa: correlation with nutritional status and potential role in resistance to weight gain J Clin Endocrinol Metab 1997 82: 1845–1851.

    CAS  Google Scholar 

  85. 85

    Stumvoll M, Fritsche A, Tschritter O, Lehmann R, Wahl HR, Renn W, Haring H . Leptin levels in humans are acutely suppressed by isoproterenol despite acipimox-induced inhibition of lipolysis, but not by free fatty acids Metabolism 2000 49: 335–339.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Mantzoros CS, Qu D, Frederich RC, Susulic VS, Lowell BB, Maratos-Flier E, Flier JS . Activation of β3 adrenergic receptors suppresses leptin expression and mediates a leptin independent inhibition of food intake in mice Diabetes 1996 45: 909–914.

    Article  CAS  Google Scholar 

  87. 87

    Li H, Matheny M, Scarpace PJ . b3-adrenergic-mediated suppression of leptin gene expression in rats Am J Physiol 1997 272: E1031–E1036.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Donahoo WT, Jensen DR, Yost TJ, Eckel RH . Isoproterenol and somatostatin decrease plasma leptin in humans; a novel mechanism regulating leptin secretion J Clin Endocrinol Metab 1997 82: 4139–4143.

    CAS  Google Scholar 

  89. 89

    Enocksson S, Shimizu M, Lonnqvist F, Nordenstrom J, Arner P . Demonstration of an in vivo functional β3-adrenoceptor in man J Clin Invest 1995 95: 2239–2245.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Trayhurn PHN, Mercer JG, Rayner DV . Leptin: fundamental aspects Int J Obes Relat Metab Disord 1999 23 (Suppl 1): 22–28.

    Article  CAS  Google Scholar 

  91. 91

    Collins S, Kuhn CM, Petro AE, Swick AG, Chrunyk BA, Surwit RS . Role of leptin in fat regulation Nature 1996 380: 677.

    Article  CAS  Google Scholar 

  92. 92

    Haynes WG, Morgan DA, Walsh SA, Mark AL, Sivitz WI . Receptor-mediated regional sympathetic nerve activation by leptin J Clin Invest 1997 100: 270–278.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Dunbar JC, Hu Y, Lu H . Intracerebroventricular leptin increases lumbar and renal sympathetic nerve activity and blood pressure in normal rats Diabetes 1997 46: 2040–2043.

    Article  CAS  Google Scholar 

  94. 94

    He Y, Chen H, Quon MJ, Reitman M . The mouse obese gene: genomic organisation, promoter activity, and activation by CCAAT/enhancer-binding protein a J Biol Chem 1995 270: 28887–28891.

    Article  CAS  Google Scholar 

  95. 95

    Miller SG, De Vos P, Guerre-Millo M, Wong K, Hermann T, Staels B, Briggs MR, Auwerx J . The adipocyte specific transcription factor C/EBPa modulates human ob gene expression Proc Natl Acad Sci USA 1996 93: 5507–5511.

    Article  CAS  Google Scholar 

  96. 96

    De Vos P, Lefebve AM, Miller SG, Guerre-Millo M, Wong K, Saladin R, Hamann LG, Steals B, Briggs MR, Auwerx J . Thiazolidinediones repress ob gene expression in rodents via activation of peroxisome proliferator-activated receptor gamma J Clin Invest 1996 98: 1004–1009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Kallen CB, Lazar MA . Antidiabetic thiazolidinediones inhibit leptin (ob) gene expression in 3T3-L1 adipocytes Proc Natl Acad Sci USA 1996 93: 5793–5796.

    Article  CAS  Google Scholar 

  98. 98

    Tartaglia L . The leptin receptor J Biol Chem 1997 272: 6093–6096.

    Article  CAS  Google Scholar 

  99. 99

    Ghilardi N, Ziegler S, Wiestner A, Stoffel R, Heim MH, Skoda RC . Defective STAT signaling by the leptin receptor in diabetic mice Proc Natl Acad Sci USA 1996 93: 6231–6235.

    Article  CAS  Google Scholar 

  100. 100

    Dvan Heek M, Mullins DE, Wirth MA, Graziano MP, Fawzi AB, Compton DS, France CF, Hoos LM, Casale RL, Sybertz EJ, Strader CD, Davis HRJ . The relationship of tissue localization, distribution and turnover to feeding after intraperitoneal 125I-leptin administration to ob/ob and db/db mice Horm Metab Res 1996 28: 653–658.

    Article  Google Scholar 

  101. 101

    De Matteis R, Dashtipour K, Ognibene A, Cinti S . Localisation of leptin receptor splice variants in mouse peripheral tissues by immunohistochemistry Proc Nutr Soc 1998 57: 441–448.

    Article  CAS  Google Scholar 

  102. 102

    Kieffer TJ, Heller RS, Habaner JF . Leptin receptors expressed on pancreatic b-cells Biochem Biophys Res Commun 1996 224: 522–527.

    Article  CAS  Google Scholar 

  103. 103

    Mercer JG, Hoggard N, Williams LM, Lawrence CB, Hannah LT, Trayhurn P . Localisation of leptin receptor mRNA and the long form splice variant (Ob-Rb) in mouse hypothalamus and adjacent brain regions by in situ hybridisation FEBS Lett 1996 387: 113–116.

    Article  CAS  Google Scholar 

  104. 104

    Fei H, Okano HJ, Li C, Lee GH, Zhao C, Darnell R, Friedman JM . Anatomical localization of alternatively spliced leptin receptors (Ob-R) in mouse brain and other tissues Proc Natl Acad Sci USA 1997 94: 7001–7005.

    Article  CAS  Google Scholar 

  105. 105

    Stephens TW, Basinski M, Bristow PK, Blue-Valleskey JM, Burgett G, Craft L, Hale J, Hoffmann J, Hsiung HM, Kriauciunas A, MacKeller W, Rosteck PR, Schoner B Jr, Smith D, Tinsley FC, Zhang XY, Heiman M . The role of neuropeptide Y in the antiobesity action of the obese gene product Nature 1995 377: 530–532.

    Article  CAS  Google Scholar 

  106. 106

    Heaney ML, Golde DW . Soluble hormone receptors Blood 1993 82: 1945–1948.

    CAS  Google Scholar 

  107. 107

    Cioffi JA, Shafer AW, Zupancic TJ, Smith-Gbur J, Mikhail D, Platika D, Snodrass . Novel B219/OB receptor isoforms; possible role of leptin in hematopoieses and reproduction Nat Med 1996 2: 585–589.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Bazan JF . Structural design and molecular evolution of a cytokine receptor superfamily Proc Natl Acad Sci USA 1990 87: 6934–6938.

    Article  CAS  Google Scholar 

  109. 109

    Miyazaki T, Maruyama M, Yamada G, Hatekeyama M, Taniguchi T . The integrity of the conserved WS motif common to IL-2 and other receptors is essential for ligand binding and signal transduction EMBO J 1991 10: 3191–3197.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

    Ihle JM . Cytokine receptor signalling Nature 1995 377: 591–594.

    Article  CAS  Google Scholar 

  111. 111

    Fong TM, Huang R-RC, Tota MR, Mao C, Smith T, Varnerin J, Karpitskiy VV, Krause JE, Van der Ploeg LHT . Localization of leptin binding domain in the leptin receptor Mol Pharmac 1998 53: 234–240.

    Article  CAS  Google Scholar 

  112. 112

    Chen H, Charlat O, Tartaglia LA, Woolf EA, Ellis SJ, Lakey ND, Culpepper J, Moore KJ, Breitbart RE, Duyk GM, Tepper RI, Morgenstern JP . Evidence that the leptin diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice Cell 1996 84: 491–495.

    Article  CAS  Google Scholar 

  113. 113

    Baumann H, Morella KK, White DW, Dembski M, Bailon PS, Kim H, Lai C-F, Tartaglia LA . The full-length leptin receptor has signalling capabilities of interleukin 6-type cytokine receptors Proc Natl Acad Sci USA 1996 93: 8374–8378.

    Article  CAS  Google Scholar 

  114. 114

    Yamashita T, Murakami T, Iida M, Kuwajima M, Shima K . Leptin receptor of Zucker fatty rat performs reduced signal transduction Diabetes 1997 46: 1077–1080.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. 115

    Devos R, Guisez Y, Van der Heyden J, White DW, Kalai M, Fountoulakis M, Plaetinck G . Ligand-independent dimerisation of the extracellular domain of the leptin receptor and determination of the stoichiometry of leptin binding J Biol Chem 1997 272: 18304–18310.

    Article  CAS  Google Scholar 

  116. 116

    White DW, Kuropatwinski KK, Devos R, Baumann H, Tartaglia LA . Leptin receptor (OB-R) signaling. Cytoplasmic domain mutational analysis and evidence for receptor homo-oligomerization J Biol Chem 1997 272: 4065–4071.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    White DW, Tartaglia LA . Evidence for ligand-independent homo-oligomerisation of leptin receptor (OB-R) isoforms: a proposed mechanism permitting productive long-form signalling in the presence of excess short-form expression J Cell Biochem 1999 73: 278–288.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

    Bjorbaek CUS, Da Silva B, Flier JS . Divergent signaling capacities of the long and short isoforms of the leptin receptor J Biol Chem 1997 272: 32686–32695.

    Article  CAS  Google Scholar 

  119. 119

    Houseknecht KL, Portocarrero CP . Leptin and its receptors of whole-body energy homeostasis Domest Anim Endocrinol 1998 15: 457–475.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Ghilardi N, Skoda RC . The leptin receptor activates Janus Kinase 2 and signals for proliferation in a factor-dependent cell line Mol Endocrinol 1997 11: 393–399.

    Article  CAS  Google Scholar 

  121. 121

    Lebrun J-J, Ali S, Ullrich A, Kelly PA . Proline-rich sequence-mediated Jak2 association to the prolactin receptor is required but not sufficient for signal transduction J Biol Chem 1995 270: 10664–10670.

    Article  CAS  Google Scholar 

  122. 122

    Joneja B, Wojchowski DM . Mitogenic signaling and inhibition of apoptosis via the erythropoietin receptor Box-1 domain J Biol Chem 1997 272: 11176–11184.

    Article  CAS  Google Scholar 

  123. 123

    Vaisse C, Halaas JL, Horvath CM, Darnell JE, Stoffel M, Friedman JM . Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice Nat Genet 1996 14: 95–97.

    Article  CAS  Google Scholar 

  124. 124

    White DW, Wang DW, Chua SCJ, Morgenstern JP, Leibel RL, Baumann H, Tartaglia LA . Constitutive and impaired signaling of leptin receptors containing the Gln-Pro extracellular domain fatty mutation Proc Natl Acad Sci USA 1997 94: 10657–10662.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. 125

    Emilsson V, Arch JRS, de Groot RP, Lister CA, Cawthorne MA . Leptin treatment increases suppressors of cytokine signalling in central and peripheral tissues FEBS Lett 1999 455: 170–174.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. 126

    Rosenblum C, Tota M, Cilly D, Smith T, Cullum R, Qureshi S, Hess JF, Philips MS, Hey P, Vongs A, Fong TM, Xu L, Chen HY, Smith RG, Schindler, Van Der Ploeg LHT . Functional STAT1 and 3 signalling by the leptin receptor (OB-R); reduced expression of he rat fatty leptin receptor in transfected cells Endocrinology 1996 137: 5178–5181.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. 127

    Stromberg H, Svensson SPS, Hermanson O . Distribution of the transcription factor Signal Transducer and Activator of Transcription 3 in the rat central nervous system and dorsal root ganglia Brain Res 2000 853: 105–114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. 128

    Starr R, Willson TA, Viney EM, Murray LJ, Rayner JR, Jenkins BJ, Gonda TJ, Alexander WS, Metcalf D, Nicola NA, Hilton DJ . A family of cytokine-inducible inhibitors of signalling Nature 1997 387: 917–921.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. 129

    Endo TA, Masuhara M, Yokouchi M, Suzuki R, Sakamoto H, Mitsui K, Matsumoto A, Tanimura S, Ohtsubo M, Misawa H, Miyazaki T, Leonor N, Taniguchi T, Fujita T, Kanakura Y, Komiya S, Yoshimura A . A new protein containing SH2 domain that inhibits JAK kinasas Nature 1997 387: 921–924.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. 130

    Naka T, Narazaki M, Hirata M, Matsumoto T, Minamoto S, Aono A, Nishimoto N, Kajita T, Taga T, Yoshizaki K, Akira S, Kishimoto T . Structure and function of a new STAT-induced STAT inhibitor Nature 1997 387: 924–929.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. 131

    Bjorbaek C, Elmquist JK, Frantz JD, Shoelson SE, Flier JS . Identification of SOCS-3 as a potential mediator of central leptin resistance Mol Cell 1998 1: 619–625.

    Article  CAS  Google Scholar 

  132. 132

    Bjorbaek C, El-haschimi K, Frantz JD, Flier JS . The role of SOCS-3 in leptin signaling and leptin resistance J Biol Chem 1999 274: 30059–30065.

    Article  CAS  Google Scholar 

  133. 133

    Banks WA, Clever CM, Farrell CL . Partial saturation and regional variation in the blood-to-brain transport of leptin in normal weight mice Am J Physiol 2000 278: E1158–E1165.

    CAS  Google Scholar 

  134. 134

    Banks WA, Kastin AJ, Huang W, Jaspan JB, Maness LM . Leptin enters the brain by a saturable system independent of insulin Peptides 1996 17: 305–311.

    Article  CAS  Google Scholar 

  135. 135

    Kastin AJ, Pan W, Maness LM, Koletsky RJ, Ernsberg P . Decreased transport of leptin across the blood-brain barrier in rats lacking the short form of the leptin receptor Peptides 1999 20: 1449–1453.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. 136

    Murakami T, Yamashita T, Ilida M, Kuwajima M, Shima K . A short for of the leptin receptor performs signal transduction Biochem Biophys Res Commun 1997 231: 26–29.

    Article  CAS  Google Scholar 

  137. 137

    Wang M, Zhou Y, Newgard C, Unger R . A novel leptin receptor isoform in rat FEBS Lett 1996 392: 87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. 138

    Chua SCJ, Koutras IK, Han L, Liu S-M, Kay J, Young SJ, Chung WK, Leibel RL . Fine structure of the murine leptin receptor gene: splice site suppression is required to form two alternatively spliced transcripts Genomics 1997 45: 264–270.

    Article  CAS  Google Scholar 

  139. 139

    Lewandowski K, Horn R, O'Callaghan CJ, Dunlop D, Medley G, O'Hare P, Brabant G . Free leptin, bound leptin and soluble leptin receptor in normal and diabetic pregnancies J Clin Endocrinol Metab 1999 84: 300–306.

    Article  CAS  Google Scholar 

  140. 140

    Clement K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D, Gourmelen M, Dina C, Chambaz J, Lacorte JM, Basdevant A, Bougneres P, Lebouc Y, Froguel P, Guy-Grand B . A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction Nature 1998 392: 398–401.

    Article  CAS  Google Scholar 

  141. 141

    Lahlou N, Clement K, Carel JC, Vaisse C, Lotton C, Le Bihan Y, Basdevant A, Lebouc Y, Froguel P, Roger M, Guy-Grand B . Soluble leptin receptor in serum of subjects with complete resistance to leptin: relation to fat mass Diabetes 2000 49: 1347–1352.

    Article  CAS  Google Scholar 

  142. 142

    Lollmann B, Gruninger S, Stricker-Krongrad A, Chiesi M . Detection and quantification of the leptin receptor splice variants Ob-Ra, b, and e in different mouse tissues Biochem Biophys Res Commun 1997 238: 648–652.

    Article  CAS  Google Scholar 

  143. 143

    Takekoshi K, Motooka M, Isobe K, Nomura F, Manmoku T, Ishii K, Nakai T . Leptin directly stimulates catecholamine secretion and synthesis in cultured porcine adrenal medullary chromaffin cells Biochem Biophys Res Commun 1999 261: 426–431.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. 144

    Serradeil-Le Gal C, Raufaste D, Brossard G, Pouzet B, Marty E, Maffrand J-P, Le Fur G . Characterization and localization of leptin receptors in the rat kidney FEBS Lett 1997 404: 185–191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. 145

    Malik KF, Young WS III . Localisation of binding sites in the central nervous system for leptin (Ob protein) in normal, obese (ob/ob), and diabetic (db/db) C57BL/6J mice Endocrinology 1996 137: 1497–1500.

    Article  CAS  Google Scholar 

  146. 146

    Golden PL, Maccagnan TJ, Pardridge WM . Human blood-brain barrier leptin receptor J Clin Invest 1997 99: 14–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. 147

    Corp ES, Conze DB, Smith F, Campfield LA . Regional localisation of specific [125I] leptin binding sites in rat forebrain Brain Res 1998 789: 40–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. 148

    Wang Y, Kuropatwinski KK, White DW, Hawley TS, Hawley RG, Tartaglia LA, Baumann H . Leptin receptor action in hepatic cells J Biol Chem 1997 272: 16216–16223.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. 149

    Uotani S, Bjorbak, Tornoe J, Flier JS . Functional properties of leptin receptor isoforms; internationalisation and degradation of leptin and ligand-induced receptor downregulation Diabetes 1999 48: 279–286.

    Article  CAS  Google Scholar 

  150. 150

    Schwartz MW, Seeley RJ, Campfield LA, Burn P, Baskin DG . Identification of targets of leptin action in rat hypothalamus J Clin Invest 1996 98: 1101–1106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. 151

    Mercer JG, Moar KM, Hoggard N . Localisation of leptin receptor (Ob-R) messenger ribonucleic acid in the rodent hindbrain Endocrinology 1998 139: 29–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. 152

    Cao G-Y, Considine RV, Lynn RB . Leptin receptors in the adrenal medulla of the rat Am J Physiol 1997 273: E448–E452.

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153

    Tsuchiya T, Shimizu H, Horie T, Mori M . Expression of leptin receptors in lung: leptin as a growth factor Eur J Pharmac 1999 365: 273–279.

    Article  CAS  Google Scholar 

  154. 154

    Dal Farra C, Zsurger N, Vincent JP, Cupo A . Binding of a pure 125I-monoiodoleptin analog to mouse tissues: a developmental study Peptides 2000 21: 577–587.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. 155

    Hill RA, Margetic S, Pegg G, Gazzola C . Leptin: its pharmokinetics and tissue distribution Int J Obes Relat Metab Disord 1998 22: 765–770.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. 156

    Zeng J, Patterson B, Klein S, Martin DR, Dagogo-Jack S, Kohrt WM, Miller SB, Landt M . Whole body leptin kinetics and renal metabolism in vivo Am J Physiol 1997 273: E1102–E1106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. 157

    Gray RS, Cowan P, di Mario U, Elton RA, Clarke BF, Duncan LJP . Influence of insulin antibodies on pharmacokinetics and bioavailability of recombinant human and highly purified beef insulins in insulin dependent diabetics Br Med J 1985 290: 1687–1691.

    Article  CAS  Google Scholar 

  158. 158

    Hill RA, Flick-Smith FC, Dye S, Pell JM . Actions of an IGF-1-enhancing antibody on IGF-1 pharmacokinetics and tissue distribution: increased IGF-1 bioavailability J Endocrinol 1997 152: 123–130.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. 159

    Bastian SEP, Walton PE, Wallace JC, Ballard FJ . Plasma clearance and tissue distribution of labelled insulin-like growth factor-1 (IGF-1) and an analogue LR3IGF-1 in pregnant rats J Endocrinol 1993 138: 327–336.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. 160

    Klein S, Coppack SW, Mohamed-Ali V, Landt M . Adipose tissue production and plasma leptin kinetics in humans Diabetes 1996 45: 984–987.

    Article  CAS  Google Scholar 

  161. 161

    Ahren B, Baldwin RM, Have lPJ . Pharmokinetics of human leptin in mice and rhesus monkeys Int J Obes Relat Metab Disord 2000 24: 1579–1585.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. 162

    Houseknecht KL, Mantzoros CS, Kuliawat R, Hadro E, Flier JS, Kahn BB . Evidence for leptin binding proteins in serum of rodents and humans; modulation with obesity Diabetes 1996 45: 1638–1643.

    Article  CAS  Google Scholar 

  163. 163

    Sinha MK, Opentanova I, Ohannesian JP . Evidence of free and bound leptin in human circulation. Studies in lean and obese subjects and during short-term fasting J Clin Invest 1996 98: 1277–1282.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. 164

    Gainsford T, Willson TA, Metcalf D, Handman E, McFarlane C, Ng A, Nicola NA, Alexander WS, Hilton DJ . Leptin can induce proliferation, differentiation, and functional activation of hemopoietic cells Proc Natl Acad Sci USA 1996 93: 14564–14568.

    Article  CAS  Google Scholar 

  165. 165

    Gainsford T, Alexander WS . A role for leptin in hemopoieses? Mol Biotech 1999 11: 149–158.

    Article  CAS  Google Scholar 

  166. 166

    Umemoto Y, Tsuji K, Yang FC, Ebihara Y, Kaneko A, Furukawa S, Nakahata T . Leptin stimulates the proliferation of murine myoletic and primitive hematopoietic progenitor cells Blood 1997 90: 3438–3443.

    CAS  PubMed  PubMed Central  Google Scholar 

  167. 167

    Nakata M, Yada T, Soejima N, Maruyama I . Leptin promotes aggregation of human platelets via the long form of its receptor Diabetes 1999 48: 426–429.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. 168

    Sierra-Honigmann MR, Nath AK, Murakami C, Garcia-Cardena G, Papapatropoulos A, Sessa WC, Madge LA, Schechner JS, Schwabb MB, Polverinin PJ, Flores-Riveros JR . Biological action of leptin as an angiogenic factor Science 1998 281: 1583–1585.

    Article  Google Scholar 

  169. 169

    Bouloumie A, Drexler HCA, Lafontan M, Busse R . Leptin, the product of ob gene, promotes angiogenesis Circul Res 1998 83: 1059–1066.

    Article  CAS  Google Scholar 

  170. 170

    Kang S-K, Kwon HM, Hong BK, Kim D, Kim IJ, Choi EY, Jang Y, Kim H-S, Kim MS, Kwon HC . Expression of leptin receptor (OB-R) in human atherosclerotic lesions: potential role in intimal neovascularisation Yonsei Med J 2000 41: 68–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. 171

    Ring BD, Scully S, Davis CR, Baker MB, Cullen MJ, Pelleymounter MA, Danilenko DM . Systemically and topically administered leptin both accelerate wound healing in diabetic ob/ob mice Endocrinology 2000 141: 446–449.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. 172

    Boado RJ, Golden PL, Levin N, Pardridge WM . Up-regulation of blood-brain barrier short-form leptin receptor gene products in rats fed a high fat diet J Neurochem 1998 71: 1761–1764.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. 173

    Margetic S, Qui XY, D'Occio MJ, Gazzola C, Hill RA . Effect of mouse leptin on angiogenesis 15th Australasian Biotechnology Conference 2000 p 79.

  174. 174

    Chehab FF, Mounzih K, Lu R, Lim ME . Early onset of reproductive function in normal female mice treated with leptin Science 1997 275: 88–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. 175

    Ashworth CJ, Hoggard N, Thomas L, Mercer JG, Wallace JM, Lea RG . Placental leptin Rev Reprod 2000 5: 18–24.

    Article  CAS  Google Scholar 

  176. 176

    Chehab FF, Lim ME, Lu RH . Correction of the sterility defect in homozygous obese female mice is treatment with the human recombinant leptin Nat Genet 1996 12: 318–320.

    Article  CAS  Google Scholar 

  177. 177

    Spicer LJ, Francisco CC . Adipose obese gene product, leptin inhibits bovine ovarian thecal cell steriodogenesis Biol Reprod 1998 58: 207–212.

    Article  CAS  Google Scholar 

  178. 178

    Karlsson C, Lindell K, Svenssen E, Bergh C, Lind P, Billing H, Carlsson LMS, Carlsson B . Expression of functional leptin receptors in the human ovary J Clin Endocrinol Metab 1997 82: 4144–4148.

    CAS  PubMed  PubMed Central  Google Scholar 

  179. 179

    Lindheim SR, Sauer MV, Carmina E, Chang PL, Zimmerman R, Lobo RA . Circulating leptin levels during ovulation induction: relation to adiposity and ovarian morphology Fertil Steril 2000 73: 493–498.

    Article  CAS  Google Scholar 

  180. 180

    Barash I, Cheung CC, Weigle DS, Ren H, Kabigting EB, Kuijper JL, Clifton DK, Steiner RA . Leptin is metabolic signal to the reproductive system Endocrinology 1996 137: 3144–3147.

    Article  CAS  Google Scholar 

  181. 181

    Mounzih K, Lu R, Chehab FF . Leptin treatment rescues the sterility of genetically obese ob/ob males Endocrinology 1997 138: 1190–1193.

    Article  CAS  Google Scholar 

  182. 182

    Shimizu H, Shimomura Y, Nakanishi Y, Futawatari T, Ohtani K, Sato N, Mori M . Oestrogen increases in vivo leptin production in rats and human subjects J Endocrinol 1997 154: 285–292.

    Article  CAS  Google Scholar 

  183. 183

    Wabitsch M, Jensen PB, Blum WF, Christoffersen CT, Englaro P, Heinze E, Rascher W, Teller W, Tornquist H, Hauner H . Insulin and cortisol promote leptin production in cultured human cells Diabetes 1996 45: 1435–1438.

    Article  CAS  Google Scholar 

  184. 184

    Jockenhovel F, Blum WF, Vogel E, Englaro P, Muler-Wieland D, Reinwein D, Rascher W, Krone W . Testosterone substitution normalises elevated serum leptin levels in hypogonadal men J Clin Endocrinol Metab 1997 82: 2510–2513.

    Article  CAS  Google Scholar 

  185. 185

    Henson MC, Castracane VD . Leptin in pregnancy Biol Reprod 2000 63: 1219–1228.

    Article  CAS  Google Scholar 

  186. 186

    Butte NF, Hopkinson JM, Nicolson MA . Leptin in human reproduction: serum leptin levels in pregnant and lactating women J Clin Endocrinol Metab 1997 82: 585–589.

    Article  CAS  Google Scholar 

  187. 187

    Helland IB, Reseland JE, Saugstad OD, Drevon CA . Leptin levels in pregnant women and newborn infants: gender differences and reduction during the neonatal period Pediatrics 1998 101: 12.

    Article  Google Scholar 

  188. 188

    Amico JA, Thomas A, Crowley RS, Burmeister LA . Concentrations of leptin in the serum of pregnant, lactating, and cycling rats and of leptin messenger ribonucleic acid in rat placental tissue Life Sci 1998 63: 1387–1395.

    Article  CAS  Google Scholar 

  189. 189

    Terada Y, Yamakawa K, Sugaya A, Toyoda N . Serum leptin levels do not rise during pregnancy in age-matched rats Biochem Biophys Res Commun 1998 235: 841–844.

    Article  Google Scholar 

  190. 190

    Henson MC, Swan KF, O'Neil JS . Expression of placental leptin and leptin receptor transcripts in early pregnancy and at term Obstet Gynecol 1998 92: 1020–1028.

    CAS  PubMed  Google Scholar 

  191. 191

    Gavrilova O, Barr V, Marcus-Samuels B, Reitman M . Hyperleptinaemia of pregnancy associated with the appearance of a circulating form of the leptin receptor J Biol Chem 1997 272: 30546–30551.

    Article  CAS  Google Scholar 

  192. 192

    Barb CR . The brain–pituitary–adipocyte axis: role of leptin in modulating neuroendocrine function J Anim Sci 1999 77: 1249–1257.

    Article  CAS  Google Scholar 

  193. 193

    Holness MJ, Munns MJ, Sugden MC . Current concepts concerning the role of leptin in reproductive function Mol Cell Endocrinol 1999 157: 11–20.

    Article  CAS  Google Scholar 

  194. 194

    Mounzih K, Qui J, Ewart-Toland A, Chehab FF . Leptin is not necessary for gestation and parturition but regulates maternal nutrition via a leptin resistance state Endocrinology 1998 139: 5259–5262.

    Article  CAS  Google Scholar 

  195. 195

    Linnemann K, Malek A, Sager R, Blum WF, Schneider H, Fusch C . Leptin production and release in the dually in vitro perfused human placenta J Clin Endocrinol Metab 2000 85: 4298–4301.

    CAS  PubMed  Google Scholar 

  196. 196

    Mukherjea R, Castonguay TW, Douglass LW, Moser-Veillon P . Elevated leptin concentrations in pregnancy and lactation: possible role as a modulator of substrate utilization Life Sci 1999 65: 1183–1193.

    Article  CAS  Google Scholar 

  197. 197

    Schubring C, Kiess W, Englaro P, Rascher W, Dotsch J, Hanitsch S, Attanasio A, Blum WF . Levels of leptin in maternal serum, amniotic fluid, and arterial and venous cord blood: relation to neonatal and placental weight J Clin Endocrinol Metab 1997 82: 1480–1483.

    Article  CAS  Google Scholar 

  198. 198

    Harigaya ANK, Nako Y, Morikawa A . Relationship between concentration of serum leptin and foetal growth J Clin Endocrinol Metab 1997 82: 3281–3284.

    Article  CAS  Google Scholar 

  199. 199

    Matsuda J, Yokota I, Iida M, Murakami T, Naito E, Ito M, Shima K, Kuroda Y . Serum leptin concentration in cord blood: relationship to birth weight and gender J Clin Endocrinol Metab 1997 82: 1642–1644.

    Article  CAS  Google Scholar 

  200. 200

    Yu WH, Kimura M, Walczewska A, Karanth S, McCann SM . Role of leptin in hypothalamic–pituitary function Proc Natl Acad Sci USA 1997 94: 1023–1028.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. 201

    Ahima RS, Dushay J, Flier SN, Prabakaran D, Flier JS . Leptin accelerates the onset of puberty in normal female mice J Clin Invest 1997 99: 391–395.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. 202

    Cheung CC, Thornton JE, Kuijper JL, Weigle DS, Clifton DK, Steiner RA . Leptin is metabolic gate for the onset of puberty in the female rat Endocrinology 1997 138: 855–858.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. 203

    Plant TM, Durrant AR . Circulating leptin does not appear to provide a signal for triggering the initiation of puberty in the male rhesus monkey (Macaca mulatta) Endocrinology 1997 138: 4505–4508.

    Article  CAS  Google Scholar 

  204. 204

    Urbanski HF, Pau K-YF . A biphasic developmental pattern of circulating leptin in the male rhesus macaque (Macaca mulatta) Endocrinology 1998 139: 2284–2286.

    Article  CAS  Google Scholar 

  205. 205

    Mann DR, Akinbami MA, Gould KG, Castracane VD . A longitudinal study of leptin during development in the male rhesus monkey: the effect of body composition and season on circulating leptin levels Biol Reprod 2000 62: 285–291.

    Article  CAS  Google Scholar 

  206. 206

    Cunningham MJ, Clifton DK, Steiner RA . Leptin's action on the reproductive axis: perspectives and mechanism Biol Reprod 1999 60: 216–222.

    Article  CAS  Google Scholar 

  207. 207

    Saad MF, Khan A, Sharma A, Michael R, Riad-Gabriel MG, Boyadjian R, Jinagouda SD, Steil GM, Kamdar V . Physiological insulinemia acutely modulates plasma leptin Diabetes 1998 47: 544–549.

    Article  CAS  Google Scholar 

  208. 208

    Utriainen T, Malmstrom R, Makimattila S, Yki-Jarvinen H . Supraphysiological hyperinsulinemia increases plasma leptin concentrations after 4 h in normal subjects Diabetes 1996 45: 1364–1366.

    Article  CAS  Google Scholar 

  209. 209

    Saladin R, De Vos P, Guerre-Millo M, Leturque A, Girard J, Staels B, Auwerx J . Transient increase in obese gene expression after food intake or insulin administration Nature 1995 377: 527–529.

    Article  CAS  Google Scholar 

  210. 210

    Koopmans SJ, Frolich M, Gribnau EH, Westendrop RG, DeFronzo RA . Effect of hyperinsulinemia on plasma leptin concentrations and food intake in rats Am J Physiol 1998 274: E998–E1001.

    CAS  PubMed  Google Scholar 

  211. 211

    Bradley RL, Cheatham B . Regulation of ob gene expression and leptin secretion by insulin and dexamethasone in rat adipocytes Diabetes 1999 48: 272–278.

    Article  CAS  Google Scholar 

  212. 212

    Leonhardt W, Horn R, Brabant G, Breidert M, Temelkova-Kurktschiev TH, Fucker K, Hanefeld M . Relationship of free and specifically bound leptin to insulin secretion in patients with impared glucose tolerance (IGT) Exp Clin Endocrinol Diabet 1999 107: 46–52.

    Article  CAS  Google Scholar 

  213. 213

    Kolaczynski JW, Nyce MR, Considine RV, Boden G, Nolan JJ, Henry RR, Mudalair SR, Olefsky J, Caro JF . Acute and chronic effect of insulin on leptin production in humans—studies in vivo and in vitro Diabetes 1996 45: 699–701.

    Article  CAS  Google Scholar 

  214. 214

    Kolaczynski JW, Ohannesian JP, Considine RV, Marco CC, Caro JF . Response of leptin to short term and prolonged overfeeding in humans J Clin Endocrinol Metab 1996 81: 4162–4165.

    CAS  Google Scholar 

  215. 215

    Kolaczynski JW, Considine RV, Ohannesian JP, Marco C, Opentanova I, Nyce MR, Myint M, Caro JF . Responses of leptin to short-term fasting and refeeding in humans: a link with ketogenesis but no ketones themselves Diabetes 1996 45: 1511–1515.

    Article  CAS  Google Scholar 

  216. 216

    Vidal HD, Auboeuf D, De Vos P, Staels B, Riou JP, Auwerx J, Laville M . The expression of ob gene is not acutely regulated by insulin and fasting in human abdominal subcutaneous adipose tissue J Clin Invest 1996 98: 251–255.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. 217

    Kulkarni RN, Whang Z-L, Wang R-M, Hurley JD, Smith DM, Ghatei MA, Withers DJ, Gardiner JV, Bailey CJ, Bloom SR . Leptin rapidly suppress insulin release from insulinoma cells, rat and human islets and, in vivo, in mice J Clin Invest 1997 100: 2729–2736.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. 218

    D'Adamo MA, Buongiorno E, Maroccia F, Leonetti F, Barbetti A, Giaccari D, Zorretta G, Tamburrano G, Sbraccia P . Increased OB gene expression leads to elevated plasma leptin concentrations in patients with chronic primary hyperinsulinemia Diabetes 1998 47: 1625–1629.

    Article  CAS  Google Scholar 

  219. 219

    Popovic V, Micic D, Danjanovic S, Zoric S, Djurovic M, Obradovic S, Petakov M, Dieguez, Casanueva FF . Serum leptin and insulin concentrations in patients with insulinoma before and after surgery Eur J Endocrinol 1998 138: 86–88.

    Article  CAS  Google Scholar 

  220. 220

    Havel PJ, Uriu-Hare JY, Liu T, Stanhope KL, Stern JS, Keen CL, Ahren B . Marked and rapid decreases of circulating leptin in streptozotocin diabetic rats; reveral by insulin Am J Physiol 1998 43: R1482–R1498.

    Google Scholar 

  221. 221

    Kieffer T, Habener JF . The adipoinsular axis: effects of leptin on pancreatic b-cells Am J Physiol 2000 278: E1–E14.

    Article  CAS  Google Scholar 

  222. 222

    Pagano C, Englaro P, Granzotto M, Blum WF, Sagrillo E, Ferretti E, Federspil E, Vettor R . Insulin induces rapid changes of plasma leptin in lean but not in genetically obese (fa/fa) rats Int J Obes Relat Metab Disord 1997 21: 614–618.

    Article  CAS  Google Scholar 

  223. 223

    Dagogo-Jack S, Fanelli C, Paramore D, Brothers J, Landt M . Plasma leptin and insulin relationships in obese and nonobese humans Diabetes 1996 45: 695–698.

    Article  CAS  Google Scholar 

  224. 224

    Fehmann H-C, Peiser C, Bode H-P, Stamm M, Staats P, Hedetoft C, Lang RE, Goke B . Leptin: a potent inhibitor of insulin secretion Peptides 1997 18: 1267–1273.

    Article  CAS  Google Scholar 

  225. 225

    Poitout V, Rauault C, Guerre-Millo M, Reach G . Does leptin regulate insulin secretion? Diabetes Metab 1998 24: 313–318.

    Google Scholar 

  226. 226

    Russell CD, Petersen RN, Rao SP, Ricci MR, Prasad A, Zhang Y, Brolin RE, Fried SK . Leptin expression in adipose tissue from obese humans: depot-specific regulation by insulin and dexamethasone Am J Physiol 1998 275: E507–E515.

    CAS  Google Scholar 

  227. 227

    Poitout V, Rauault C, Guerre-Millo M, Briaud I, Reach G . Inhibition of insulin secretion by leptin in normal rodent islets of Langerhans Endocrinology 1998 139: 822–826.

    Article  CAS  Google Scholar 

  228. 228

    Emilsson V, Liu Y, Cawthorne MA, Morton NM, Devenport M . Expression and functional leptin receptor mRNA in pancreatic islets and direct inhibitory action of leptin on insulin secretion Diabetes 1997 46: 313–316.

    Article  CAS  Google Scholar 

  229. 229

    Kieffer T, Scott-Heller R, Leech CA, Holz G, Habener JF . Leptin suppression of insulin secretion by the activation of ATP-sensitive K+ channels in pancreatic b-cells Diabetes 1997 46: 1087–1093.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. 230

    Seufert J, Kieffer TJ, Leech CA, Holz GG, Moritz W, Ricordi C, Habener JF . Leptin suppression of insulin secretion and gene expression in human pancreatic islets: implications for the development of adipogenic diabetes mellitus J Clin Endocrinol Metab 1999 84: 670–676.

    CAS  PubMed  PubMed Central  Google Scholar 

  231. 231

    Ceddia RB, William WNJ, Carpinelli AR, Curi R . Modulation of insulin secretion by leptin Gen Pharmac 1999 32: 2323–2327.

    Google Scholar 

  232. 232

    Tanizawa Y . Direct stimulation of basal insulin secretion by physiological concentrations of leptin in pancreatic b cells Endocrinology 1997 138: 4513–4516.

    Article  CAS  Google Scholar 

  233. 233

    Leclercq-Meyer V, Malaisse WJ . Failure of human and mouse leptin to affect insulin, glucagon and somatostatin secretion by the perfused rat pancreas at physiological glucose concentrations Mol Cell Endocrinol 1998 141: 111–118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. 234

    Leclercq-Meyer V, Considine RV, Sener A, Malaisse WJ . Does leptin receptor play a functional role in the endocrine pancreas? Biochem Biophys Res Commun 1996 239: 794–798.

    Article  Google Scholar 

  235. 235

    Chen N-G, Swick AG, Romsos DR . Leptin constrains acetylcholine induced insulin secretion from pancreatic islets of ob/ob mice J Clin Invest 1997 100: 1174–1179.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. 236

    Cawthorne MA, Morton NM, Pallet AL, Liu YL, Emilsson V . Peripheral metabolic actions of leptin Proc Nutr Soc 1998 57: 449–453.

    Article  CAS  Google Scholar 

  237. 237

    Walder K, Filipps A, Clark S, Zimmet P, Collier GR . Leptin inhibits insulin binding in isolated rat adipocytes J Endocrinol 1997 155: R5–R7.

    Article  CAS  Google Scholar 

  238. 238

    Muller G, Ertl J, Gerl M, Preibisch G . Leptin impairs metabolic actions of insulin on isolated rat adipocytes J Biol Chem 1997 272: 10585–10593.

    Article  CAS  Google Scholar 

  239. 239

    Zierath JR, Frevert EU, Ryder JW, Berggren P-O, Kahn BB . Evidence against a direct effect of leptin on glucose transport in skeletal muscle and adipocytes Diabetes 1998 47: 1–4.

    Article  CAS  Google Scholar 

  240. 240

    Ranganathan S, Ciaraldi TP, Henry RR, Mudaliar S, Kern PA . Lack of effect of leptin on glucose transport, lipoprotein lipase, and insulin action in adipose and muscle cells Endocrinology 1998 139: 2509–2513.

    Article  CAS  Google Scholar 

  241. 241

    Clement K, Lahlou N, Rutz J . Association of poorly controlled diabetes with low serum leptin in morbid obesity Int J Obes Relat Metab Disord 1997 21: 556–561.

    Article  CAS  Google Scholar 

  242. 242

    Mantzoros CS, Liolias AD, Tritos NA, Kaklamani VG, Doulgerakis DE, Griveas I, Moses A, Flier JS . Circulating insulin concentrations, smoking, and alcohol intake are important independent predictor of leptin in young healthy men Obes Res 1998 6: 179–186.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. 243

    Segal K, Land M, Klein S . Relationship between insulin sensitivity and plasma leptin concentration inlean and obese men Diabetes 1996 45: 987–991.

    Article  Google Scholar 

  244. 244

    Dunaif A . Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis Endocr Rev 1997 18: 774–800.

    CAS  Google Scholar 

  245. 245

    Blache D, Tellam RL, Chagas LM, Blackberry MA, Vercoe PE, Martin GB . Level of nutrition affects leptin concentrations in plasma and cerebrospinal fluid in sheep J Endocrinol 2000 165: 625–637.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. 246

    Mizuno T, Bergen H, Kleopoulos S, Bauman WA, Mobbs CV . Effects of nutritional status and ageing on leptin gene expression in mice: importance of glucose Horm Metab Res 1996 28: 679–684.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. 247

    Mueller WM, Gregoire FM, Stanhope KL, Mobbs CV, Mizuno TM, Warden CH, Stern JS, Havel PJ . Evidence that glucose metabolism regulates leptin secretion from cultured rat adipocytes Endocrinology 1998 139: 551–558.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. 248

    Kamohara S, Burcelin R, Halaas JL, Friedman JM, Charron MJ . Acute stimulation of glucose metabolism in mice by leptin treatment Nature 1997 389: 374–377.

    Article  CAS  Google Scholar 

  249. 249

    Muoio DM, Dohm GL, Tapscott EB, Coleman RA . Leptin opposes insulin's effects on fatty acid partitioning in muscle isolated from obese ob/ob mice Am J Physiol 1999 276: E913–E921.

    CAS  Google Scholar 

  250. 250

    Cohen B, Novick D, Rubinstein M . Modulation of insulin activities by leptin Science 1996 274: 1185–1188.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  251. 251

    Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Muller C, Carling D, Kahn BB . Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase Nature 2002 415: 339–343.

    Article  CAS  Google Scholar 

  252. 252

    Muoio DM, Dohm GL, Fiedorek FT, Tapscott EB, Coleman RA . Leptin directly alters lipid partitioning in skeletal muscle Diabetes 1997 46: 1360–1363.

    Article  CAS  Google Scholar 

  253. 253

    Burcelini RSK, Li J, Tannenbaum GS, Charron MJ, Friedman JM . Acute intravenous leptin infusion increases glucose turnover but not skeletal muscle glucose uprtake in ob/ob mice Diabetes 1999 48: 1264–1269.

    Article  Google Scholar 

  254. 254

    Solini A, Bonora E, Bonadonna R, Castellino P, DeFronzo RA . Protein metabolism in human obesity: relationship with glucose and lipid metabolism and with visceral adipose tissue J Clin Endocrinol Metab 1997 82: 2552–2558.

    CAS  Google Scholar 

  255. 255

    Ceddia RB, William WNJ, Curi R . Comparing effects of leptin and insulin on glucose metabolism in skeletal muscle; evidence for an effect of leptin on glucose uptake and decarboxylation Int J Obes Relat Metab Disord 1999 23: 75–82.

    Article  CAS  Google Scholar 

  256. 256

    Liu Y-L, Emilsson V, Cawthorne MA . Leptin inhibits glycogen synthesis in the isolated soleus muscle of obese (ob/ob) mice FEBS Lett 1997 411: 351–355.

    Article  CAS  Google Scholar 

  257. 257

    Berti L, Kellerer M, Capp E, Haring HU . Leptin stimulates glucose transport and glycogen synthesis in C2C12 myotubes; evidence for a PI3-kinase mediated effect Diabetologia 1997 40: 606–609.

    Article  CAS  Google Scholar 

  258. 258

    Berti L, Gammeltoft S . Leptin stimulates glucose uptake in C2C12 muscle cells by activation of ERK2 Mol Cell Endocrinol 1999 157: 121–130.

    Article  CAS  Google Scholar 

  259. 259

    Nowak K, Mackowiak P, Nogowski L, Szkudelski T, Malendowicz . Acute action on insulin blood level and liver insulin receptor in the rat Life Sci 1998 63: 1347–1352.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  260. 260

    Zhao AZ, Shinohara MM, Huang D, Schimizu M, Eldar-Finkelman H, Krebs EG, Beavo JA, Bornfeldt KE . Leptin induces insulin-like signaling that antagonises cAMP elevation by glucagon in hepatocytes J Biol Chem 2000 275: 11348–11354.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  261. 261

    Ahren B, Havel PJ . Leptin inhibits insulin secretion induced by cellular cAMP in pancreatic B cell line (INS-1 cells) Am J Physiol 1999 277: R959–R966.

    CAS  Google Scholar 

  262. 262

    Considine RV, Cooksey RC, Williams LB, Fawcett RL, Zhang P, Ambrosius WT, Whitfield RM, Jones R, Inman M, Huse J, McClain DA . Hexosamines regulate leptin production in human subcutaneous adipocytes J Clin Endocrinol Metab 2000 85: 3551–3556.

    CAS  PubMed  PubMed Central  Google Scholar 

  263. 263

    McClain DA . Hexosamines as mediators of nutrient sensing and regulation in diabetes J Diabetes Complications 2002 16: 72–80.

    Article  PubMed  PubMed Central  Google Scholar 

  264. 264

    Hawkins M, Barzilai N, Liu R, Hu M, Chen W, Rossetti L . Role of the glucosamine pathway in fat-induced insulin resistance J Clin Invest 1997 99: 2173–2182.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  265. 265

    Virkamaki A, Daniels MC, Hamalainen S, Utriainen T, McClain D, Yki-Jarvinen H . Activation of the hexosamine pathway by glucosamine in vivo induces insulin resistance in multiple insulin sensitive tissues Endocrinology 1997 138: 2501–2507.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  266. 266

    Zhang P, Klenk ES, Lazzaro MA, Williams LB, Considine RV . Hexosamines regulate leptin production in 3T3-L1 adipocytes through transcriptional mechanisms Endocrinology 2002 143: 99–106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  267. 267

    Ciaraldi TP, Carter L, Nikoulina S, Mudaliar S, McClain DA, Henry RR . Glucosamine regulation of glucose metabolism in cultured human skeletal muscle cells: divergent effects on glucose transport/phosphorylation and glycogen synthase in non-diabetic and type 2 diabetic subjects Endocrinology 1999 140: 3971–3980.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  268. 268

    McClain DA, Alexander T, Cooksey RC, Considine RV . Hexosamines stimulate leptin production in transgenic mice Endocrinology 2000 141: 1999–2002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  269. 269

    Rossetti L . Perspective: Hexosamines and nutrient sensing Endocrinology 2000 141: 1922–1925.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  270. 270

    Luiken JJFP, Dyck DJ, Han X-X, Tandon NN, Arumugam Y, Glatz JFC, Bonen A . Insulin induces the translocation of the fatty acid transporter FAT/CD36 to the plasma membrane Am J Physiol Endocrinol Metab 2002 282: E491–495.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  271. 271

    Berk PD, Zhou SL, Bradbury M, Stump D, Kiang CL, Isola LM . Regulated membrane transport of free fatty acids in adipocytes: role in obesity and non-insulin dependent diabetes mellitus Trans Am Clin Climatol Assoc 1996 108: 26–40 [discussion 41–43]

    Google Scholar 

  272. 272

    Zhou SL, Stump D, Sorrentino D, Potter BJ, Berk PD . Adipocyte differentiation of 3T3-L1 cells involves augmented expression of a 43-kDa plasma membrane fatty acid-binding protein J Biol Chem 1992 267: 14456–14461.

    CAS  PubMed  PubMed Central  Google Scholar 

  273. 273

    Randle PJ, Garland PB, Hales CN, Newsholme EA . The glucose-fatty acid cycle: its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus Lancet 1963 1: 785–789.

    Article  CAS  Google Scholar 

  274. 274

    Ceddia RB, William WN Jr, Curi R . The response of skeletal muscle to leptin Front Biosci 2001 6: D90–D97.

    Article  CAS  Google Scholar 

  275. 275

    Bryson JM, Phuyal JL, Swan V, Caterson ID . Leptin has acute effects on glucose and lipid metabolism in both lean and gold thioglucose-obese mice Am J Physiol Endocrinol Metab 1999 277: E417–E422.

    Article  CAS  Google Scholar 

  276. 276

    Slieker LJ, Sloop KW, Surface PL, Kriauciunas A, LaQuier F, Manetta J, Blue-Valleskey J, Stephens TW . Regulation of expression of ob mRNA and protein by glucocorticoids and cAMP J Biol Chem 1996 271: 5301–5304.

    Article  CAS  Google Scholar 

  277. 277

    Wabitsch M, Jensen PB, Blum WF, Christoffersen CT, Englaro P, Heinze E, Rascher W, Teller W, Tornqvist H, Hauner H . Insulin and cortisol promote leptin production in cultured human fat cells Diabetes 1996 45: 1435–1438.

    Article  CAS  Google Scholar 

  278. 278

    Tempel DL, Leibowitz SF . Adrenal steroid receptors: interactions with brain neuropeptide systems in relation to nutritient intake and metabolism J Neuroendocrinol 1994 6: 479–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  279. 279

    Tataranni P, Larsen DE, Snitker S, Young JB, Flatt JP, Ravussin E . Effects of glucocorticoids on energy metabolism and food intake in humans Am J Physiol 1996 271: E317–E325.

    CAS  PubMed  PubMed Central  Google Scholar 

  280. 280

    Dagogo-Jack S, Selke G, Melson AK, Newcomer JW . Robust leptin secretory responses to dectamethasone in obese subjects J Clin Endocrinol Metab 1997 82: 3230–3233.

    CAS  PubMed  PubMed Central  Google Scholar 

  281. 281

    Miell JP, Englaro P, Blum WF . Dexamethasone induces an acute and sustained rise in circulating leptin levels in normal human subjects Horm Metab Res 1996 28: 704–707.

    Article  CAS  Google Scholar 

  282. 282

    Solano JM, Jacobson L . Glucocorticoids reverse leptin effects on food intake and body fat in mice without increasing NPY mRNA Am J Physiol 1999 E708–E716.

  283. 283

    Kiess W, Englaro P, Hanitsch S, Rascher W, Attanasio A, Blum WF . High leptin concentrations in serum of very obese children are further stimulated by dexamethasone Horm Metab Res 1996 28: 708–710.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  284. 284

    De Vos P, Saladin R, Auwerx J, Staels B . Induction of ob gene expression by corticosteroids is accompanied by body weight loss and reduced food intake J Biol Chem 1995 270: 15958–15961.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  285. 285

    De Vos P, Lefebvre AM, Shrivo I, Fruchart JC, Auwerx J . Glucocorticoids induce the expression of the leptin gene through a non-classical mechanism of transcriptional activation Eur J Biochem 1998 253: 619–626.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  286. 286

    Schwartz MW, Baskin DG, Bukowski TR, Kuijper JL, Foster D, Lasser G, Prunkard DE, Porte DJ, Woods SC, Seeley RJ, Weigle DS . Specificity of leptin action on elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob/ob mice Diabetes 1996 45: 531–535.

    Article  CAS  Google Scholar 

  287. 287

    Considine RV . Weight regulation, leptin growth hormone Horm Res 1997 48: 116–121.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  288. 288

    Nyomba BLG, Johnson M, Berard L, Murphy LJ . Relationship between serum leptin and the insulin-like growth factor-I system in humans Metab Clin Exp 1999 48: 840–844.

    Article  CAS  Google Scholar 

  289. 289

    Carro E, Senaris R, Considine RV, Casanueva FF, Dieguez C . Regulation of in vivo growth hormone secretion by leptin Endocrinology 1997 138: 2203–2206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  290. 290

    Carro E, Senaris RM, Seoane LM, Frohman LA, Arimura A, Casanueva FF, Dieguez C . Role of growth hormone (GH)-releasing hormone and somatostatin on leptin-induced GH secretion Neuroendocrinology 1999 69: 3–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  291. 291

    Tannenbaum GS, Gurd W, Laponte M . Leptin is a potent stimulator of spontaneous pulsatile growth hormone (GH) secretion and the GH response to GH-releasing hormone Endocrinology 1998 139: 3871–3875.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  292. 292

    Dyer CJ, Simmons JM, Matteri L, Keisler DH . Leptin receptor mRNA is expressed in ewe anterior pituitary and adipose tissue and is differentially expressed in hypothalamic regions of well-fed and feed-restricted ewes Domest Anim Endocrinol 1997 14: 119–128.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  293. 293

    Roh SH, Clarke IJ, Xu RW, Goding JW, Loneragan K, Chen C . The in vitro effect of leptin on basal and growth hormone-releasing secretion from the ovine pituitary gland Neuroendocrinology 1998 68: 361–364.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  294. 294

    Williams LM, Adam CL, Mercer JG, Moar KM, Slater D, Hunter L, Findlay PA, Hoggard N . Leptin receptor and neuropeptide Y gene expression in the sheep brain J Neuroendocrinol 1999 11: 165–169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  295. 295

    Barb CR, Yan X, Azain MJ, Kraeling RR, Rampacek GB, Ramsay TG . Recombinant porcine leptin reduces feed intake and stimulates growth hormone secretion in swine Domest Anim Endocrinol 1998 15: 77–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  296. 296

    Houseknecht KL, Portocarrero CP, Lamenager R, Spurlock ME . Growth hormone regulates leptin gene expresion in bovine adipose tissue: correlation with adipose IGF-1 expression J Endocrinol 2000 164: 51–57.

    Article  CAS  Google Scholar 

  297. 297

    Rauch F, Westermann F, Englaro P, Blum WF, Schonau E . Serum leptin is suppressed by growth hormone therapy in growth-hormone-deficient children Horm Res 1998 50: 18–21.

    CAS  PubMed  Google Scholar 

  298. 298

    Isozaki O, Tsushima T, Miyakawa M, Nozoe Y, Demura H, Seki H . Growth hormone directly inhibits leptin gene expression in viscelar fat tissue in fatty Zucker rats J Endocrinol 1999 161: 511–516.

    Article  CAS  Google Scholar 

  299. 299

    Chen XL, Hausman DB, Dean RG, Hausman HJ . Hormonal regulation of leptin mRNA expression and preadipcyte recruitment and differentiation in porcine primary cultures and S-V cells Obes Res 1998 6: 164–172.

    Article  CAS  Google Scholar 

  300. 300

    Wabitsch M, Blum WF, Muche R, Braun M, Hube F, Rascher W, Heinze E, Teller W, Hauner H . Contribution of androgens to the gender difference in leptin production in obese children and adolescents J Clin Invest 1997 100: 808–813.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  301. 301

    Boni-Schnetzler M, Gosteli-Peter MA, Moritz W, Froesch ER, Zapf J . Reduced ob mRNA in hypophysectomised rats is not restored by growth hormone (GH), but further suppressed by exogenously administered insulin-like growth factor (IGF) 1 Biochem Biophys Res Commun 1996 225: 296–301.

    Article  CAS  Google Scholar 

  302. 302

    Boni-Schnetzler M, Hauri C, Zapf J . Leptin is suppressed during infusion of recombinant human insulin-like growth factor I (rhIGFI) in normal rats Diabetologia 1999 42: 160–166.

    Article  CAS  Google Scholar 

  303. 303

    Janik JE, Cutri BD, Considine RV, Rager HC, Powers GC, Alvord WG, Smith JW II, Gause BL, Kopp WC . Interleukin 1a increases serum leptin concentrations in humans J Clin Endocrinol Metab 1997 82: 3084–3086.

    CAS  PubMed  Google Scholar 

  304. 304

    Zumbach MS, Boehme MWJ, Wahl P, Stremmel W, Ziegler R, Nawroth PP . Tumor necrosis factor increases serum leptin levels in humans J Clin Endocrinol Metab 1997 82: 4080–4082.

    Article  CAS  Google Scholar 

  305. 305

    Matarese G . Leptin and the immune system: how nutritional status influences the immune response Eur Cytokine Netw 2000 11: 7–13.

    CAS  PubMed  Google Scholar 

  306. 306

    Mantzoros CS, Moschos S, Avramopoulos L, Kaklamani V, Liolios A, Doulgerakis DE, Griveas I, Katsilambros N, Flier JS . Leptin concentrations in relation to body mass index and the tumour necrosis factor—a system in humans J Clin Endocrinol Metab 1997 82: 3408–3413.

    CAS  Google Scholar 

  307. 307

    Grunfeld C, Zhao C, Fuller J, Pollock A, Moser A, Friedman J, Feingold KR . Endotoxin and cytokines induce expression of leptin, the ob gene product, in hamster J Clin Invest 1996 97: 2152–2157.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  308. 308

    Langhans W, Hrupka B . Interleukins and tumor necrosis factor as inhibitors of food intake Neuropeptides 1999 33: 415–424.

    Article  CAS  Google Scholar 

  309. 309

    Mantzoros CS, Moschos SJ . Leptin: in search of role(s) in human physiology and pathophysiology Clin Endocrinol 1998 49: 551–567.

    Article  CAS  Google Scholar 

  310. 310

    Shintani M, Nishimura H, Yonemitsu S, Masuzaki H, Ogawa Y, Hosoda K, Inoue G, Yoshimasa Y, Nakao K . Downregulation of leptin by free fatty acids in rat adipocytes: effects of triascin C, palmitate, and 2-bromopalmitate Metabolism 2000 49: 326–330.

    Article  CAS  Google Scholar 

  311. 311

    Fain JN, Coronel EC, Beauchamp MJBS . Expression of leptin and β2-adrenergic receptors in rat adipose tissue in altered thyroid states Biochem J 1997 322: 145–150.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  312. 312

    Yoshida T, Monkawa T, Hayashi M, Saruta T . Regulation of expression of leptin mRNA and secretion of leptin by thyroid hormone in 3T3-L1 adipocyte Biochem Biophys Res Commun 1997 232: 822–826.

    Article  CAS  Google Scholar 

  313. 313

    Mantzoros CS, Rosen HN, Greenspan SL, Flier JS, Moses AC . Short-term hyperthyroidism has no effect on leptin levels in man J Clin Endocrinol Metab 1997 82: 497–499.

    CAS  Google Scholar 

  314. 314

    Sesmilo G, Casamitjana R, Halperin I, Gomis R, Vilardell E . Role of thyroid hormones on serum leptin levels Eur J Endocrinol 1998 139: 428–430.

    Article  CAS  Google Scholar 

  315. 315

    Frederich RC, Hamann A, Anderson S, Lollmann B, Lowell BB, Flier JS . Leptin levels reflect body lipid content in mice; evidence for diet-induced resistance to leptin action Nat Med 1995 1: 1311–1314.

    Article  CAS  Google Scholar 

  316. 316

    Iida M, Murakami T, Yamada M, Sei M, Kuwajima M, Mizuno A, Noma Y, Aono T, Shima K . Hyperleptinaemia in chronic renal failure Horm Metab Res 1996 28: 724–727.

    Article  CAS  Google Scholar 

  317. 317

    Merabet E, Dagogo-Jack S, Coyne DW, Klein S, Santiago JV, Hmiel SP, Landt M . Increased plasma leptin concentration in end-stage renal disease J Clin Endocrinol Metab 1997 82: 847–850.

    CAS  PubMed  Google Scholar 

  318. 318

    Leroy P, Dessolin S, Villageois P, Moon BM, Friedman JM, Ailhaud G, Dani C . Expression of ob gene in adipose cells: regulation by insulin J Biol Chem 1996 271: 2365–2368.

    Article  CAS  Google Scholar 

  319. 319

    Kolaczynski JW, Golstein BJ, Considine RV . Dexamethasone, ob gene and leptin in humans: effect of exogenous hyperleptinaemia J Clin Endocrinol Metab 1997 82: 3895–3897.

    CAS  Google Scholar 

  320. 320

    Papaspyrou-Rao S, Schneider SH, Petersen RN, Fried SK . Dexamethosone increases leptin expression in humans in vivo J Clin Endocrinol Metab 1997 82: 1635–1637.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  321. 321

    Zhang HH, Kumara S, Barnett AH, Eggo MC . Tumor necrosis factor-α exerts dual effect on human adipose leptin synthesis and release Mol Cell Endocrinol 2000 159: 79–88.

    Article  CAS  Google Scholar 

  322. 322

    Qian H, Barb CR, Compton MM, Hausman GJ, Azain MJ, Kraeling RR, Bailie CA . Leptin mRNA expression and serum leptin concentrations as influenced by age, weight and estradiol in pigs Domest Anim Endocrinol 1999 16: 135–143.

    Article  CAS  Google Scholar 

  323. 323

    Ghorbani M, Himms-Hagen J . Treatment with CL 316,242 a β3-adrenoceptor agonist, reduces serum leptin in rats with aging-associated obestiy but not in Zucker rats with genetic (fa.fa) obesity Int J Obes Relat Metab Disord 1998 22: 63–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  324. 324

    Gettys TW, Harkness PJ, Watson PM . The β3-adrenergic receptor inhibits insulin-stimulated leptin secretion from isolated rat adipocytes Endocrinology 1996 137: 4054–4057.

    Article  CAS  Google Scholar 

  325. 325

    Hodge AM, Westerman RA, de Courten MP, Collier GR, Zimmet PZ . Is leptin sensitivity the link between smoking cessation and weight gain Int J Obes Relat Metab Disord 1997 21: 50–53.

    Article  CAS  Google Scholar 

  326. 326

    Wei M, Stern MP, Haffner SM . Serum leptin levels in Mexican Americans and non-Hispanic whites: association with body mass index and cigarette smoking Ann Epidemiol 1997 7: 81–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  327. 327

    Miyata G, Meguid MM . Is leptin involved in the acute anorectic effect of nicotine? Nutrition 2000 16: 141–142.

    Article  CAS  Google Scholar 

  328. 328

    Pallett AL, Morton NM, Cawthorne MA, Emilsson V . Leptin inhibits insulin secretion and reduces insulin mRNA levels in rat isolated pancreatic cells Biochem Biophys Res Commun 1997 238: 267–270.

    Article  CAS  Google Scholar 

  329. 329

    Ishida K, Murakami T, Yamada M, Sei M, Kuwajima M, Shima K . Leptin suppresses basal insulin secretion from rat pancreatic islets Regul Peptides 1997 70: 179–182.

    Article  CAS  Google Scholar 

  330. 330

    Roduit R, Thorens B . Inhibition of glucose-induced insulin secretion by long-term preexposure of pancreatic islets to leptin FEBS Lett 1997 425: 179–182.

    Article  Google Scholar 

  331. 331

    Glick ME . Fat, bodyweight regulated by newly discovered hormone 1996 URL Date accessed March 26, 1998

Download references


This work was supported in part by the Australian Research Council.