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.

Body weight is regulated by the brain: a link between feeding and emotion


Regulated energy homeostasis is fundamental for maintaining life. Unfortunately, this critical process is affected in a high number of mentally ill patients. Eating disorders such as anorexia nervosa are prevalent in modern societies. Impaired appetite and weight loss are common in patients with depression. In addition, the use of neuroleptics frequently produces obesity and diabetes mellitus. However, the neural mechanisms underlying the pathophysiology of these behavioral and metabolic conditions are largely unknown. In this review, we first concentrate on the established brain machinery of food intake and body weight, especially on the melanocortin and neuropeptide Y (NPY) systems as illustration. These systems play a critical role in receiving and processing critical peripheral metabolic cues such as leptin and ghrelin. It is also notable that both systems modulate emotion and motivated behavior as well. Secondly, we discuss the significance and potential promise of multidisciplinary molecular and neuroanatomic techniques that will likely increase the understanding of brain circuitries coordinating energy homeostasis and emotion. Finally, we introduce several lines of evidence suggesting a link between the melanocortin/NPY systems and several neurotransmitter systems on which many of the psychotropic agents exert their influence.


Maintaining energy homeostasis is fundamental for survival. However, obesity due to over-nutrition is an increasing worldwide public health problem.1 In psychiatric practice, on the other hand, impaired appetite is one of the crucial issues. Anorexia and weight loss are common, for example, in patients suffering from depression. Eating disorders are medically intractable and life threatening. In addition, the so-called ‘atypical’ antipsychotic agents, currently and widely used to treat psychoses, often induce hyperphagia, obesity, and diabetes mellitus.2,3,4

In the past decade, fortunately, there has been remarkable progress in understanding the molecular mechanisms of food intake and body weight. This is due in large part to increased research activity towards combating the rising incidences of obesity and associated metabolic disorders. As a result, it is now established that the central nervous system (CNS) senses and processes peripheral metabolic cues including leptin5 and ghrelin,6,7 resulting in coordinated energy homeostasis. However, the pathophysiology of the disequilibrium between energy intake and expenditure in psychiatric disorders remains largely unknown. Nevertheless, evidence suggests that several CNS systems regulating energy balance may be dysregulated in patients with mental illnesses, for example, eating disorders, and drug addiction.8,9,10,11,12,13,14

In the current review, we will illustrate the neuroanatomic and molecular genetic aspects of the melanocortin and neuropeptide Y (NPY) systems residing in the CNS downstream of leptin and ghrelin, to discuss the neural bases of feeding, metabolism, and emotion. Additionally, we point the reader to recent reviews for other critical CNS systems regulating food intake and body weight, including those by Barsh and Schwartz,15 Elmquist et al,16 Friedman and Halaas,17 Friedman,1 Grill and Kaplan,18 O'Rahilly et al,19 Saper et al,20 Sawchenko,21 Schwartz et al,22 Spiegelman and Flier,23 van den Pol,24 Woods et al,25 Zigman and Elmquist.26

Anatomic and molecular bases for metabolic/autonomic control of body weight

The classic ‘dual-center’ model has been modified

A primary CNS site controlling food intake and body weight is the hypothalamus. The underpinnings of this view are largely due to classic descriptions that date back to Bramwell27 and Fröhlich.28 These are based on clinical observations in many patients with pituitary tumors who developed excessive fat mass and hypogonadism (see Elmquist et al16 for discussion). Whether this syndrome resulted from the tumor per se or its intrusion into the hypothalamus was controversial at that time. Subsequently, the resection of the dog pituitary gland without hypothalamic damage was demonstrated not to produce obesity by Aschner.29

In 1940, Hetherington and Ranson30 performed a seminal study to further investigate the role of the hypothalamus in maintaining body weight homeostasis, in which bilateral and extensive hypothalamic lesions were made. Subsequent studies including those by Anand and Brobeck placed smaller lesions in the lateral hypothalamus.31 Such a sequence of attempts led to the ‘dual-center’ model that defines the lateral hypothalamus as a ‘feeding’ center, and the ventromedial hypothalamic nucleus as a ‘satiety’ center (Figure 1). Moreover, data developed over ensuing years challenged components of this model.32 However, the anatomic substrate underlying coordinated food intake control still remained obscure, as scientists in the field lacked key tools to unravel this complex hypothalamic puzzle. Nevertheless, several molecular discoveries in 1990s, especially identification of leptin5 and melanocortin receptors33,34,35 implicated other hypothalamic and extra-hypothalamic sites in regulating energy homeostasis.

Figure 1

Schematic illustration showing the arcuate nucleus of the hypothalamus (Arc), a primary site of leptin action, which is located bilaterally at the median and ventralmost region of the hypothalamus. (a) Lateral view of the rat brain. (b) Coronal section of the rat brain at a rostral-to-caudal level shown by a vertical line in (a). The Arc is gray-colored. CeA, central nucleus of the amygdala; LHA, lateral hypothalamic area; ME, medial eminence; VMH, ventromedial nucleus of the hypothalamus.

Leptin as an antiobesity hormone

A fundamental hormone was discovered in 1994 and named ‘leptin’ for a Greek root ‘leptos’ meaning thin.5 Leptin is produced mainly by adipose tissue, circulates, and reaches the CNS.5,17 Leptin inhibits ingestive behavior and stimulates energy expenditure by normalizing reduced sympathetic activity, thermogenesis, oxygen consumption, and locomotor activity. Accordingly, mutations in the ob gene encoding leptin produce hyperphagia and morbid obesity in mice (ob/ob mice)5,17 and humans.36,37,38,39,40 Similar to states of starvation, leptin deficiency also leads to deficits in the reproductive, thyroid, and adrenal axes.41,42,43,44 Moreover, exogenous leptin corrects these manifestations in leptin-deficient mice45,46,47,48 and humans.38,40 Finally, the significance of leptin in adaptive endocrine and metabolic responses to fasting was demonstrated in healthy subjects.49 In this study, a replacement dose of recombinant human leptin administered during fasting prevented the starvation-induced changes of endocrine axes.

The leptin receptor (Ob-R) belongs to the class-1 cytokine receptor superfamily.50,51 The Ob-R has a single transmembrane spanning domain and functions via the JAK-STAT pathway.51,52 Thus far, splice variants of Ob-R mRNA encoding six isoforms have been identified, and only the long form (Ob-Rb) has intracellular signaling motifs of leptin.51 Consequently, the db/db mice lacking Ob-Rbs and ob/ob mice exhibit an almost identical obesity phenotype.53,54,55 Moreover, the phenotype in db/db mice is not corrected by exogenous leptin.53,54,55 Mutations in the human Ob-Rb also produce morbid obesity.56 Importantly, the gene expression of the Ob-Rb is evident in the mediobasal hypothalamic sites including the arcuate nucleus.57,58,59,60 The leptin receptor has also been identified in the human brain.61

The arcuate nucleus: a site of leptin action

Evidence indicates that leptin directly acts on the arcuate nucleus of the hypothalamus (Arc; Figure 1): (i) Radiolabeled leptin binds highly to the mediobasal hypothalamic region involving the Arc;62 (ii) cells expressing Ob-Rb mRNA populate in the Arc and several other brain sites;57,58,59,60,61 (iii) leptin induces the expression of an immediate early gene, c-fos (a marker of neuronal activation)63,64,65,66 and suppressor of cytokine signaling-3 (SOCS-3, a cellular marker of direct leptin action)65,66,67 in the Arc; (iv) Arc cells are directly hyperpolarized and depolarized by leptin.68,69

The central melanocortin system mediates leptin action

The term ‘melanocortin’ indicates a series of peptides that are cleaved from pro-opiomelanocortin (POMC).70 One of the POMC products, adrenocorticotropic hormone, is secreted by the anterior pituitary and stimulates adrenocortical cells. In the CNS, POMC neurons are localized in two sites in rodents and humans, the Arc (Figure 2a, c)71,72 and the nucleus of the solitary tract (NTS).70 Currently, considerable attention has focused on another POMC product, α-melanocyte-stimulating hormone (α-MSH). Accumulating evidence strongly suggests that α-MSH is a critical regulator of food intake, body weight, and glucose homeostasis, and that α-MSH mediates several of the biological effects of leptin. For example, most of POMC-expressing Arc neurons coexpress Ob-Rb mRNA.73 Leptin increases POMC mRNA in the Arc74 and induces the expression of c-fos and SOCS-3 mRNA in Arc POMC neurons.65,66 In addition, POMC mRNA in the Arc is markedly reduced in leptin-deficient ob/ob mice as well as in fasted rodents (when leptin levels rapidly fall).75,76 The decrease in POMC expression is prevented by leptin administration.74,75,76 Finally, leptin directly depolarizes POMC neurons.69

Figure 2

A series of photomicrographs showing α-MSH-immunoreactive (α-MSH-IR) neurons in the human hypothalamus (modified from Elias et al72 with permission). (a) α-MSH-IR neurons are localized in the arcuate nucleus of the hypothalamus, especially in the lateral region of this nucleus. (b) α-MSH-IR fibers are densely distributed in the perifornical region of the LHA. (c) Higher magnification of a boxed area in (a). (d) Higher power view of a boxed area in (b). fx, fornix; 3v, third ventricle. Scale bars=200 μm in (a) (also applied to (b)), 100 μm in (c); 50 μm in (d).

Of importance, α-MSH acts as an agonist for the melanocortin-4 receptor (MC4-R),70,77,78 a Gs-protein-coupled receptor distributed in the CNS.35,79,80 The MC4-R is an established regulator of food intake and body weight, and blockade of this receptor causes obesity.77,78 An overeating/obesity syndrome is produced, for example, by targeted deletion of the MC4-R81 and by mutations in the human MC4-R.82,83,84,85,86,87,88 The importance of MC4-Rs in humans is highlighted by an estimate that 3–5% of the population suffering from morbid obesity may result from MC4-R mutations.89 Another important piece of data supporting this model is that POMC-deficient mice and humans display similar obesity phenotypes.90,91

A unique component of the melanocortin regulatory system is an endogenous MC4-R antagonist, agouti-related protein (AgRP).92,93,94 Interestingly, AgRP is produced exclusively in the Arc in rodents, monkeys, and humans.71,72,93,94,95,96,97 Alpha-MSH-producing (Figure 2a, c) and AgRP-producing (Figure 3c, e) neurons are distributed and segregated in the medial and lateral regions of the Arc, respectively.71,72 In line with the results from the aforementioned molecular genetic studies on the MC4-R, transgenic overexpression of AgRP produces obesity.93,94 In contrast to POMC mRNA, AgRP mRNA is increased in leptin-deficient ob/ob mice and leptin-resistant db/db mice, and during periods of fasting when leptin levels rapidly fall.97,98 Finally, it is important to note that AgRP is coexpressed with NPY in the Arc (see the section ‘the NPY/Y1-receptor system’).71,98

Figure 3

A series of photomicrographs showing AgRP-immunoreactive (AgRP-IR) axons and neurons in the human hypothalamus (modified from Elias et al72 with permission. (a, b) Low-power photomicrographs demonstrating AgRP-IR neurons localized in the rostral (a) and caudal (b) regions of the arcuate nucleus. In (b), AgRP-IR fibers are observed to stream dorsally out of this nucleus. A boxed area in (b) is magnified in (c), and a boxed area in (c) is further magnified in (e). Arrows indicate AgRP-IR cells. (d, f) AgRP-IR axons in the perifornical region of the LHA. A boxed area in (d) is magnified in (f). Scale bars=2 mm in (b) (also applied to (a)), 200 μm in (d) (also applied to (c)), 100 μm in (f) (also applied to (e)). ARC, arcuate nucleus; fx, fornix; ot, optic tract; 3v, third ventricle.

A popular current model suggests that leptin stimulates melanocortin signaling, resulting in decreased energy intake and increased energy expenditure, whereas opposite effects by AgRP are inhibited by leptin (Figure 4). Such an interrelation between leptin and melanocortins is supported by pharmacological evidence demonstrating that leptin-induced anorexia can be attenuated by coadministration of MC4-R antagonists,99 as can the effects of leptin on heat production.100,101 Brown adipose tissue (BAT), located at the interscapular region, regulates body temperature and diet-induced thermogenesis, and is therefore critical in energy expenditure.100,101 Leptin increases uncoupling protein-1 (UCP-1) via the sympathetic nervous system, which is produced by BAT in the process of thermogenesis. MC4-R antagonism suppresses the expression of UCP-1 mRNA by leptin.102

Figure 4

Summary diagram showing the central melanocortin system that counterpoises the NPY/Y1-R system to contribute to coordinated emotion and motivated behavior. These systems mediate peripheral metabolic cues such as leptin and ghrelin. Arc, arcuate nucleus of the hypothalamus; CeA, central nucleus of the amygdala; PVH, paraventricular nucleus of the hypothalamus, 3v, third ventricle.

Recently, our laboratory provided evidence concerning the functional importance of leptin action on POMC neurons by deleting leptin receptors specifically from this cellular population in mice.103 Notably, mice lacking leptin signaling in POMC neurons display mild obesity, hyperleptinemia, and altered expression levels of hypothalamic peptides. The significance of this study will be discussed in a later section.

Moreover, Cowley et al69 substantiated that NPY/AgRP neurons inhibited POMC neurons in the Arc. By using a strain of transgenic mice expressing green fluorescent protein (GFP) under the control of the POMC promoter, the authors demonstrated that leptin increased the frequency of action potentials in POMC neurons by two mechanisms: depolarization through a cation channel; and disinhibition by inhibiting NPY/AgRP neurons that contain γ-amino butyric acid (GABA) and tonically inhibit POMC neurons.

Apparently, MC4-R-mediated melanocortin signaling is one of the targets of leptin action. Clearly, however, several other CNS systems are also involved in leptin-signaling brain systems. Indeed, it is now clear that leptin-independent melanocortinergic CNS pathways exist.103,104,105 Nonetheless, it is clearly established that α-MSH acting through MC4-Rs is a fundamental regulator of coordinated energy homeostasis. Key questions that remain include what metabolic and neural cues, beside leptin, drive the melanocortinergic neural circuits. The MC4-R-positive sites that function to suppress excessive weight gain are also to be identified.

Melanocortin neurons project to MC4-R-positive CNS sites involved in regulating food intake and body weight

Despite the very limited distribution of POMC and AgRP cells bodies,71,72,106 their axonal projections are widespread across the CNS. Several immunohistochemical studies have demonstrated CNS distributions of α-MSH-positive and AgRP-positive axons in rodents, monkeys, and humans.71,72,96,106,107 The CNS localization of MC4-R has also been examined in the rat and mouse.35,79,80 For this purpose, radioisotopic in situ hybridization histochemistry has been applied, as high-affinity antibodies against MC4-R protein are unavailable. Notably, nearly all the CNS sites thought to be critical for energy balance regulation display overlapping distributions of melanocortinergic axons and MC4-R mRNA in rodents.35,79,80 Some of these representative sites are discussed below.

1. Paraventricular nucleus of the hypothalamus (PVH): Lesions of the PVH cause hyperphagia in the rat, indicating that a regulator of food intake resides in this nucleus.32 Several lines of evidence nominate subsets of MC4-R-positive PVH neurons as candidates for the regulator (Figure 5). For example, microinjections of a synthetic MC4-R agonist MT-II into the rat PVH inhibit food intake, whereas PVH administration of a synthetic MC4-R antagonist SHU9119 exerts opposite effects.108,109 In addition, levels of POMC mRNA in the Arc and α-MSH in the PVH are lower in genetically obese Zucker rats that have a mutant Ob-Rb isoforms, than are those in lean rats, suggesting a role of the melanocortinergic Arc-PVH projection in energy homeostasis regulation.110

Figure 5

(a) Radioisotopic in situ hybridization demonstrates MC4-R mRNA expression (white silver grains) in the PVH in the rat (modified from Kishi et al,79 with permission). The expression is evident especially in the medial parvicellular division (mp) that contains hypophysiotropic neurons, as well as in the dorsal parvicellular (dp) and ventral parvicellular (vp) divisions that contain neurons projecting to autonomic preganglionic neurons in the medulla and spinal cord. (b) Lateral view of the rat brain. (c) Coronal section of the rat brain at a rostral-to-caudal level shown by a vertical line in b. A boxed area in (c) indicates the location of the PVH in the coronal section. pm, posterior magnocellular division; 3v, third ventricle.

In the rat, the PVH is composed of parvicellular and magnocellular divisions, and the former is further divided into several subdivisions (Figure 5).111,112,113 These divisions and subdivisions can be readily and cytoarchitectonically distinguished by Nissl staining. In the rat, neurons innervating parasympathetic and sympathetic preganglionic neurons are located in the dorsal, ventral, and lateral parvicellular subdivisions, while hypophysiotropic neurons are characteristically distributed in the medial parvicellular subdivision.111,112,113 Relevant to current discussions, these subdivisions display overlapping distributions of MC4-R mRNA and axon terminals containing α-MSH or AgRP. First, a population of MC4-R-positive PVH neurons may relay inputs from leptin-responsive α-MSH neurons in the Arc to autonomic preganglionic neurons, supporting the implication of melanocortins and MC4-Rs in autonomic regulation.35,79,80

Secondly, Lu and colleagues provided evidence that melanocortins regulate the hypothalamic–pituitary–adrenal axis via MC4-R-positive PVH neurons.114 The authors demonstrated a subset of PVH cells that coexpresses MC4-R and corticotropin-releasing hormone (CRH) mRNAs. Centrally administered MT-II (a melanocortin receptor agonist) rapidly induced CRH gene transcription, and MT-II-induced increase in plasma corticosterone levels was suppressed by a selective MC4-R antagonist HS014.

Thirdly, evidence supporting the role of leptin and melanocortin action on the thyroid axis is also increasing. For example, the PVH contains a number of cells coexpressing pro-thyrotropin-releasing hormone (proTRH) and MC4-R mRNAs.115 Transcriptional control of the TRH gene is regulated by leptin and melanocortin signaling.115 An electron-microscopic study demonstrated α-MSH-positive terminals that synapse on TRH-producing PVH neurons.116 Recently, the effect of AgRP on the thyroid axis was examined in wild-type (WT) and MC4-R-deficient mice.117 As a result, centrally administered AgRP suppressed circulating levels of thyroxine and inhibited proTRH mRNA expression in the PVH of WT mice, whereas these effects were not observed in mice lacking MC4-Rs.

Taken together, once again, these observations suggest that subsets of PVH neurons expressing MC4-Rs may mediate leptin action to control the autonomic and neuroendocrine systems responsible for maintaining energy equilibrium.

2. Lateral hypothalamic area (LHA): Alpha-MSH-positive and AgRP-positive fibers densely terminate in LHA, especially in the perifornical region (Figures 2b, d and 3d, f).71,72 Notably, subsets of these neurons providing these inputs are leptin-responsive.66 As noted, the LHA has long been considered to play an essential role in regulating food intake. Recently, two orexigenic peptides produced by discrete populations of LHA neurons in rodents and humans refocused attention on the LHA: melanin-concentrating hormone (MCH)118,119,120 and the orexins (ORX, also called hypocretins).121 One of the unique features of both sets of neurons is that they provide monosynaptic projections to a variety of CNS sites including the cerebral cortex, amygdala, and the spinal cord.118,119,120,121 Similarly, a broad distribution of the receptors that bind these peptides has also been reported.122,123,124,125

MCH stimulates feeding behavior when administered centrally.119 Levels of MCH mRNA are increased during fasting when leptin levels rapidly fall. Importantly, mice lacking MCH are hypophagic and lean despite lowered levels of POMC mRNA and leptin,120 whereas mice overexpressing MCH are obese and hyperleptinemic.126 More importantly, mice lacking both MCH and Ob-Rbs display a significant reduction in fat mass, compared with ob/ob mice.127 Taken together, it is persuasive that MCH signaling is downstream of leptin.

ORX knockout mice exhibit deficits in sleep/wake control and a narcolepsy-like phenotype.128 Dogs lacking the ORX-2 receptor are also narcoleptic.129 Notably, a very high percentage of narcoleptic patients are ORX-deficient.130,131 Like MCH, ORX exerts a stimulatory effect on food intake, although the effect on consolidating sleep/wake states is more profound and clearly established.121,128,129,130,131,132 Therefore, it is conceivable that ORX may maintain arousal and locomotor activity, both of which are essential for food-seeking behavior following periods of fasting.133 Finally, as noted, the distribution of MCH- and ORX-positive terminals is widespread not only in subcortical regions but also in cortical regions.118,119,120,121,133 This unique hypothalamo-cortical innervation pattern implicates both peptides in regulating complex cognitive function. This concept is worth noting when attempting to link sites regulating body weight homeostasis and those involved in several psychiatric disorders. Clearly, feeding represents a fundamental goal-oriented behavior.

Based on the aforementioned neuroanatomic data,71,72 one might expect that MCH and/or ORX neurons coexpress MC4-Rs. However, the levels of MC4-R mRNA expression in the rodent LHA are relatively low, and only a few MC4-R-positive cells are scattered in the perifornical region.79,80 In addition, an electrophysiological study reported no detectable effect of synthetic MC4-R/MC3-R ligands on membrane potentials or firing rate in MCH cells.134 On the other hand, a presynaptic action of α-MSH on PVH-projecting GABAergic neurons has been demonstrated electrophysiologically.135 Thus, whether endogenous melanocortins act presynaptically on MC4-Rs expressed on axon terminals that synapse on MCH and/or ORX neurons deserves future analysis.

3. Central nucleus of the amygdala (CeA): The amygdala has received relatively little attention in the field of obesity research; however, this limbic site is potentially important in regulating food intake. For example, amygdala lesions produce hyperphagia and obesity in rodents.136 Bilateral microinjections of a selective MC4-R antagonist HS014 into the CeA increase food intake.137 Within the CeA (Figure 1b), a subnucleus of the amygdala, α-MSH- or AgRP-positive axons are accumulated preferentially in the medial region107 in which MC4-R-positive cells populate.35,79,80 Thus, although relatively understudied, the CeA represents a potentially important site of melanocortin action.

4. Intermediolateral nucleus of the spinal cord (IML): Subsets of Arc POMC neurons project to the IML in which sympathetic preganglionic cholinergic neurons113 and cells expressing MC4-R mRNA reside.79 These MC4-R-positive cells are sympathetic preganglionic neurons, as they coexpress choline acetyltransferase mRNA.79 Notably, a population of Arc POMC neurons projecting to the IML is leptin-responsive.65 Additionally, cholinergic cells in the dorsal motor nucleus of the vagus (ie, parasympathetic preganglionic neurons) also express MC4-R mRNA.79 These findings support a critical role of MC4-Rs in autonomic regulation, as did the expression of MC4-R mRNA in the PVH. Put another way, this model predicts that both the direct Arc-IML and indirect Arc-PVH-IML pathways likely contribute to the autonomic and metabolic effects of melanocortin receptor agonists.138,139,140,141

Combinations of genetic and anatomic approaches to characterize leptin–melanocortin signaling CNS circuits

1. Deletion of leptin receptors specifically from POMC neurons: As stressed above, a large body of evidence indicates that POMC neurons in the Arc mediate leptin action. However, Ob-Rbs are not localized exclusively in the Arc. As noted, leptin-independent melanocortinergic pathways also exist.103,104,105 Therefore, our laboratory has recently tested the extent to which Arc POMC neurons contribute to CNS leptin signaling by using the Cre/loxP system.103 First, transgenic mice expressing Cre in POMC neurons (POMC-Cre mice) were generated by using a POMC bacterial artificial chromosome. Subsequently, POMC-Cre mice were crossed with mice bearing the lox-modified leptin receptor allele (POMC-Cre, Leprflox/flox mice). This cross successfully deleted leptin receptors specifically from POMC neurons, resulting in increased fat mass, hyperleptinemia, and altered hypothalamic peptide levels. However, the loss of leptin receptors on POMC neurons did not significantly affect food intake and energy expenditure.

These observations indicate that Ob-Rb expression by POMC neurons is required for normal body weight homeostasis and that leptin action on neurons other than POMC neurons contributes to the varied effects of this hormone. Deletion of leptin receptors in other brain sites (alone and in combination with POMC deletion) may help to unravel this complex web of circuitries. This attempt will include the use of other transgenic mice expressing Cre in selected neuronal populations, as well as of stereotaxic injections of an adenoassociated viral vector that drive the Cre expression.142 Clearly, these combined approaches will continue to evolve strategies to survey the physiologically important CNS circuitries mediating the effects of key metabolic signals including leptin, glucose, and ghrelin.

2. Labeling of MC4-R-positive cells with GFP: The melanocortinergic CNS network has hitherto been difficult to trace, as sensitive and specific antibodies against the MC4-R protein are unavailable. Therefore, it remains unknown whether α-MSH- and/or AgRP-positive terminals synapse on MC4-R-positive cell bodies, dendrites, or axon terminals. The brain sites downstream of neurons expressing MC4-Rs are also to be determined. Moreover, relevant research is behind in identifying chemical profiles of MC4-R-positive neurons (ie, potential neurotransmitters by which melanocortinergic pathways are engaged), with only a few notable exceptions such as TRH-producing or CRH-producing PVH cells,114,115 and cholinergic autonomic preganglionic cells in the DMV and IML.79,80

To help address these issues, we recently validated a transgenic mouse line expressing GFP under the control of the MC4-R promoter, which had been generated by Friedman and coworkers.80 For this purpose, we confirmed that the brain distribution patterns of GFP-immunoreactive cells are reconciled with those of cells expressing MC4-R mRNA in WT mice (Figure 6), that MC4-R mRNA is expressed on nearly all the GFP-immunoreactive cells, and that MT-II, a synthetic MC3-R/MC4-R agonist, depolarizes GFP-positive cells. This animal model will facilitate the demonstration of melanocortinergic axon terminals that make synaptic contacts with MC4-R-positive cells using electron microscopy. Moreover, the projection patterns of MC4-R-positive neurons can be determined by using retrograde tract tracing, an established neuroanatomic technique that is based on the ability of axon terminals to take up substances (eg, cholera toxin B subunit and fluorogold) from extracellular space and transport them back to cell bodies. This mouse model will also promote the identification of the chemical phenotypes of cells expressing MC4-Rs. In this model, for example, we identified oxytocin-positive, GABAergic, and CRH-positive GFP cells, respectively, in the PVH, LHA, and in the CeA by using a combination of immunohistochemistry for GFP and in situ hybridization histochemistry.80 Consistent with the electrophysiological evidence introduced earlier,134 no GFP cells coexpressed MCH mRNA in the LHA. ORX cells were also MC4-R-negative.

Figure 6

(a–g) A series of line drawings arranged rostrocaudally showing the distribution of cells (red dots) showing immunoreactivity for GFP in the transgenic mouse expressing GFP under the control of the MC4-R promoter (modified from Liu et al (2003), with permission). h: GFP-producing cell labeling the MC4-R. Bar=10 μm. ac, anterior commissure; Acb, nucleus accumbens; ACo, anterior cortical nucleus of the amygdala; AHP, anterior hypothalamic nucleus, posterior part; AVPV, anteroventral periventricular nucleus; BLA, basolateral nucleus of the amygdala, anterior part; BLP, basolateral nucleus of the amygdala, posterior part; BMA, basomedial nucleus of the amygdala; BST, bed nucleus of the stria terminalis; CA1, hippocampal field of CA1; CA3, hippocampal field of CA3; CeA, central nucleus of the amygdala; Cg, cingulated cortex; CPu, caudate-putamen; DG, dentate gyrus; DMH, dorsomedial nucleus of the hypothalamus; Ect, ectorhinal cortex; fx, fornix; IL, infralimbic cortex; Ins, insular cortex; LA, lateral nucleus of the amygdala; LEnt, lateral entorhinal cortex; LHA, lateral hypothalamic area; LHb, lateral habenular nucleus; LOT, nucleus of the lateral olfactory tract; LSN, lateral septal nucleus; lv, lateral ventricle; MeA, medial nucleus of the amygdala; Mo, motor cortex; MPO, medial preoptic nucleus; PFA, perifornical area; Pir, piriform cortex; PLCo, posterolateral cortical nucleus of the amygdala; PRh, perirhinal cortex; PVH, paraventricular nucleus of the hypothalamus; Re, nucleus reuniens; SFO, subfornical organ; SS, somatosensory cortex; Tu, olfactory tubercle; VMH, ventromedial nucleus of the hypothalamus; VMPO, ventromedial preoptic nucleus; ZI, zona incerta.

Clearly, this approach is useful for identifying the MC4-R system in the CNS. A larger point is that the use of several similar mouse models will drive the field of ‘molecular neuroanatomy’. Moreover, these tools provide more invaluable information concerning a multitude of neuropeptide and neurotransmitter systems that have so far been difficult to study due to the inherent lack of specific and sensitive regents.

The MC3-R underlying diverse melanocortin effects on energy homeostasis

Another melanocortin receptor subtype, the MC3-R coupled to Gs/Gq, is also expressed in the brain and plays a role in regulating metabolism, albeit much less studied.33,34,143 Notably, another POMC-derived peptide γ-MSH binds to MC3-Rs with a high affinity, and AgRP antagonizes γ-MSH action on MC3-Rs.33,143 The brain distribution of MC3-Rs also significantly differs from that of MC4-Rs. The rat PVH, for example, expresses MC4-R mRNA but apparently not MC3-R mRNA.33,79 Conversely, the ventromedial nucleus of the hypothalamus (VMH) is one of the sites that express high levels of MC3-R mRNA, whereas MC4-R-positive VMH cells are relatively few.33,79 Another noticeable difference is that POMC and AgRP neurons in the Arc express MC3-Rs but not MC4-Rs, suggesting a potential role of MC3-Rs in regulating the melanocortinergic local circuits within the Arc.107 Although MC3-R-deficient mice are not hyperphagic, they do display an increased fat mass.144,145 Clearly, more studies are needed to identify the MC3-R-positive sites responsible for energy balance regulation. Nevertheless, these observations indicate the existence of anatomically and functionally divergent melanocortinergic CNS pathways.

The NPY/Y1-receptor system: another feeding regulator counterpoised to the melanocortin system

NPY is an established potent stimulator of food intake.146,147,148 NPY also affects endocrine/autonomic responses, seizures, and anxiety.146,147,148 NPY neurons are distributed in many CNS sites, including the Arc.149,150 Importantly, NPY-producing Arc neurons coexpress AgRP and are inhibited by leptin.66,68,69,97,98 Of NPY receptor subtypes, the Y1-, (Y1-R), Y2-, and Y5-receptors have been implicated in the regulation of feeding.146,147,148,151,152,153,154,155 NPY neurons in the Arc may contribute to ORX's effects on food intake, as ORX neurons innervate this NPY neuronal population and stimulate it.156 Presently, we will focus on the Y1-R, as accumulating evidence suggests that this Y-receptor subtype contributes to NPY action not only on consummatory behavior but also on emotional responses.

Here, it should also be noted that several genetic studies do not generally support a role of NPY/Y1-R system in food intake. For example, NPY−/− and Y1-R−/− mice are not hypophagic,157,158,159,160 although this may be dependent on the background strain of the mouse studied. Nevertheless, other lines of evidence indicate that such discrepancies do not diminish the potential therapeutic efficacy of NPYergic agents. When ob/ob mice are crossed with NPY−/− mice, the obesity phenotype is partially corrected.161 Moreover, Y1-R−/− mice display a markedly blunted feeding response to fasting.159 Finally, the stomach-derived hormone, ghrelin, increases food intake and can directly act on Arc NPY neurons,6,7,26,162,163,164 supporting an important role of Arc NPY/AgRP neurons in feeding regulation. Ghrelin is the endogenous ligand for the growth hormone secretagogue receptor.6,7,26,162,163,164 Ghrelin administration not only increases food intake but also causes hypothermia and decreased oxygen consumption. Deletion of ghrelin also affects metabolic responses to high-fat diet feeding in mice.165

Like MC4-R mRNA, Y1-R mRNA is expressed in several brain sites critical for energy balance regulation in rodents, including the PVH and CeA.166,167,168 Moreover, by using the MC4-R/GFP mice line, we identified MC4-R-positive cells coexpressing Y1-R mRNA in these forebrain sites that receive both NPY and melanocortinergic inputs.80,107,149,150 Consequently, relevant to current discussions,15,23 we hypothesize that the convergence of leptin/melanocortin and NPY signaling pathways likely contributes to their counterpoised relationship in energy balance regulation (Figure 4).

The intersection of body weight homeostasis, classic neurotransmitters, and psychiatry

Ideally, when discussing body weight homeostasis, one could distinguish ‘appetite’ from other metabolic processes such as the regulation of energy storage and expenditure, insulin secretion, and gastrointestinal mobility. However, this is inherently difficult as various homeostatic control systems are intrinsically linked and interconnected. Nonetheless, in this section, we will discuss the melanocortin and NPY systems once again from this point of view, and classic neurotransmitters, as well on which many of psychotropic agents exert their influence. We will also discuss a link between feeding and emotion, and relevant several psychiatric issues.

The brain reward mechanism is a key to trace the neural mechanism of appetite. The reader is referred to reviews by Saper et al,20 and by Figlewicz and Woods169 that outline the hedonic aspect of feeding.

The dopaminergic projection to the nucleus accumbens (Acb) from the ventral tegmental area (VTA) is clearly important in reward processes.170 The VTA–Acb pathway has also been implicated in motivating and rewarding aspects of food intake, for example, by electrochemically monitoring dopamine transmission in the Acb of rats lever-pressing to feed.171 Here, it is interesting to note that high levels of MC3-R mRNA are expressed in the VTA, where γ-MSH-positive axon terminals are distributed.33,107 As opioid receptor antagonists block the feeding-stimulatory effect of AgRP, the melanocortin system may regulate appetite.172 Thus, whether dopaminergic VTA neurons projecting to the Acb coexpress MC3-Rs is worth exploring.

Cancer-induced cachexia (ie, anorexia and weight loss) is another example that implicates the melanocortin system in the control of appetite. Notably, in anorectic tumor-bearing rats, food intake can be markedly increased by treatment with a synthetic MC4-R antagonist SHU9119.173 MC4-R−/− mice and mice treated with AgRP also resist tumor-induced weight loss.174

It has also been speculated that melanocortins may counteract addiction. Chronic morphine administration reduces levels of MC4-R mRNA in the olfactory tubercle, striatum, Acb, and the periaqueductal gray (PAG) in the rat.12,13,14 Interestingly, the μ-opioid receptor (μ-R) is enriched in these sites.175 Melanocortins can antagonize the addictive properties of opiates and can provoke signs analogous to those by opiate withdrawal in drug-naive animals.13,176 In addition, β-endorphin, like α-MSH and γ-MSH, is cleaved from POMC,13,70,177 suggesting that the endogenous opioid peptide and melanocortins may be coreleased.13,77 Moreover, mice lacking β-endorphin display a deficit in the ability of food reward to increase bar-pressing behavior.178 As hypothesized by Alvaro et al,13 melanocortin and opioid signaling may converge on neurons coexpressing the MC4-R and μ-R, in which functional antagonism could occur intracellularly at the second messenger level. Interestingly, the PAG receives melanocortin inputs and expresses MC4-R mRNA and μ-R mRNAs.77,79,80,107,175 In addition, the PAG is more deeply implicated in morphine dependence than is the VTA.179 Collectively, it is attractive to speculate that melanocortinergic agents may be effective in treating addiction.

Alcohol can also be regarded as a reward. Evidence suggests that the NPY/Y1-R system regulates ethanol consumption and resistance. NPY-deficient mice consume significantly more ethanol than do WT mice, and are less sensitive to the sedative effect.180 In contrast, transgenic overexpression of the NPY gene in neurons results in a lower preference for ethanol in mice.180 Moreover, Y1-R−/− mice exhibit significantly increased voluntary consumption of ethanol solutions, compared to WT control mice.181 Evidence that implicates the dopaminergic reward system in alcoholism is also growing.182 Clearly, however, more studies are required to better understand the relation between the NPY/Y1-R and reward systems, and that between these systems and alcoholism. Nonetheless, it has been demonstrated that the Acb receives NPY inputs149,150 and expresses Y1-R mRNA in rodents.166,167,168 Additionally, Y1-R mRNA is faintly expressed in the mouse VTA but not at all in the rat VTA.166,167,168

Historically, serotonin 5-hydroxytryptamine (5-HT) remains one of the amines most intensively studied in psychopharmacology.183 Currently, serotonin-selective reuptake inhibitors (SSRIs) are widely used for the treatment of depression and bulimia nervosa. Melanocortins including α-MSH also influence several classes of emotion and motivated behavior.70 In addition, the significance of MC4-Rs in regulating emotion has been re-evaluated pharmacologically. When administered centrally, for example, a MC4-R-selective antagonist HS014 attenuates anorexia induced by restraint stress.184 A novel MC4-R-selective antagonist MCL0020 also prevents stress-induced behavioral changes in rodents.185

As noted above, the melanocortin system is involved in regulating the hypothalamo–pituitary–adrenal (HPA) axis.114 The dysregulation of this axis is likely associated with mood disorders including depression, although it remains unclear whether deficits in the HPA axis cause depression or are secondary to it.186,187 In either case, excessive activation of the HPA axis is common in patients with depressive mood and is corrected by treatment with antidepressants.186 Interestingly, an electrophysiological study demonstrated that MT-II, a synthetic agonist for MC3-R/MC4-R, increased the firing rate of 5-HTergic dorsal raphe (DR) neurons that may play a role in regulating emotion and behavior.188 Consistent with this finding, the DR contains cells expressing MC4-R mRNA in rodents.35,79,80 Collectively, PVH and DR neurons expressing MC4-Rs may be involved in the pathophysiology of anxiety and mood disorders.

Serotonergic drugs significantly reduce appetite, whereas 5-TH2cR-deficient mice are hyperphagic and obese.189 Notably, the Arc receives inputs from 5-HT-positive raphe nucleus neurons.190 Recently, Heisler et al191 reported that a subset of Arc POMC cells coexpressed 5-TH2c receptors (5-HT2cRs) and was activated by anorectic doses of d-fenfluramine (d-Fen), a drug that blocks the reuptake of 5-HT and stimulates its release. In the mid-1990s, d-Fen was prescribed to millions of patients suffering from morbid obesity in the United States, frequently in combination with phentermine.192 This treatment regimen proved to be very effective in decreasing food intake and body weight. However, after reports of adverse cardiopulmonary events, the Food and Drug Administration withdrew d-Fen from clinical use in 1997.193 Nevertheless, the existence of 5-HT-responsive POMC cells strongly suggests that the central melanocortin system contributes to the anorectic effects of 5-HT. It is also interesting to speculate based on the observation that auto-antibodies are raised against α-MSH and adrenocorticotropic hormone in patients with anorexia and bulimia nervosa.9 Taken together, it is conceivable that 5-HT action on Arc melanocortinergic neurons may contribute to the pathophysiology of morbid ingestive behavior. The Arc provides reciprocal innervation to the DR nucleus,194,195 supporting an interaction between these two brain sites. In mood disorders, however, the relationship between 5-HT and prevalent anorexia is paradoxical. Serotonergic agents apparently suppress appetite, whereas 5-HT levels in anorectic depressed patients are presumably low. Many of the commonly used antidepressants inhibit the uptake of serotonin. As serotonergic innervation is widespread across the brain, 5-HT neural circuits underlying feeding and emotion have been inherently difficult to discern. However, the serotonergic pathway to the Arc from raphe nuclei merits further investigation.

Antipsychotic agents, especially ‘atypical’ antipsychotics, often produce obesity and diabetes mellitus, and infrequently diabetic ketoacidosis or coma.2,3,4 On one hand, there is a possibility that antipsychotics directly influence peripheral organs per se, including pancreatic β-cells, liver, adipose tissue, and skeletal muscle, resulting in impaired glucose tolerance.196,197 On the other hand, antipsychotics may affect CNS systems regulating glucose metabolism. The 5-HT/5-HT2cR system is one of the candidates, as several antipsychotic agents bind to 5-HT2cRs with high affinities.198 As noted, a population of Arc α-MSH neurons expresses 5-HT2cRs and is leptin-responsive. In addition, the MC4-R likely regulates pancreatic β-cell function, as MC4-R−/− mice exhibit hyperglycemia and impaired insulin tolerance before the onset of obesity.138 The MC4-R is also involved in sensitizing peripheral tissue to insulin action.139,140,141 Centrally administered α-MSH markedly enhances insulin action on glucose uptake as well as on hepatic glucose production, whereas MC4-R antagonism exerts opposite effects.139 Finally, patients with MC4-R mutations are very insulin-resistant.84 Collectively, these findings suggest that dysregulation of the 5-HT-driven melanocortin system may be involved in obesity and diabetes as adverse effects of antipsychotic agents.

Additionally, the use of antipsychotics often produces hyperleptinemia.2,3,4 It is unknown, though, whether this condition is due to the use of antipsychotics itself or obesity resulting from it. Nonetheless, rapid increases in leptin levels may be a marker to predict long-term weight gain in patients on medication with clozapine.199

Acetylcholine has also been indicated to influence MCH signaling; for example, a cholinergic agonist carbachol increases MCH mRNA expression in hypothalamic slices.200 MCH is, as stressed, an established regulator of energy balance118,119,120,126,127 and is produced at the LHA that receives leptin and melanocortinergic signals.66,71,72 Notably, a subset of MCH neurons coexpresses the M3 muscarinic acetylcholine receptor (M3Ach-R), and M3Ach-R−/− mice are hypophagic despite extremely low levels of serum leptin.201 MCH accelerates feeding in M3Ach-R−/− mice when administered centrally, whereas an AgRP analogue does not. This study indicates that M3Ach-R-mediated acetylcholine signaling at a site downstream of the leptin/melanocortin system and upstream of the MCH system is critical in facilitating food intake.201 Anticholinergic agents are occasionally used to alleviate extrapyramidal adverse effects by neuroleptics. It is significant to examine if and how anticholinergic medication in psychiatric practice influences body weight homeostasis.

The ascending cholinergic projections to the lateral hypothalamus originate in the laterodorsal tegmental and pedunculopontine tegmental nuclei in the brainstem.200,202 These nuclei are responsible for regulating sleep and wakefulness, especially for rapid-eye-movement (REM) sleep.132 Thus, it is plausible that subsets of MCH neurons may integrate sleep and metabolic cues into coordinated behavioral responses.

Cognitive function, regulated by cortical circuits, should also be mentioned to discuss feeding, a class of goal-oriented behavior. The hippocampus is noteworthy in this respect, as this limbic structure is thought to integrate neocortical information, resulting in coordinated emotional and behavioral responses to external stimuli.203 The efferent pathways from the hippocampus are glutamatergic.203 Importantly, the medial and perifornical hypothalamic regions receive dense hippocampal inputs204 and are enriched with ionotropic glutamate receptors.205 A recent electrophysiological study demonstrated that glutamate release excited MCH cells, in which a viral approach was used to label MCH cells with GFP expression.134 In contrast, NPY was found to be inhibitory by pre- and postsynaptic mechanisms in this study.

NPY-positive fibers densely terminate in the perifornical area of the lateral hypothalamus (PFA), many of which originate in the Arc.71,72 Whereas levels of Y1-R mRNA expression are relatively low in the PFA, the subiculum (a major output source of the hippocampus203,204) expresses high levels of Y1-R mRNA in rodents.166,167,168 The expression of Y1-R mRNA in the hippocampus has also been demonstrated in humans.206 Collectively, these findings imply that multi-modal cortical information may influence the activity of MCH neurons via the hippocampus–hypothalamus pathway to regulate ingestive behavior. In addition, Arc-derived NPY may act presynaptically on Y1-Rs expressed on hippocampal axon terminals that synapse on a subset of MCH neurons, in order to modulate the cortical information by mediating peripheral metabolic cues. Consistent with this hypothesis, Y1-R-immunoreactive axons are densely distributed in the lateral hypothalamus.167

When administered centrally, an antisense oligodeoxynucleotide for the Y1-R produces behavioral signs of anxiety measured with plus maze testing.207 Transgenic overexpression of NPY in the rat markedly attenuated behavioral sensitivity to restraint stress and decreased NPY-Y1-R binding in the hippocampus.208 Thus, Y1-R-mediated hippocampal NPY signaling may be involved in anxiety and related disorders.

As mentioned earlier, the hypothalamus innervates a wide extent of cortical areas via neurons producing MCH or ORX.118,121,133 Thus, metabolic, emotional, and cognitive information may be assimilated at the hypothalamus, and in turn forwarded to the neocortex, resulting in the ultimate decision to eat or not to eat. An interrelation between cortical glutamatergic and ascending dopaminergic systems has also been discussed to re-evaluate the classic dopamine hypothesis of schizophrenia,209 which may also be relevant to the CNS mechanisms of feeding as a motivated behavior. Needless to say, GABA is also important not only in cortico-subcortical circuits but also in subcortical circuits.24 It is notable that GABA plays a role in regulating key hypothalamic circuits, as illustrated by Cowley et al,69 and van den Pol et al.134 Clearly, neuropeptides have received much attention in the field of obesity research. However, the regulation of hypothalamic synaptic activity critical for coordinated food intake and body weight likely relies on the action of amino-acid transmitters including glutamate and GABA.

Conclusion and perspectives

A series of classic lesion studies established that certain hypothalamic cell groups regulate food intake and body weight. The discovery of leptin in 1994 catalyzed a remarkable increase in understanding of hypothalamic mechanisms of energy homeostasis regulation.5 Since then, an enormous amount of work traced the CNS machinery downstream of leptin signaling, including the central melanocortin and NPY systems. These systems are critical to explore the mechanism of the disequilibrium between energy intake and expenditure by mental disorders and/or by psychotropic agents. In addition to a variety of molecules involved in feeding regulation, neuromedin U (NMU) has recently been established as a novel anorexigenic hypothalamic peptide independent of leptin signaling.210 Like the MC4-R and Y1-R, a subtype of NMU receptors is expressed in the rat hypothalamus.211,212 If and how NMU affects CNS systems regulating emotion and behavior remain open to future analysis. Moreover, there are undoubtedly other molecules that will be discovered and may serve as links between obesity and psychiatry research.

Apparently, focusing on such functionally and anatomically defined brain systems should promote a new line of psychiatric research. These types of studies have long been very difficult to undertake despite a large body of evidence that several CNS neurotransmitter systems mediate psychotropic action. This was due in large part to the lack of CNS molecules that define respective psychiatric disorders, and therefore the target brain sites have been unspecified. Nevertheless, food intake and body weight are psychiatric parameters that are readily quantified, and thus, relevant genetically modified animals are useful in psychiatry research. Moreover, as discussed, several CNS systems responsible for energy balance are also involved in regulating emotion and several classes of behavior. We believe that the use of multidisciplinary molecular and neuroanatomic techniques illustrated in this article will elucidate the brain circuits underlying energy homeostasis and emotion, and will contribute to establishing new therapeutic strategies for psychiatric illnesses.


  1. 1

    Friedman JM . Obesity in the new millennium. Nature 2000; 404: 632–634.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2

    McIntyre RS, Mancini DA, Basile VS . Mechanisms of antipsychotic-induced weight gain. J Clin Psychiatry 2001; 62(Suppl 23): 23–29.

    CAS  PubMed  Google Scholar 

  3. 3

    Meyer JM . Effects of atypical antipsychotics on weight and serum lipid levels. J Clin Psychiatry 2001; 62(Suppl 27): 27–34.

    CAS  PubMed  Google Scholar 

  4. 4

    Wirshing DA . Adverse effects of atypical antipsychotics. J Clin Psychiatry 2001; 62(Suppl 21): 7–10.

    CAS  PubMed  Google Scholar 

  5. 5

    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.

    CAS  Article  Google Scholar 

  6. 6

    Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K . Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999; 402: 656–660.

    CAS  Article  Google Scholar 

  7. 7

    Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K et al. A role for ghrelin in the central regulation of feeding. Nature 2001; 409: 194–198.

    CAS  Article  Google Scholar 

  8. 8

    Inui A . Eating behavior in anorexia nervosa—an excess of both orexigenic and anorexigenic signalling? Mol Psychiatry 2001; 6: 620–624.

    CAS  PubMed  Article  Google Scholar 

  9. 9

    Fetissov SO, Hallman J, Oreland L, Af Klinteberg B, Grenback E, Hulting AL et al. Autoantibodies against alpha-MSH, ACTH, and LHRH in anorexia and bulimia nervosa patients. Proc Natl Acad Sci USA 2002; 99: 17155–17160.

    CAS  PubMed  Article  Google Scholar 

  10. 10

    Tanaka M, Naruo T, Muranaga T, Yasuhara D, Shiiya T, Nakazato M et al. Increased fasting plasma ghrelin levels in patients with bulimia nervosa. Eur J Endocrinol 2002; 146: R1–R3.

    CAS  Article  Google Scholar 

  11. 11

    Branson R, Potoczna N, Kral JG, Lentes KU, Hoehe MR, Horber FF . Binge eating as a major phenotype of melanocortin 4 receptor gene mutations. N Engl J Med 2003; 348: 1096–1103.

    CAS  Article  Google Scholar 

  12. 12

    Alvaro JD, Tatro JB, Quillan JM, Fogliano M, Eisenhard M, Lerner MR et al. Morphine down-regulates melanocortin-4 receptor expression in brain regions that mediate opiate addiction. Mol Pharmacol 1996; 50: 583–591.

    CAS  PubMed  Google Scholar 

  13. 13

    Alvaro JD, Tatro JB, Duman RS . Melanocortins and opiate addiction. Life Sci 1997; 61: 1–9.

    CAS  PubMed  Article  Google Scholar 

  14. 14

    Alvaro JD, Taylor JR, Duman RS . Molecular and behavioral interactions between central melanocortins and cocaine. Pharmacol Exp Ther 2003; 304: 391–399.

    CAS  Article  Google Scholar 

  15. 15

    Barsh GS, Schwartz MW . Genetic approaches to studying energy balance: perception and integration. Nat Rev Genet 2002; 3: 589–600.

    CAS  PubMed  Article  Google Scholar 

  16. 16

    Elmquist JK, Elias CF, Saper CB . From lesions to leptin: hypothalamic control of food intake and body weight. Neuron 1999; 22: 221–232.

    CAS  PubMed  Article  Google Scholar 

  17. 17

    Friedman JM, Halaas JL . Leptin and the regulation of body weight in mammals. Nature 1998; 395: 763–770.

    CAS  Article  Google Scholar 

  18. 18

    Grill HJ, Kaplan JM . The neuroanatomical axis for control of energy balance. Front Neuroendocrinol 2002; 23: 2–40.

    CAS  PubMed  Article  Google Scholar 

  19. 19

    O'Rahilly S, Farooqi IS, Yeo GS, Challis BG . Minireview: human obesity—lessons from monogenic disorders. Endocrinology 2003; 144: 3757–3764.

    CAS  PubMed  Article  Google Scholar 

  20. 20

    Saper CB, Chou TC, Elmquist JK . The need to feed: homeostatic and hedonic control of eating. Neuron 2002; 36: 199–211.

    CAS  PubMed  Article  Google Scholar 

  21. 21

    Sawchenko PE . Toward a new neurobiology of energy balance, appetite, and obesity: the anatomists weigh in. J Comp Neurol 1998; 402: 435–441.

    CAS  PubMed  Article  Google Scholar 

  22. 22

    Schwartz MW, Woods SC, Porte Jr D, Seeley RJ, Baskin DG . Central nervous system control of food intake. Nature 2000; 404: 661–671.

    CAS  Article  Google Scholar 

  23. 23

    Spiegelman BM, Flier JS . Obesity and the regulation of energy balance. Cell 2001; 104: 531–543.

    CAS  Article  Google Scholar 

  24. 24

    van den Pol AN . Weighing the role of hypothalamic feeding neurotransmitters. Neuron 2003; 40: 1059–1061.

    CAS  PubMed  Article  Google Scholar 

  25. 25

    Woods SC, Seeley RJ, Porte Jr D, Schwartz MW . Signals that regulate food intake and energy homeostasis. Science 1998; 280: 1378–1383.

    CAS  Article  Google Scholar 

  26. 26

    Zigman JM, Elmquist JK . Minireview: From anorexia to obesity—the yin and yang of body weight control. Endocrinology 2003; 144: 3749–3756.

    CAS  PubMed  Article  Google Scholar 

  27. 27

    Bramwell B . Intracranial Tumors. Edinburgh: Pentland, 1888.

    Google Scholar 

  28. 28

    Frölich A . Ein fall von tumor der hypophysis cerebri ohne akromegalie. Wien Kin Rundsch 1901; 15: 883–886.

    Google Scholar 

  29. 29

    Aschner B . Uber die function der hypophyse. Pflügers Arch Physiol 1912; 146: 1–146.

    Article  Google Scholar 

  30. 30

    Hetherington AW, Ranson SW . Hypothalamic lesions and adiposity in the rat. Anat Rec 1940; 78: 149–172.

    Article  Google Scholar 

  31. 31

    Anand BK, Brobeck JR . Localization of a ‘feeding center’ in the hypothalamus of the rat. Proc Soc Exp Biol Med 1951; 77: 323–324.

    CAS  PubMed  Article  Google Scholar 

  32. 32

    Gold RM . Hypothalamic obesity: the myth of the ventromedial nucleus. Science 1973; 182: 488–490.

    CAS  PubMed  Article  Google Scholar 

  33. 33

    Roselli-Rehfuss L, Mountjoy KG, Robbins LS, Mortrud MT, Low MJ, Tatro JB et al. Identification of a receptor for gamma melanotropin and other proopiomelanocortin peptides in the hypothalamus and limbic system. Proc Natl Acad Sci USA 1993; 90: 8856–8860.

    CAS  PubMed  Article  Google Scholar 

  34. 34

    Magenis RE, Smith L, Nadeau JH, Johnson KR, Mountjoy KG, Cone RD . Mapping of the ACTH, MSH, and neural (MC3 and MC4) melanocortin receptors in the mouse and human. Mamm Genome 1994; 5: 503–508.

    CAS  PubMed  Article  Google Scholar 

  35. 35

    Mountjoy KG, Mortrud MT, Low MJ, Simerly RB, Cone RD . Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. Mol Endocrinol 1994; 8: 1298–1308.

    CAS  PubMed  Google Scholar 

  36. 36

    Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997; 387: 903–908.

    CAS  Article  Google Scholar 

  37. 37

    Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD . A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet 1998; 18: 213–215.

    CAS  Article  Google Scholar 

  38. 38

    Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 1999; 341: 879–884.

    CAS  Article  Google Scholar 

  39. 39

    Ozata M, Ozdemir IC, Licinio J . Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects. J Clin Endocrinol Metab 1999; 84: 3686–3695.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40

    Licinio J, Caglayan S, Ozata M, Yildiz BO, de Miranda PB, O'Kirwan F et al. Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults. Proc Natl Acad Sci USA 2004; 101: 4531–4536.

    CAS  PubMed  Article  Google Scholar 

  41. 41

    Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E et al. Role of leptin in the neuroendocrine response to fasting. Nature 1996; 382: 250–252.

    CAS  Article  Google Scholar 

  42. 42

    Legradi G, Emerson CH, Ahima RS, Flier JS, Lechan RM . Leptin prevents fasting-induced suppression of prothyrotropin-releasing hormone messenger ribonucleic acid in neurons of the hypothalamic paraventricular nucleus. Endocrinology 1997; 138: 2569–2576.

    CAS  PubMed  Article  Google Scholar 

  43. 43

    Ahima RS, Prabakaran D, Flier JS . Postnatal leptin surge and regulation of circadian rhythm of leptin by feeding. Implications for energy homeostasis and neuroendocrine function. J Clin Invest 1998; 101: 1020–1027.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44

    Guo F, Bakal K, Minokoshi Y, Hollenberg AN . Leptin signaling targets the thyrotropin-releasing hormone gene promoter in vivo. Endocrinology 2004; 145: 2221–2227.

    CAS  PubMed  Article  Google Scholar 

  45. 45

    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 

  46. 46

    Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 1995; 269: 543–546.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47

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

    CAS  Article  Google Scholar 

  48. 48

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

    CAS  PubMed  Article  Google Scholar 

  49. 49

    Chan JL, Heist K, DePaoli AM, Veldhuis JD, Mantzoros CS . The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men. J Clin Invest 2003; 111: 1409–1421.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. 50

    Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R et al. Identification and expression cloning of a leptin receptor, OB-R. Cell 1995; 83: 1263–1271.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51

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

    CAS  Article  Google Scholar 

  52. 52

    Vaisse C, Halaas JL, Horvath CM, Darnell Jr JE, Stoffel M, Friedman JM . Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice. Nat Genet 1996; 14: 95–97.

    CAS  Article  Google Scholar 

  53. 53

    Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ et al. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 1996; 84: 491–495.

    CAS  Article  Google Scholar 

  54. 54

    Chua Jr SC, Chung WK, Wu-Peng XS, Zhang Y, Liu SM, Tartaglia L et al. Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor. Science 1996; 271: 994–996.

    CAS  Article  Google Scholar 

  55. 55

    Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI et al. Abnormal splicing of the leptin receptor in diabetic mice. Nature 1996; 379: 632–635.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. 56

    Clement K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 1998; 392: 398–401.

    CAS  Article  Google Scholar 

  57. 57

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

    CAS  Article  Google Scholar 

  58. 58

    Elmquist JK, Bjorbaek C, Ahima RS, Flier JS, Saper CB . Distributions of leptin receptor mRNA isoforms in the rat brain. J Comp Neurol 1998; 395: 535–547.

    CAS  PubMed  Article  Google Scholar 

  59. 59

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

    CAS  Article  Google Scholar 

  60. 60

    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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 61

    Couce ME, Burguera B, Parisi JE, Jensen MD, Lloyd RV . Localization of leptin receptor in the human brain. Neuroendocrinology 1997; 66: 145–150.

    CAS  PubMed  Article  Google Scholar 

  62. 62

    Baskin DG, Breininger JF, Bonigut S, Miller MA . Leptin binding in the arcuate nucleus is increased during fasting. Brain Res 1999; 828: 154–158.

    CAS  PubMed  Article  Google Scholar 

  63. 63

    Elmquist JK, Ahima RS, Maratos-Flier E, Flier JS, Saper CB . Leptin activates neurons in ventrobasal hypothalamus and brainstem. Endocrinology 1997; 138: 839–842.

    CAS  Article  Google Scholar 

  64. 64

    Elmquist JK, Ahima RS, Elias CF, Flier JS, Saper CB . Leptin activates distinct projections from the dorsomedial and ventromedial hypothalamic nuclei. Proc Natl Acad Sci USA 1998; 95: 741–746.

    CAS  PubMed  Article  Google Scholar 

  65. 65

    Elias CF, Lee C, Kelly J, Aschkenasi C, Ahima RS, Couceyro PR et al. Leptin activates hypothalamic CART neurons projecting to the spinal cord. Neuron 1998; 21: 1375–1385.

    CAS  Article  Google Scholar 

  66. 66

    Elias CF, Aschkenasi C, Lee C, Kelly J, Ahima RS, Bjorbaek C et al. Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area. Neuron 1999; 23: 775–786.

    CAS  Article  Google Scholar 

  67. 67

    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.

    CAS  Article  Google Scholar 

  68. 68

    Spanswick D, Smith MA, Groppi VE, Logan SD, Ashford ML . Leptin inhibits hypothalamic neurons by activation of ATP-sensitive potassium channels. Nature 1997; 390: 521–525.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69

    Cowley MA, Smart JL, Rubinstein M, Cerdan MG, Diano S, Horvath TL et al. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 2001; 411: 480–484.

    CAS  Article  Google Scholar 

  70. 70

    Eberle AN . Proopiomelanocortin and the melanocortin peptides. In: Cone RD (ed). The Melanocortin Receptors. Humana Press: New Jersey, 2000, pp 3–67.

    Google Scholar 

  71. 71

    Broberger C, De Lecea L, Sutcliffe JG, Hokfelt T . Hypocretin/orexin- and melanin-concentrating hormone-expressing cells form distinct populations in the rodent lateral hypothalamus: relationship to the neuropeptide Y and agouti gene-related protein systems. J Comp Neurol 1998; 402: 460–474.

    CAS  PubMed  Article  Google Scholar 

  72. 72

    Elias CF, Saper CB, Maratos-Flier E, Tritos NA, Lee C, Kelly J et al. Chemically defined projections linking the mediobasal hypothalamus and the lateral hypothalamic area. J Comp Neurol 1998; 402: 442–459.

    CAS  PubMed  Article  Google Scholar 

  73. 73

    Cheung CC, Clifton DK, Steiner RA . Proopiomelanocortin neurons are direct targets for leptin in the hypothalamus. Endocrinology 1997; 138: 4489–4492.

    CAS  Article  Google Scholar 

  74. 74

    Schwartz MW, Seeley RJ, Woods SC, Weigle DS, Campfield LA, Burn P et al. Leptin increases hypothalamic pro-opiomelanocortin mRNA expression in the rostral arcuate nucleus. Diabetes 1997; 46: 2119–2123.

    CAS  Article  Google Scholar 

  75. 75

    Thornton JE, Cheung CC, Clifton DK, Steiner RA . Regulation of hypothalamic proopiomelanocortin mRNA by leptin in ob/ob mice. Endocrinology 1997; 138: 5063–5066.

    CAS  Article  Google Scholar 

  76. 76

    Mizuno TM, Kleopoulos SP, Bergen HT, Roberts JL, Priest CA, Mobbs CV . Hypothalamic pro-opiomelanocortin mRNA is reduced by fasting and [corrected] in ob/ob and db/db mice, but is stimulated by leptin. Diabetes 1998; 47: 294–297.

    CAS  Article  Google Scholar 

  77. 77

    Cone RD . The melanocortin-4 receptor. In: Cone RD (ed). The Melanocortin Receptors. Humana Press: New Jersey, 2000, pp 405–447.

    Chapter  Google Scholar 

  78. 78

    O'Rahilly S, Yeo GS, Farooqi IS . Melanocortin receptors weigh in. Nat Med 2004; 10: 351–352.

    CAS  PubMed  Article  Google Scholar 

  79. 79

    Kishi T, Aschkenasi CJ, Lee CE, Mountjoy KG, Saper CB, Elmquist JK . Expression of melanocortin 4 receptor mRNA in the central nervous system of the rat. J Comp Neurol 2003; 457: 213–235.

    CAS  PubMed  Article  Google Scholar 

  80. 80

    Liu H, Kishi T, Roseberry AG, Cai X, Lee CE, Montez JM et al. Transgenic mice expressing green fluorescent protein under the control of the melanocortin-4 receptor promoter. J Neurosci 2003; 23: 7143–7154.

    CAS  PubMed  Article  Google Scholar 

  81. 81

    Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 1997; 88: 131–141.

    CAS  PubMed  Article  Google Scholar 

  82. 82

    Vaisse C, Clement K, Guy-Grand B, Froguel P . A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat Genet 1998; 20: 113–114.

    CAS  Article  Google Scholar 

  83. 83

    Yeo GS, Farooqi IS, Aminian S, Halsall DJ, Stanhope RG, O'Rahilly S . A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat Genet 1998; 20: 111–112.

    CAS  Article  Google Scholar 

  84. 84

    Farooqi IS, Yeo GS, Keogh JM, Aminian S, Jebb SA, Butler G et al. Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency. J Clin Invest 2000; 106: 271–279.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. 85

    Vaisse C, Clement K, Durand E, Hercberg S, Guy-Grand B, Froguel P . Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. J Clin Invest 2000; 106: 253–262.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. 86

    Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T, O'Rahilly S . Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med 2003; 348: 1085–1095.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. 87

    Lubrano-Berthelier C, Durand E, Dubern B, Shapiro A, Dazin P, Weill J et al. Intracellular retention is a common characteristic of childhood obesity-associated MC4R mutations. Hum Mol Genet 2003; 12: 145–153.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. 88

    Yeo GS, Lank EJ, Farooqi IS, Keogh J, Challis BG, O'Rahilly S . Mutations in the human melanocortin-4 receptor gene associated with severe familial obesity disrupts receptor function through multiple molecular mechanisms. Hum Mol Genet 2003; 12: 561–574.

    CAS  Article  Google Scholar 

  89. 89

    Barsh GS, Farooqi IS, O'Rahilly S . Genetics of body-weight regulation. Nature 2000; 404: 644–651.

    CAS  Article  Google Scholar 

  90. 90

    Krude H, Biebermann H, Luck W, Horn R, Brabant G, Gruters A . Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 1998; 19: 155–157.

    CAS  Article  Google Scholar 

  91. 91

    Krude H, Biebermann H, Gruters A . Mutations in the human proopiomelanocortin gene. Ann NY Acad Sci 2003; 994: 233–239.

    CAS  PubMed  Article  Google Scholar 

  92. 92

    Shutter JR, Graham M, Kinsey AC, Scully S, Luthy R, Stark KL . Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice. Genes Dev 1997; 11: 593–602.

    CAS  Article  Google Scholar 

  93. 93

    Graham M, Shutter JR, Sarmiento U, Sarosi I, Stark KL . Overexpression of Agrt leads to obesity in transgenic mice. Nat Genet 1997; 17: 273–274.

    CAS  Article  Google Scholar 

  94. 94

    Ollmann MM, Wilson BD, Yang YK, Kerns JA, Chen Y, Gantz I et al. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 1997; 278: 135–138.

    CAS  PubMed  Article  Google Scholar 

  95. 95

    Broberger C, Johansen J, Johansson C, Schalling M, Hokfelt T . The neuropeptide Y/agouti gene-related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamate-treated mice. Proc Natl Acad Sci USA 1998; 95: 15043–15048.

    CAS  Article  Google Scholar 

  96. 96

    Haskell-Luevano C, Chen P, Li C, Chang K, Smith MS, Cameron JL et al. Characterization of the neuroanatomical distribution of agouti-related protein immunoreactivity in the rhesus monkey and the rat. Endocrinology 1999; 140: 1408–1415.

    CAS  PubMed  Article  Google Scholar 

  97. 97

    Mizuno TM, Mobbs CV . Hypothalamic agouti-related protein messenger ribonucleic acid is inhibited by leptin and stimulated by fasting. Endocrinology 1999; 140: 814–817.

    CAS  Article  Google Scholar 

  98. 98

    Hahn TM, Breininger JF, Baskin DG, Schwartz MW . Coexpression of Agrp and NPY in fasting-activated hypothalamic neurons. Nat Neurosci 1998; 1: 271–272.

    CAS  Article  Google Scholar 

  99. 99

    Seeley RJ, Yagaloff KA, Fisher SL, Burn P, Thiele TE, van Dijk G et al. Melanocortin receptors in leptin effects. Nature 1997; 390: 349.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  100. 100

    Scarpace PJ, Matheny M, Pollock BH, Tumer N . Leptin increases uncoupling protein expression and energy expenditure. Am J Physiol 1997; 273: E226–E230.

    CAS  Google Scholar 

  101. 101

    Kotz CM, Briggs JE, Pomonis JD, Grace MK, Levine AS, Billington CJ . Neural site of leptin influence on neuropeptide Y signaling pathways altering feeding and uncoupling protein. Am J Physiol 1998; 275: R478–R484.

    CAS  PubMed  Google Scholar 

  102. 102

    Satoh N, Ogawa Y, Katsuura G, Numata Y, Masuzaki H, Yoshimasa Y et al. Satiety effect and sympathetic activation of leptin are mediated by hypothalamic melanocortin system. Neurosci Lett 1998; 249: 107–110.

    CAS  Article  Google Scholar 

  103. 103

    Balthasar N, Coppari R, McMinn J, Liu SM, Lee CE, Tang V et al. Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron 2004; 42: 983–991.

    CAS  PubMed  Article  Google Scholar 

  104. 104

    Boston BA, Blaydon KM, Varnerin J, Cone RD . Independent and additive effects of central POMC and leptin pathways on murine obesity. Science 1997; 278: 1641–1644.

    CAS  Article  Google Scholar 

  105. 105

    Marsh DJ, Hollopeter G, Huszar D, Laufer R, Yagaloff KA, Fisher SL et al. Response of melanocortin-4 receptor-deficient mice to anorectic and orexigenic peptides. Nat Genet 1999; 21: 119–122.

    CAS  Article  Google Scholar 

  106. 106

    Watson SJ, Akil H . The presence of two alpha-MSH positive cell groups in rat hypothalamus. Eur J Pharmacol 1979; 58: 101–103.

    CAS  PubMed  Article  Google Scholar 

  107. 107

    Bagnol D, Lu XY, Kaelin CB, Day HE, Ollmann M, Gantz I et al. Anatomy of an endogenous antagonist: relationship between Agouti-related protein and proopiomelanocortin in brain. J Neurosci 1999; 19: RC26.

    CAS  PubMed  Article  Google Scholar 

  108. 108

    Giraudo SQ, Billington CJ, Levine AS . Feeding effects of hypothalamic injection of melanocortin 4 receptor ligands. Brain Res 1998; 809: 302–306.

    CAS  PubMed  Article  Google Scholar 

  109. 109

    Wirth MM, Olszewski PK, Yu C, Levine AS, Giraudo SQ . Paraventricular hypothalamic alpha-melanocyte-stimulating hormone and MTII reduce feeding without causing aversive effects. Peptides 2001; 22: 129–134.

    CAS  PubMed  Article  Google Scholar 

  110. 110

    Kim EM, O'Hare E, Grace MK, Welch CC, Billington CJ, Levine AS . ARC POMC mRNA and PVN alpha-MSH are lower in obese relative to lean zucker rats. Brain Res 2000; 862: 11–16.

    CAS  PubMed  Article  Google Scholar 

  111. 111

    Swanson LW, Sawchenko PE . Hypothalamic integration: organization of the paraventricular and supraoptic nuclei. Annu Rev Neurosci 1983; 6: 269–324.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  112. 112

    Sawchenko PE, Brown ER, Chan RK, Ericsson A, Li HY, Roland BL et al. The paraventricular nucleus of the hypothalamus and the functional neuroanatomy of visceromotor responses to stress. Prog Brain Res 1996; 107: 201–222.

    CAS  PubMed  Article  Google Scholar 

  113. 113

    Saper CB . Central autonomic system. In: Paxinos G (ed). The Rat Nervous System, 3rd edn. Academic Press: San Diego, 2004, pp 761–796.

    Chapter  Google Scholar 

  114. 114

    Lu XY, Barsh GS, Akil H, Watson SJ . Interaction between alpha-melanocyte-stimulating hormone and corticotropin-releasing hormone in the regulation of feeding and hypothalamo-pituitary-adrenal responses. J Neurosci 2003; 23: 7863–7872.

    CAS  PubMed  Article  Google Scholar 

  115. 115

    Harris M, Aschkenasi C, Elias CF, Chandrankunnel A, Nillni EA, Bjoorbaek C et al. Transcriptional regulation of the thyrotropin-releasing hormone gene by leptin and melanocortin signaling. J Clin Invest 2001; 107: 111–120.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  116. 116

    Fekete C, Legradi G, Mihaly E, Huang QH, Tatro JB, Rand WM et al. alpha-Melanocyte-stimulating hormone is contained in nerve terminals innervating thyrotropin-releasing hormone-synthesizing neurons in the hypothalamic paraventricular nucleus and prevents fasting-induced suppression of prothyrotropin-releasing hormone gene expression. J Neurosci 2000; 20: 1550–1558.

    CAS  PubMed  Article  Google Scholar 

  117. 117

    Fekete C, Marks DL, Sarkar S, Emerson CH, Rand WM, Cone RD et al. Effect of Agouti-related protein in regulation of the hypothalamic–pituitary–thyroid axis in the melanocortin 4 receptor knockout mouse. Endocrinology 2004; 145: 4816–4821.

    CAS  PubMed  Article  Google Scholar 

  118. 118

    Bittencourt JC, Presse F, Arias C, Peto C, Vaughan J, Nahon JL et al. The melanin-concentrating hormone system of the rat brain: an immuno- and hybridization histochemical characterization. J Comp Neurol 1992; 319: 218–245.

    CAS  Article  Google Scholar 

  119. 119

    Qu D, Ludwig DS, Gammeltoft S, Piper M, Pelleymounter MA, Cullen MJ et al. A role for melanin-concentrating hormone in the central regulation of feeding behaviour. Nature 1996; 380: 243–247.

    CAS  Article  Google Scholar 

  120. 120

    Shimada M, Tritos NA, Lowell BB, Flier JS, Maratos-Flier E . Mice lacking melanin-concentrating hormone are hypophagic and lean. Nature 1998; 396: 670–674.

    CAS  Article  Google Scholar 

  121. 121

    Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 1998; 92: 573–585.

    CAS  Article  Google Scholar 

  122. 122

    Hervieu GJ, Cluderay JE, Harrison D, Meakin J, Maycox P, Nasir S et al. The distribution of the mRNA and protein products of the melanin-concentrating hormone (MCH) receptor gene, slc-1, in the central nervous system of the rat. Eur J Neurosci 2000; 12: 1194–1216.

    CAS  Article  Google Scholar 

  123. 123

    Marcus JN, Aschkenasi CJ, Lee CE, Chemelli RM, Saper CB, Yanagisawa M et al. Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol 2001; 435: 6–25.

    CAS  PubMed  Article  Google Scholar 

  124. 124

    Sailer AW, Sano H, Zeng Z, McDonald TP, Pan J, Pong SS et al. Identification and characterization of a second melanin-concentrating hormone receptor, MCH-2R. Proc Natl Acad Sci USA 2001; 98: 7564–7569.

    CAS  Article  Google Scholar 

  125. 125

    Saito Y, Cheng M, Leslie FM, Civelli O . Expression of the melanin-concentrating hormone (MCH) receptor mRNA in the rat brain. J Comp Neurol 2001; 435: 26–40.

    CAS  PubMed  Article  Google Scholar 

  126. 126

    Ludwig DS, Tritos NA, Mastaitis JW, Kulkarni R, Kokkotou E, Elmquist J et al. Melanin-concentrating hormone overexpression in transgenic mice leads to obesity and insulin resistance. J Clin Invest 2001; 107: 379–386.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  127. 127

    Segal-Lieberman G, Bradley RL, Kokkotou E, Carlson M, Trombly DJ, Wang X et al. Melanin-concentrating hormone is a critical mediator of the leptin-deficient phenotype. Proc Natl Acad Sci USA 2003; 100: 10085–10090.

    CAS  PubMed  Article  Google Scholar 

  128. 128

    Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 1999; 98: 437–451.

    CAS  PubMed  Article  Google Scholar 

  129. 129

    Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin X et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 1999; 98: 365–376.

    CAS  Article  Google Scholar 

  130. 130

    Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E . Hypocretin (orexin) deficiency in human narcolepsy. Lancet 2000; 355: 39–40.

    CAS  Article  Google Scholar 

  131. 131

    Mignot E, Taheri S, Nishino S . Sleeping with the hypothalamus: emerging therapeutic targets for sleep disorders. Nat Neurosci 2002; 5(Suppl): 1071–1075.

    CAS  PubMed  Article  Google Scholar 

  132. 132

    Saper CB, Chou TC, Scammell TE . The sleep switch: hypothalamic control of sleep and wakefulness. Trends Neurosci 2001; 24: 726–731.

    CAS  PubMed  Article  Google Scholar 

  133. 133

    Sakurai T . Roles of orexins in regulation of feeding and wakefulness. Neuroreport 2002; 13: 987–995.

    CAS  PubMed  Article  Google Scholar 

  134. 134

    van den Pol AN, Acuna-Goycolea C, Clark KR, Ghosh PK . Physiological properties of hypothalamic MCH neurons identified with selective expression of reporter gene after recombinant virus infection. Neuron 2004; 42: 635–652.

    CAS  PubMed  Article  Google Scholar 

  135. 135

    Cowley MA, Pronchuk N, Fan W, Dinulescu DM, Colmers WF, Cone RD . Integration of NPY, AGRP, and melanocortin signals in the hypothalamic paraventricular nucleus: evidence of a cellular basis for the adipostat. Neuron 1999; 24: 155–163.

    CAS  Article  Google Scholar 

  136. 136

    King BM, Rollins BL, Stines SG, Cassis SA, McGuire HB, Lagarde ML . Sex differences in body weight gains following amygdaloid lesions in rats. Am J Physiol 1999; 277: R975–R980.

    CAS  PubMed  Google Scholar 

  137. 137

    Kask A, Schioth HB . Tonic inhibition of food intake during inactive phase is reversed by the injection of the melanocortin receptor antagonist into the paraventricular nucleus of the hypothalamus and central amygdala of the rat. Brain Res 2000; 887: 460–464.

    CAS  PubMed  Article  Google Scholar 

  138. 138

    Fan W, Dinulescu DM, Butler AA, Zhou J, Marks DL, Cone RD . The central melanocortin system can directly regulate serum insulin levels. Endocrinology 2000; 141: 3072–3079.

    CAS  PubMed  Article  Google Scholar 

  139. 139

    Obici S, Feng Z, Tan J, Liu L, Karkanias G, Rossetti L . Central melanocortin receptors regulate insulin action. J Clin Invest 2001; 108: 1079–1085.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  140. 140

    Obici S, Zhang BB, Karkanias G, Rossetti L . Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med 2002; 8: 1376–1382.

    CAS  PubMed  Article  Google Scholar 

  141. 141

    Elmquist JK, Marcus JN . Rethinking the central causes of diabetes. Nat Med 2003; 9: 645–647.

    CAS  PubMed  Article  Google Scholar 

  142. 142

    Chamberlin NL, Du B, de Lacalle S, Saper CB . Recombinant adeno-associated virus vector: use for transgene expression and anterograde tract tracing in the CNS. Brain Res 1998; 793: 169–175.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  143. 143

    Kesterson RA . The melanocortin-3 receptor. In: Cone RD (ed). The Melanocortin Receptors. Humana Press: New Jersey, 2000, pp 385–403.

    Google Scholar 

  144. 144

    Butler AA, Kesterson RA, Khong K, Cullen MJ, Pelleymounter MA, Dekoning J et al. A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse. Endocrinology 2000; 141: 3518–3521.

    CAS  Article  Google Scholar 

  145. 145

    Chen AS, Marsh DJ, Trumbauer ME, Frazier EG, Guan XM, Yu H et al. Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass. Nat Genet 2000; 26: 97–102.

    CAS  Article  Google Scholar 

  146. 146

    Blomqvist AG, Herzog H . Y-receptor subtypes—how many more? Trends Neurosci 1997; 20: 294–298.

    CAS  Article  Google Scholar 

  147. 147

    Hökfelt T, Broberger C, Zhang X, Diez M, Kopp J, Xu Z et al. Neuropeptide Y: some viewpoints on a multifaceted peptide in the normal and diseased nervous system. Brain Res Brain Res Rev 1998; 26: 154–166.

    PubMed  Article  Google Scholar 

  148. 148

    Inui A . Neuropeptide Y feeding receptors: are multiple subtypes involved? Trends Pharmacol Sci 1999; 20: 43–46.

    CAS  PubMed  Article  Google Scholar 

  149. 149

    Allen YS, Adrian TE, Allen JM, Tatemoto K, Crow TJ, Bloom SR et al. Neuropeptide Y distribution in the rat brain. Science 1983; 221: 877–879.

    CAS  PubMed  Article  Google Scholar 

  150. 150

    Chronwall BM, DiMaggio DA, Massari VJ, Pickel VM, Ruggiero DA, O'Donohue TL . The anatomy of neuropeptide-Y-containing neurons in rat brain. Neuroscience 1985; 15: 1159–1181.

    CAS  PubMed  Article  Google Scholar 

  151. 151

    Eva C, Keinanen K, Monyer H, Seeburg P, Sprengel R . Molecular cloning of a novel G protein-coupled receptor that may belong to the neuropeptide receptor family. FEBS Lett 1990; 271: 81–84.

    CAS  PubMed  Article  Google Scholar 

  152. 152

    Kanatani A, Mashiko S, Murai N, Sugimoto N, Ito J, Fukuroda T et al. Role of the Y1 receptor in the regulation of neuropeptide Y-mediated feeding: comparison of wild-type, Y1 receptor-deficient, and Y5 receptor-deficient mice. Endocrinology 2000; 141: 1011–1016.

    CAS  Article  Google Scholar 

  153. 153

    Batterham RL, Cowley MA, Small CJ, Herzog H, Cohen MA, Dakin CL et al. Gut hormone PYY(3-36) physiologically inhibits food intake. Nature 2002; 418: 650–654.

    CAS  PubMed  Article  Google Scholar 

  154. 154

    Sainsbury A, Schwarzer C, Couzens M, Fetissov S, Furtinger S, Jenkins A et al. Important role of hypothalamic Y2 receptors in body weight regulation revealed in conditional knockout mice. Proc Natl Acad Sci USA 2002; 99: 8938–8943.

    CAS  PubMed  Article  Google Scholar 

  155. 155

    Gerald C, Walker MW, Criscione L, Gustafson EL, Batzl-Hartmann C, Smith KE et al. A receptor subtype involved in neuropeptide-Y-induced food intake. Nature 1996; 382: 168–171.

    CAS  Article  Google Scholar 

  156. 156

    Yamanaka A, Kunii K, Nambu T, Tsujino N, Sakai A, Matsuzaki I et al. Orexin-induced food intake involves neuropeptide Y pathway. Brain Res 2000; 859: 404–409.

    CAS  PubMed  Article  Google Scholar 

  157. 157

    Erickson JC, Clegg KE, Palmiter RD . Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y. Nature 1996; 381: 415–421.

    CAS  Article  Google Scholar 

  158. 158

    Kushi A, Sasai H, Koizumi H, Takeda N, Yokoyama M, Nakamura M . Obesity and mild hyperinsulinemia found in neuropeptide Y–Y1 receptor-deficient mice. Proc Natl Acad Sci USA 1998; 95: 15659–15664.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  159. 159

    Pedrazzini T, Seydoux J, Kunstner P, Aubert JF, Grouzmann E, Beermann F et al. Cardiovascular response, feeding behavior and locomotor activity in mice lacking the NPY Y1 receptor. Nat Med 1998; 4: 722–726.

    CAS  PubMed  Article  Google Scholar 

  160. 160

    Qian S, Chen H, Weingarth D, Trumbauer ME, Novi DE, Guan X et al. Neither agouti-related protein nor neuropeptide Y is critically required for the regulation of energy homeostasis in mice. Mol Cell Biol 2002; 22: 5027–5035.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  161. 161

    Erickson JC, Hollopeter G, Palmiter RD . Attenuation of the obesity syndrome of ob/ob mice by the loss of neuropeptide Y. Science 1996; 274: 1704–1707.

    CAS  Article  Google Scholar 

  162. 162

    Tschop M, Smiley DL, Heiman ML . Ghrelin induces adiposity in rodents. Nature 2000; 407: 908–913.

    CAS  Article  Google Scholar 

  163. 163

    Cowley MA, Smith RG, Diano S, Tschop M, Pronchuk N, Grove KL et al. The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 2003; 37: 649–661.

    CAS  PubMed  Article  Google Scholar 

  164. 164

    Chen HY, Trumbauer ME, Chen AS, Weingarth DT, Adams JR, Frazier EG et al. Orexigenic action of peripheral ghrelin is mediated by neuropeptide Y (NPY) and agouti-related protein (AgRP). Endocrinology 2004; 145: 2607–2612.

    CAS  PubMed  Article  Google Scholar 

  165. 165

    Wortley KE, Anderson KD, Garcia K, Murray JD, Malinova L, Liu R et al. Genetic deletion of ghrelin does not decrease food intake but influences metabolic fuel preference. Proc Natl Acad Sci USA 2004; 101: 8227–8232.

    CAS  PubMed  Article  Google Scholar 

  166. 166

    Naveilhan P, Neveu I, Arenas E, Ernfors P . Complementary and overlapping expression of Y1, Y2 and Y5 receptors in the developing and adult mouse nervous system. Neuroscience 1998; 87: 289–302.

    CAS  PubMed  Article  Google Scholar 

  167. 167

    Kopp J, Xu ZQ, Zhang X, Pedrazzini T, Herzog H, Kresse A et al. Expression of the neuropeptide Y Y1 receptor in the CNS of rat and of wild-type and Y1 receptor knock-out mice. Focus on immunohistochemical localization. Neuroscience 2002; 111: 443–532.

    CAS  PubMed  Article  Google Scholar 

  168. 168

    Kishi T, Aschkenasi CJ, Choi BJ, Lee CE, Liu H, Hollenberg AN et al. Neuropeptide Y Y1 receptor mRNA in the rat and mouse brain: Distribution and colocalization with melanocortin-4 receptor. J Comp Neurol 2005, in press.

  169. 169

    Figlewicz DP, Woods SC . Adiposity signals and brain reward mechanisms. Trends Pharmacol Sci 2000; 21: 235–236.

    CAS  PubMed  Article  Google Scholar 

  170. 170

    Saper CB . Brainstem modulation of sensation, movement, and consciousness. In: Kandel ER, Schwartz JH, Jessell TM (eds). Principles of Neural Science, 4th edn. McGraw-Hill: New York, 2000, pp 889–909.

    Google Scholar 

  171. 171

    Richardson NR, Gratton A . Behavior-relevant changes in nucleus accumbens dopamine transmission elicited by food reinforcement: an electrochemical study in rat. J Neurosci 1996; 16: 8160–8169.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  172. 172

    Hagan MM, Rushing PA, Benoit SC, Woods SC, Seeley RJ . Opioid receptor involvement in the effect of AgRP- (83-132) on food intake and food selection. Am J Physiol Regul Integr Comp Physiol 2001; 280: R814–R821.

    CAS  PubMed  Article  Google Scholar 

  173. 173

    Wisse BE, Frayo RS, Schwartz MW, Cummings DE . Reversal of cancer anorexia by blockade of central melanocortin receptors in rats. Endocrinology 2001; 142: 3292–3301.

    CAS  PubMed  Article  Google Scholar 

  174. 174

    Marks DL, Ling N, Cone RD . Role of the central melanocortin system in cachexia. Cancer Res 2001; 61: 1432–1438.

    CAS  Google Scholar 

  175. 175

    Mansour A, Fox CA, Burke S, Meng F, Thompson RC, Akil H et al. Mu, delta, and kappa opioid receptor mRNA expression in the rat CNS: an in situ hybridization study. J Comp Neurol 1994; 350: 412–438.

    CAS  Article  Google Scholar 

  176. 176

    Jacquet YF . Opiate effects after adrenocorticotropin or beta-endorphin injection in the periaqueductal gray matter of rats. Science 1978; 201: 1032–1034.

    CAS  PubMed  Article  Google Scholar 

  177. 177

    Alvaro JD, Taylor JR, Duman RS . Molecular and behavioral interactions between central melanocortins and cocaine. J Pharmacol Exp Ther 2003; 304: 391–399.

    CAS  PubMed  Article  Google Scholar 

  178. 178

    Hayward MD, Pintar JE, Low MJ . Selective reward deficit in mice lacking beta-endorphin and enkephalin. J Neurosci 2002; 22: 8251–8258.

    CAS  Article  Google Scholar 

  179. 179

    Bozarth MA, Wise RA . Anatomically distinct opiate receptor fields mediate reward and physical dependence. Science 1984; 224: 516–517.

    CAS  Article  Google Scholar 

  180. 180

    Thiele TE, Marsh DJ, Ste Marie L, Bernstein IL, Palmiter RD . Ethanol consumption and resistance are inversely related to neuropeptide Y levels. Nature 1998; 396: 366–369.

    CAS  Article  Google Scholar 

  181. 181

    Thiele TE, Koh MT, Pedrazzini T . Voluntary alcohol consumption is controlled via the neuropeptide Y Y1 receptor. J Neurosci 2002; 22: RC208.

    PubMed  Article  Google Scholar 

  182. 182

    Oswald LM, Wand GS . Opioids and alcoholism. Physiol Behav 2004; 81: 339–358.

    CAS  Article  Google Scholar 

  183. 183

    Kandel ER . Disorders of mood: depression, mania, and anxiety disorders. In: Kandel ER, Schwartz JH, Jessell TM (eds). Principles of Neural Science, 4th edition. McGraw-Hill: New York, 2000, pp 1209–1226.

    Google Scholar 

  184. 184

    Vergoni AV, Bertolini A, Wikberg JE, Schioth HB . Selective melanocortin MC4 receptor blockage reduces immobilization stress-induced anorexia in rats. Eur J Pharmacol 1999; 369: 11–15.

    CAS  PubMed  Article  Google Scholar 

  185. 185

    Chaki S, Ogawa S, Toda Y, Funakoshi T, Okuyama S . Involvement of the melanocortin MC4 receptor in stress-related behavior in rodents. Eur J Pharmacol 2003; 474: 95–101.

    CAS  PubMed  Article  Google Scholar 

  186. 186

    Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM . Neurobiology of depression. Neuron 2002; 34: 13–25.

    CAS  Article  Google Scholar 

  187. 187

    Quiroz JA, Singh J, Gould TD, Denicoff KD, Zarate CA, Manji HK . Emerging experimental therapeutics for bipolar disorder: clues from the molecular pathophysiology. Mol Psychiatry 2004; 9: 756–776.

    CAS  PubMed  Article  Google Scholar 

  188. 188

    Kawashima N, Chaki S, Okuyama S . Electrophysiological effects of melanocortin receptor ligands on neuronal activities of monoaminergic neurons in rats. Neurosci Lett 2003; 353: 119–122.

    CAS  PubMed  Article  Google Scholar 

  189. 189

    Tecott LH, Sun LM, Akana SF, Strack AM, Lowenstein DH, Dallman MF et al. Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors. Nature 1995; 374: 542–546.

    CAS  Article  Google Scholar 

  190. 190

    Kiss J, Leranth C, Halasz B . Serotoninergic endings on VIP-neurons in the suprachiasmatic nucleus and on ACTH-neurons in the arcuate nucleus of the rat hypothalamus. A combination of high resolution autoradiography and electron microscopic immunocytochemistry. Neurosci Lett 1984; 44: 119–124.

    CAS  PubMed  Article  Google Scholar 

  191. 191

    Heisler LK, Cowley MA, Tecott LH, Fan W, Low MJ, Smart JL et al. Activation of central melanocortin pathways by fenfluramine. Science 2002; 29: 609–611.

    Article  Google Scholar 

  192. 192

    Heisler LK, Cowley MA, Kishi T, Tecott LH, Fan W, Low MJ et al. Central serotonin and melanocortin pathways regulating energy homeostasis. Ann N Y Acad Sci 2003; 994: 169–174.

    CAS  PubMed  Article  Google Scholar 

  193. 193

    Connolly HM, Crary JL, McGoon MD, Hensrud DD, Edwards BS, Edwards WD et al. Valvular heart disease associated with fenfluramine–phentermine. N Engl J Med 1997; 337: 581–588.

    CAS  Article  Google Scholar 

  194. 194

    Zec N, Filiano JJ, Kinney HC . Anatomic relationships of the human arcuate nucleus of the medulla: a DiI-labeling study. J Neuropathol Exp Neurol 1997; 56: 509–522.

    CAS  PubMed  Article  Google Scholar 

  195. 195

    Sim LJ, Joseph SA . Arcuate nucleus projections to brainstem regions which modulate nociception. J Chem Neuroanat 199; 4: 97–109.

    Article  Google Scholar 

  196. 196

    Nonogaki K . New insights into sympathetic regulation of glucose and fat metabolism. Diabetologia 2000; 43: 533–549.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  197. 197

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

    CAS  Article  Google Scholar 

  198. 198

    Meltzer HY, Li Z, Kaneda Y, Ichikawa J . Serotonin receptors: their key role in drugs to treat schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2003; 27: 1159–1172.

    CAS  Article  Google Scholar 

  199. 199

    Monteleone P, Fabrazzo M, Tortorella A, La Pia S, Maj M . Pronounced early increase in circulating leptin predicts a lower weight gain during clozapine treatment. J Clin Psychopharmacol 2002; 22: 424–426.

    CAS  PubMed  Article  Google Scholar 

  200. 200

    Bayer L, Risold PY, Griffond B, Fellmann D . Rat diencephalic neurons producing melanin-concentrating hormone are influenced by ascending cholinergic projections. Neuroscience 1999; 91: 1087–1101.

    CAS  PubMed  Article  Google Scholar 

  201. 201

    Yamada M, Miyakawa T, Duttaroy A, Yamanaka A, Moriguchi T, Makita R et al. Mice lacking the M3 muscarinic acetylcholine receptor are hypophagic and lean. Nature 2001; 410: 207–212.

    CAS  Article  Google Scholar 

  202. 202

    Hallanger AE, Wainer BH . Ascending projections from the pedunculopontine tegmental nucleus and the adjacent mesopontine tegmentum in the rat. J Comp Neurol 1988; 274: 483–515.

    CAS  PubMed  Article  Google Scholar 

  203. 203

    Swanson LW, Köhler C, Björklund A . The limbic region. I: the septohippocampal system. In: Björklund A, Hökfelt T, Swanson LW (eds). Handbook of Chemical Neuroanatomy, vol 5, Integrated Systems. Elsevier: Amsterdam, 1987, pp 125–277.

    Google Scholar 

  204. 204

    Kishi T, Tsumori T, Ono K, Yokota S, Ishino H, Yasui Y . Topographical organization of projections from the subiculum to the hypothalamus in the rat. J Comp Neurol 2000; 419: 205–222.

    CAS  PubMed  Article  Google Scholar 

  205. 205

    Eyigor O, Centers A, Jennes L . Distribution of ionotropic glutamate receptor subunit mRNAs in the rat hypothalamus. J Comp Neurol 2001; 434: 101–124.

    CAS  PubMed  Article  Google Scholar 

  206. 206

    Caberlotto L, Fuxe K, Sedvall G, Hurd YL . Localization of neuropeptide Y Y1 mRNA in the human brain: abundant expression in cerebral cortex and striatum. Eur J Neurosci 1997; 9: 1212–1225.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  207. 207

    Wahlestedt C, Pich EM, Koob GF, Yee F, Heilig M . Modulation of anxiety and neuropeptide Y-Y1 receptors by antisense oligodeoxynucleotides. Science 1993; 259: 528–531.

    CAS  Article  Google Scholar 

  208. 208

    Thorsell A, Michalkiewicz M, Dumont Y, Quirion R, Caberlotto L, Rimondini R et al. Behavioral insensitivity to restraint stress, absent fear suppression of behavior and impaired spatial learning in transgenic rats with hippocampal neuropeptide Y overexpression. Proc Natl Acad Sci USA 2000; 97: 12852–12857.

    CAS  Article  Google Scholar 

  209. 209

    Winterer G, Weinberger DR . Genes, dopamine and cortical signal-to-noise ratio in schizophrenia. Trends Neurosci 2004; 27: 683–690.

    CAS  PubMed  Article  Google Scholar 

  210. 210

    Hanada R, Teranishi H, Pearson JT, Kurokawa M, Hosoda H, Fukushima N et al. Neuromedin U has a novel anorexigenic effect independent of the leptin signaling pathway. Nat Med 2004; 10: 1067–1073.

    CAS  PubMed  Article  Google Scholar 

  211. 211

    Howard AD, Wang R, Pong SS, Mellin TN, Strack A, Guan XM et al. Identification of receptors for neuromedin U and its role in feeding. Nature 2000; 406: 70–74.

    CAS  PubMed  Article  Google Scholar 

  212. 212

    Graham ES, Turnbull Y, Fotheringham P, Nilaweera K, Mercer JG, Morgan PJ et al. Neuromedin U and Neuromedin U receptor-2 expression in the mouse and rat hypothalamus: effects of nutritional status. J Neurochem 2003; 87: 1165–1173.

    CAS  PubMed  Article  Google Scholar 

Download references


This work was supported by the National Institute of Health; Grant number DK56116; Grant number DK53301; Grant number MH61583; Grant number DK 567658; Grant number 2 R01 DK041096-14A1, as well as by the Yamada Science Foundation and Kato Memorial Bioscience Foundation.

Author information



Corresponding author

Correspondence to T Kishi.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kishi, T., Elmquist, J. Body weight is regulated by the brain: a link between feeding and emotion. Mol Psychiatry 10, 132–146 (2005).

Download citation


  • energy homeostasis
  • hypothalamus
  • leptin
  • melanocortin
  • neuropeptide Y
  • reward
  • emotion
  • amines
  • amino-acid transmitters

Further reading


Quick links