The hypothalamus has a critical role in the regulation of feeding behavior, energy metabolism and reproduction. Galanin-like peptide (GALP), a novel 60 amino-acid peptide with a nonamidated C-terminus, was first discovered in porcine hypothalamus. GALP is mainly produced in the hypothalamic arcuate nucleus and is involved in the regulation of feeding behavior and energy metabolism, with GALP-containing neurons forming networks with several feeding-regulating peptide-containing neurons. The effects of GALP on food intake and body weight are complex. In rats, the central effect of GALP is to first stimulate and then reduce food intake, whereas in mice, GALP has an anorectic function. Furthermore, GALP regulates plasma luteinizing hormone levels through activation of gonadotropin-releasing hormone-producing neurons, suggesting that it is also involved in the reproductive system. This review summarizes the research on these topics and discusses current evidence regarding the function of GALP, particularly in relation to feeding and energy metabolism. We also discuss the effects of GALP activity on food intake, body weight and locomotor activity after intranasal infusion, a clinically viable mode of delivery.
Galanin, which was originally isolated from porcine upper small intestine, is a 29 amino-acid orexigenic peptide (30 in humans).1 Galanin has a widespread distribution in various brain regions such as the bed nucleus of the stria terminalis, amygdala, hippocampus, locus coeruleus, hypothalamus containing the preoptic suprachiasmatic nuclei, the supraoptic, the hypothalamic periventricular, the paraventricular (PVH) and the arcuate nucleus (ARC).2 In addition, galanin is also present in the sensory dorsal root ganglion cells, interneurons in the spinal cord and sympathetic neurons innervating the islet of Langerhans in the pancreas.3, 4 The galanin receptors are a member of the G-protein-coupled receptor family and have three known subtypes, GALR1, GALR2 and GALR3. On the basis of studies using pharmacological reagents, and the GALR1 and GALR2 knockout and galanin-overexpressing transgenic animals, galanin has been implicated in stimulating feeding behavior, cognitive performance and mood through the central mechanisms.5, 6
In 1999, galanin-like peptide (GALP) was isolated from the porcine hypothalamus by Ohtaki et al.7 on the basis of its ability to bind and activate galanin receptors in vitro. GALP is a novel 60 amino-acid peptide, the amino-acid residues (9th-21st) of which are identical with the biologically active N-terminal (1st-13th) portion of galanin,7 and its cDNA has been cloned from pig,7 rat,7, 8 mouse,9, 10 monkey11 and human.7 GALP can be detected in the general circulation, with a high concentration being found in the blood. Fasting for 48 h, but not for 24 h decreases both plasma GALP levels and GALP influx into the brain.12 To date, GALP has been shown to act as an agonist at all three galanin receptor subtypes in vitro, although it shows preference for GALR2 and GALR3, as compared with GALR1.7, 13
There is a considerable body of evidence linking GALP to the regulation of food intake, energy metabolism and reproduction,13, 14, 15, 16, 17, 18, 19 as well as fluid intake.20, 21 Furthermore, recent reports have suggested that GALP has a role in conditions such as epilepsy, Alzheimer's disease22 and diabetes,22, 23, 24 in addition to serving a vasoactive function.25 Here, we review a number of lines of investigation that have advanced our understanding of GALP systems in the hypothalamic nuclei, including localization and regulatory studies, and suggest possible future research that may help to clarify the precise functional significance of GALP.
GALP and its receptors
GALP was originally discovered as an endogenous ligand for galanin receptors in the porcine hypothalamus.7, 11, 26 The GALP gene comprises six exons with a structural organization similar to that of galanin (Figure 1).7, 11 GALP is encoded by a distinct gene located on chromosome 19 in humans, chromosome 7 in mice and chromosome 1 in rat. GALP (1st-60th) is cleaved from the precursor peptide preproGALP, which consists of 115–120 amino acids depending on the species, with GALP residues 9–21 being homologous to residues 1–13 of galanin (Figure 2). The second region of GALP (14th-60th) is dissimilar to any other known peptides and may represent the binding portion for a GALP-specific receptor.
Although the existence of a putative receptor for endogenous GALP has been suggested,27 the molecular identity of this receptor remains unknown. The members of the galanin peptide family were initially described as high-affinity agonists for both GALR1 and GALR2, with GALP binding preferentially to GALR2.7 In a later study, binding of GALP was observed at all three human galanin receptor subtypes expressed in human neuroblastoma cells, with the highest affinity being observed for GALR3, followed by GALR2; the putative fragment GALP (3rd-32nd) was also more effective than mature GALP (1st-60th) at displacing 125I-galanin.13
In situ hybridization mapping studies have shown that all three galanin receptor (GALR1–3) transcripts are present throughout the hypothalamus, including the PVH, dorsomedial nucleus (DMH), lateral hypothalamus (LHA) and periventricular nucleus, although each subtype exhibits a unique profile in terms of its abundance and distribution. In addition, GALR1 is expressed in the supraoptic nucleus and nucleus tractus solitarius.28, 29 When GALP is injected centrally, GALR2-expressing neurons in the PVH do not show c-Fos expression, whereas GALR1-expressing neurons in the supraoptic nucleus display strong c-Fos expression. Thus, there are differences in the distribution of neurons activated by GALP and those expressing its receptor. These results imply the existence of an unidentified galanin receptor that may be specific for GALP.
The receptor responsible for the anorectic function of GALP is currently unknown. GALP reduces food intake and body weight to the same degree in GALR1- and GALR2-deficient mice when compared with wild-type mice,30 and GALR2-deficient mice do not show abnormal feeding behavior.15 Furthermore, the GALR2/3 agonist (AR-M1896) has no effect on feeding or body weight in either the rat or the mouse.19 Therefore, more studies are required to determine the receptor mediating the anorectic actions of GALP but, as this peptide can act differently in rodents when compared with galanin, a new/unidentified GALP-specific receptor is likely to be involved.
Distribution and localization of GALP-containing neurons
Galanin is widely distributed in the brain, but GALP is found only in neurons in the hypothalamic ARC, the median eminence and the posterior pituitary gland. Using in situ hybridization, GALP mRNA has been shown to be distributed within the periventricular regions of the ARC,26, 31, 32 as well as in the median eminence26, 31 and posterior pituitary gland of the rat.21 Larm et al.32 have reported that GALP mRNA is highly expressed in the periventricular region of the ARC, gradually increasing between postnatal days 8 and 14, before markedly increasing between days 14 and 40, which represent the weaning and pubertal period in rats.33 The expression of GALP may therefore be associated with developmental changes linked to weaning, feeding and maturation of reproductive function.33
Subsequently, based on immunohistochemical analysis using an anti-GALP monoclonal antibody, GALP-positive neuronal cell bodies have been demonstrated in the ARC, being particularly dense in its medial posterior section and in the posterior pituitary.34, 35, 36 In addition, GALP-positive cell bodies are distributed in the median eminence and in infundibular stalk, but are absent from other hypothalamic nuclei and brain loci.9, 35 GALP-containing neurons in the ARC are reported to be different from the leptin receptor-expressing neurons that express neuropeptide Y (NPY)/agouti-related protein and galanin.32, 36, 37, 38 GALP has been shown to be coexpressed with α-melanocyte-stimulating hormone, which is derived from pro-opiomelanocortin in neurons in the ARC,36 with orexin-1 receptor immunoreactivity also being observed in a few GALP-positive neurons.38 We have previously reported that 3–12% of GALP-positive cells contain α-melanocyte-stimulating hormone-like immunoreactivity.36 In spite of these findings, there are no other neuropeptides or transmitters that are colocalized with GALP in the ARC, suggesting that it is a unique peptide.
GALP-positive fibers in the rat ARC project to several hypothalamic nuclei. There are at least two major proposed GALP neural pathways, one in which GALP-containing neurons project from the ARC to the PVH and the other in which they project to the medial preoptic area, the bed nucleus of the stria terminalis and the lateral septal nucleus (Figure 3). GALP-positive cell bodies are present from the rostral to the caudal part of the ARC, with fibers projecting to PVH, bed nucleus of the stria terminalis, medial preoptic area and lateral septal nucleus.35, 39 In addition, GALP-positive fibers are found in the LHA near the fornix.39
With regard to the target for GALP-containing neurons, morphological studies have shown that GALP-positive fibers appear to have direct contact with orexin- and melanin-concentrating hormone (MCH)-containing neurons in the LHA.39 In addition, we have found that GALP-positive nerve fibers appear to make direct contact with tyrosine hydroxylase-containing neurons in the ARC,40 suggesting that GALP may interact with dopaminergic neurons in this region. At the ultrastructural level, GALP-containing neurons in the ARC receive synapses from immunonegative axon terminals that are symmetrical in the case of synapses on the perikarya, and both asymmetric and symmetric for dendritic processes.41 The axon terminals of these GALP-positive neurons also often make synapses, all of which are symmetric, on immunonegative dendrites.41 Synapses are also found between axon terminals and perikarya, as well as dendrites, of GALP-positive neurons.41 GALP-positive axon terminals have been found to make synapses on orexin-positive cell bodies and dendrites, but not on MCH-positive neurons in the LHA.42 Further, in vitro studies have suggested additional targets for GALP in the hypothalamus, with activation of growth hormone-releasing hormone-containing neurons isolated from the ARC, this being reflected by increased cytosolic Ca2+ levels.43 In electrophysiological studies of ARC neurons in hypothalamic slices, GALP was shown to inhibit excitatory and inhibitory postsynaptic currents in a similar way to galanin, whereas the two peptides differentially affected the intrinsic membrane properties, with galanin inducing hyperpolarization of the resting membrane potential and GALP having no effect.44 Galanin also suppressed spontaneous firing in the ARC, whereas GALP produced a mixture of suppression and enhancement of firing, and appeared to antagonize the galanin effects.44
Regulation of GALP neurons
Morphological studies have shown that GALP-containing neurons in the ARC may be a target for the orexigenic neuropeptides, NPY and orexin. Orexin-containing neurons have been reported to make contact with GALP-positive neurons in the ARC, with 9% of these neurons expressing orexin-1 receptor protein.38 Furthermore, NPY-positive fibers project to GALP-containing neurons in the ARC and PVH.36 These morphological studies suggest a potential role for GALP in feeding and energy metabolism. GALP may exert this effect through the galanin receptors GALR1–3, and is a potential target for NPY and/or orexin.
It has previously been shown that >85% of GALP-containing neurons express the leptin receptor.35 Fasting decreases both the number of GALP-expressing neurons26 and the expression of GALP mRNA.45 Leptin administration restores GALP-expressing cells in fasted rats26 and ob/ob mice.9 It also induces a significant increase in GALP mRNA levels in the hypothalamus, and GALP mRNA levels are reduced in the hypothalamus of Zucker obese rats and db/db and ob/ob obese mice,10 with GALP mRNA expression in ob/ob mice being reversed by leptin replacement.10 These findings clearly show that leptin positively regulates GALP-related neuronal activity in the hypothalamus. Fraley et al.23 have also demonstrated that GALP-containing neurons are responsive to changes in circulating concentrations of insulin using streptozotocin-induced diabetic rats and central injection of insulin into the fasted rat.
On the basis of studies using castrated, ovariectomized, adrenalectomized and growth hormone-deficient rats, neither gonadal or adrenal steroids nor growth hormone appear to be involved in the expression of GALP mRNA in the pituicytes of the posterior pituitary.46 Thyroidectomy in rats leads to a reduction in GALP mRNA expression, as compared with the intact control, with thyroxine replacement normalizing this expression.46 The expression of GALP mRNA is increased in the posterior pituitary of lactating rats, whereas GALP mRNA expression in the hypothalamic ARC is not affected by lactation.46 These findings suggest that GALP mRNA in the pituicytes is controlled by thyroid hormone, and that GALP mRNA is physiologically associated with the activation of oxytocin- and vasopressin-secreting neurons during lactation.46 Catecholaminergic neurons in the A1/C1 region in the medulla oblongata are glucose responsive and project to the ARC,47 and A1/C1 efferents to the hypothalamus are involved in the glucostatic regulation of GALP mRNA, feeding behavior and LH secretion.47
Neuronal network of GALP neurons
Central administration of GALP activates neurons in various regions of the rat brain (Figure 4). However, different doses of GALP lead to different patterns of GALP-induced c-Fos expression. Injection of GALP into the lateral ventricle activates several brain regions, including the hypothalamic ARC, medial preoptic area, supraoptic nucleus, DMH, periventricular nucleus and LHA, as well as the nucleus tractus solitarius of the medulla.48 Furthermore, the same paradigm activates astrocytes but not microglia.48 In contrast, infusion of GALP into the third ventricle induces c-Fos expression in the caudal preoptic area, ARC, median eminence and horizontal limb of the diagonal band of Broca.49 However, it has not yet been determined what kind of neurons are activated by GALP, and further studies are required to reveal the physiological significance of the effect of GALP on both neurons and astrocytes.
NPY- and orexin-containing axon terminals lie in close apposition with GALP-containing neurons in the ARC.36, 38 Using a double-labeling in situ hybridization method, Cunningham et al.50 have demonstrated that GALP-containing neurons in the macaque express both NPY Y1 and serotonin 2C receptor. In an in vitro study of GALP-treated hypothalamic explants, GALP-induced hyperphagia appeared to be mediated through an increase in NPY release and a decrease in cocaine- and amphetamine-regulated transcript (CART) release.26 However, GALP may not be the target of neurons that contain NPY and/or pro-opiomelanocortin, as these neurons do not respond to GALP in vitro.43
Orexigenic effect of GALP on feeding behavior and energy metabolism
The intracerebroventricular (i.c.v.) infusion of GALP into the rat lateral ventricle increases cumulative food intake in the first 1–2 h.48, 49, 51 The potency of GALP is 10 times higher than that of galanin in terms of the stimulation of food intake,49, 52 and thus it is considered that GALP is an orexigenic peptide. Furthermore, the orexigenic effects of GALP are intensified in high-fat-diet-induced obese rats,53 although these findings have yet to be confirmed in mice. In an in vitro study of GALP-treated rat hypothalamic explants, it was shown that GALP-induced hyperphagia could be mediated by an increase in NPY release and a decrease in CART release.51 In vivo, the number of pro-opiomelanocortin mRNA-expressing cells in the ARC of the ob/ob mouse is reduced after chronic GALP injection.54 NPY release in the DMH has been proposed to have a role in mediating the effects of GALP on feeding regulation,55 although another study reported no such effect.56 Furthermore, inhibition of endogenous NPY or NPY receptors suppresses GALP-induced acute orexigenic effect in rats.55 These findings suggest that GALP promotes feeding behavior through suppression of the anorexigenic pro-opiomelanocortin system and NPY release from the DMH.
Our recent experimental data suggest that the orexigenic actions of GALP are mediated by orexin in the LHA, based on the electromicroscopic observation that GALP-positive axon terminal appears to have made synapse with orexin-positive perikaryon and dendritic process in the rat LHA.39, 42 Furthermore, i.c.v. injection of GALP in the rat induces expression of c-Fos in orexin-positive neurons in the LHA, and blocking the actions of orexin with an anti-orexin antibody inhibits GALP-induced hyperphagia.42 However, injection of GALP into the LHA fails to stimulate feeding.55, 56 One possible explanation is that the distribution of orexin is different within the LHA, which is long between rostral and caudal part.57 Therefore, it is not yet known whether a position for infusions is suitable. Further study is required to address the issue whether GALP has a direct effect on orexin-containing neurons in the LHA.
GALP-containing fibers also make direct contact with MCH-containing neurons in the LHA.39 However, in contrast to orexin, i.c.v. injection of GALP fails to induce c-Fos expression in MCH neurons.42 Thus, the contribution of MCH to the orexigenic actions of GALP remains unknown. Our findings, together with those of others, suggest that GALP stimulates feeding through the release of orexin in the LHA and/or NPY in the DMH of rats. Nonetheless, the relationship between the action of GALP on these two neuropeptides needs to be clarified in further studies. Direct microinjection of GALP into the medial preoptic area or PVH also promotes food intake,56 suggesting the possibility that other nuclei such as the medial preoptic area and PVH may have roles in the regulation of feeding behavior.
The receptor responsible for the orexigenic effect of GALP in rats is likely to be GALR1, as it has been shown to be expressed in the LHA and DMH,28 and in vivo studies using agonists of GALR1–3 have demonstrated that activation of GALR1 stimulates feeding behavior.29 There is no evidence to support a role for GALR2 or GALR3 in orexigenic function in rats.19, 29, 51 It is possible that the GALR1 mediates the transient orexigenic effects of GALP through actions on orexin- and NPY-containing neurons in the LHA and DMH, respectively.
Recently, it was reported that high-fat diet-fed GALP-deficient mice gain less body weight compared with wild-type animals.58 Moreover, GALP-deficient mice do not change the balance of energy intake and expenditure under normal nutritional conditions,58 suggesting that GALP may regulate energy balance to imposed nutritional circumstances.58
Anorexigenic effect of GALP on feeding behavior and energy metabolism
In experiments with rat and mouse, both body weight gain and food intake were reduced at 24 h after injection of GALP.52, 59 In genetically obese rodents, such as the ob/ob, db/db mice and Zucker rats (fa/fa), both gene and/or peptide expression of GALP is undetectable in the ARC9, 10, 60, 61 as well as in hypoleptinemic diabetic animals, and in rats that are acutely or chronically deprived of food.23, 61 Although some studies using rat, but not mouse, have indicated a transient increase in food intake after i.c.v. injection of GALP, it is possible that decrease in GALP level in the ARC causes obesity. Thus, it is possible that GALP has a physiologically important role in anorexigenic action.18, 47 Interestingly, GALP can be detected in the general circulation, and fasting decreases both plasma levels and GALP influx into the brain.12 These findings suggest that GALP conveys a satiety signal from peripheral organs to brain, although there are few studies mentioning the presence of GALP-producing cells in the peripheral organs. Central and/or peripheral infusion of leptin restores to normal level of the expression of GALP mRNA in the ARC of fasted rats and leptin-deficient obese ob/ob mice.9, 10, 26 Leptin directly up-regulates GALP neuronal activity in the hypothalamus, as more than 85% of GALP neurons express leptin receptors in the ARC of rats and macaques.23,35 However, the effect of elevated endogenous leptin on GALP expression in the normal animals is less clear. Although rats fed a diet high in either saturated or polyunsaturated fats become hyperleptinemic, GALP mRNA is only increased in the ARC of the obese rat fed a high polyunsaturated fat diet 62. This result indicated that apart from leptin, GALP mRNA expression level might be affected by various forms of dietary fat.
Although the injection of GALP into the lateral ventricle results in a decrease in food intake in the first hour after infusion in mice, this is not the case for rats.59 Krasnow et al.59 speculate that the observed recovery of food intake and body weight are attributable to the activation of a compensatory neural feeding pathway, driving the animals to eat in an attempt to restore body weight back to normal. Although the i.c.v. injection of GALP into ob/ob mice initially decreases both food intake and body weight gain,54 chronic GALP injection, results in a sustained decrease in body weight and an increase in core body temperature, despite the recovery of food intake.54 In a pair-fed study, chronic GALP administration produced a greater decrease in body weight than that which occurred in the control.54 Taken together, these findings lead us to theorized that GALP-positive neurons in the ARC are a target for leptin, and that GALP could be used as a replacement for leptin.
Core body temperature increased in a dose-dependent manner, and this increase was maintained for 6–8 h after injection of GALP.52 Cytokines such as interleukin-1 (IL-1) and IL-6 are important mediators of inflammation that induce fever by the release of prostaglandins in the hypothalamus. Central administration of GALP induced c-Fos expression in astrocytes or neurons in the peri-third ventricle. Astrocytes express cyclooxygenase, which is a rate-limiting enzyme for the biosynthesis of prostaglandins.48 Pretreatment of cyclooxygenase inhibitor completely blocks GALP-induced thermogenesis.52 Moreover, the studies using IL-1α, IL-1β or IL-1 type-I receptor-deficient mice demonstrates that GALP-induced thermogenesis, body weight loss and anorexic actions are mediated by IL-1 type-I receptor.63 Leptin reduces food intake and body weight, but increases the core body temperature in rodents, partly through IL-1 system.64 These findings suggest that proinflammatory cytokines mediate the thermogenesis by GALP.18, 65
Brown adipose tissue is recognized as the primary site of thermogenesis, and potentially functions to regulate body weight in rodents.66 GALP treatment has been shown to increase both uncoupling protein-1 mRNA and protein expression in brown adipose tissue thermogenesis in the ob/ob mouse.54 These findings suggest that GALP may partly mediate energy metabolism through thermogenesis by long-term activation of the sympathetic nervous system. Polysaccharide was reported to induce GALP mRNA expression in the rat posterior pituitary, suggesting that GALP may also be involved in exacerbated thermogenesis in response to inflammatory stress.67 Thus, GALP can have both an anorectic and a catabolic action.
The hypothalamo–pituitary–thyroid axis and activation of uncoupling protein-1 by way of sympathetic nervous system stimulation are known to influence thermogenesis and basal metabolic rate.68, 69 The PVH, which is associated with the regulation of food ingestion and contains numerous thyrotropin-releasing-hormone-containing neurons,70 acts as the central hypothalamic regulator of the hypothalamo–pituitary–thyroid axis. Similar to other orexigenic peptides such as NPY71 and agouti-related protein,72 administration of GALP into the PVH decreases the level of plasma thyroid-simulating hormone within 10 min.51 In other words, orexigenic peptides exhibit an anabolic action by the suppression of thyroid hormone release. However, GALP has no effect on the release of thyroid-simulating hormone directly from dispersed rat pituitary cells. Although GALP inhibits the release of thyrotropin-releasing hormone from hypothalamic explants in vitro, GALP-positive nerve terminals are associated with few thyrotropin-releasing hormone neurons in the medial parvocellular subdivision of the PVH.70 These findings suggest that, although GALP has an anabolic action during an acute phase, it may influence the hypothalamo–pituitary–thyroid axis through an indirect mechanism to suppress circulating thyroid-simulating hormone levels.
Recently, our group has been investigating the intranasal delivery of GALP into the brain in order to determine the potential clinical efficacy based on anorexigenic effect of GALP. Intranasal infusion provided a 40-to 100-fold improvement in targeting brain versus peripheral tissue compared with intravenous infusion.73 This study indicates that intranasal administration is an effective route for the delivery of GALP into the brain.73 We have also been studying the physiological effects of intranasal infusion of GALP on body weight, food intake, water intake and locomotor activity in mice. Intranasal infusion of GALP significantly reduced body weight over the course of a week. However, food and water intake, as well as locomotor activity, remained unchanged (Shiba et al., manuscript in preparation). Our results strongly suggest that intranasal administration of GALP will be useful for obese people to control obesity and life-style-related diseases in the future. However, the authors emphasize that the mechanism of body weight loss by intranasal administration of GALP remains to be clarified.
GALP has dichotomous actions on energy balance in rat (transient hyperphagia followed by reduction of food intake and body weight), in contrast to acting as a reducing agent in both feeding behavior and body weight loss in mouse. Transient orexigenic actions of GALP are mediated through NPY and orexin pathway in the rat. The long-term anorectic and thermogenesis of GALP are mediated through proinflammatory pathway in rodents. The findings of the studies reviewed here highlight the fact that GALP is involved in numerous physiological processes, including feeding behavior and energy metabolism (Table 1), through neuronal networks in the hypothalamus (Figure 5). Further elucidation of the functions of GALP is important for the discovery of therapeutic drugs, and for the treatment and prevention of obesity and related disorders.
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We thank Dr Tetsuya Ohtaki of the Takeda Pharmaceutical Company Ltd. (Japan) and Ms Sachi Kato for their support in completing this work. We are also grateful to Dr Randeep Rakwal (Showa University) for his help in reading the manuscript. This study was supported, in part, by the High-Technology Research Center Project from the Ministry of Education, Sports, Science and Technology (Japan).
The authors declare no conflict of interest.
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