Transcriptomic (DNA Microarray) and Metabolome (LC-TOF-MS) Analyses of the Liver in High-Fat Diet Mice after Intranasal Administration of GALP (Galanin-like Peptide).

The aim of this research was to test the efficacy and potential clinical application of intranasal administration of galanin-like peptide (GALP) as an anti-obesity treatment under the hypothesis that GALP prevents obesity in mice fed a high-fat diet (HFD). Focusing on the mechanism of regulation of lipid metabolism in peripheral tissues via the autonomic nervous system, we confirmed that, compared with a control (saline), intranasally administered GALP prevented further body weight gain in diet-induced obesity (DIO) mice with continued access to an HFD. Using an omics-based approach, we identified several genes and metabolites in the liver tissue of DIO mice that were altered by the administration of intranasal GALP. We used whole-genome DNA microarray and metabolomics analyses to determine the anti-obesity effects of intranasal GALP in DIO mice fed an HFD. Transcriptomic profiling revealed the upregulation of flavin-containing dimethylaniline monooxygenase 3 (Fmo3), metallothionein 1 and 2 (Mt1 and Mt2, respectively), and the Aldh1a3, Defa3, and Defa20 genes. Analysis using the DAVID tool showed that intranasal GALP enhanced gene expression related to fatty acid elongation and unsaturated fatty acid synthesis and downregulated gene expression related to lipid and cholesterol synthesis, fat absorption, bile uptake, and excretion. Metabolite analysis revealed increased levels of coenzyme Q10 and oleoylethanolamide in the liver tissue, increased levels of deoxycholic acid (DCA) and taurocholic acid (TCA) in the bile acids, increased levels of taurochenodeoxycholic acid (TCDCA), and decreased levels of ursodeoxycholic acid (UDCA). In conclusion, intranasal GALP administration alleviated weight gain in obese mice fed an HFD via mechanisms involving antioxidant, anti-inflammatory, and fatty acid metabolism effects and genetic alterations. The gene expression data are publicly available at NCBI GSE243376.

Molecular programs of regional specification and neural stem cell fate progression in macaque telencephalon.

During early telencephalic development, intricate processes of regional patterning and neural stem cell (NSC) fate specification take place. However, our understanding of these processes in primates, including both conserved and species-specific features, remains limited. Here, we profiled 761,529 single-cell transcriptomes from multiple regions of the prenatal macaque telencephalon. We deciphered the molecular programs of the early organizing centers and their cross-talk with NSCs, revealing primate-biased galanin-like peptide (GALP) signaling in the anteroventral telencephalon. Regional transcriptomic variations were observed along the frontotemporal axis during early stages of neocortical NSC progression and in neurons and astrocytes. Additionally, we found that genes associated with neuropsychiatric disorders and brain cancer risk might play critical roles in the early telencephalic organizers and during NSC progression.

Effects of Galp and alarin peptides on HPA axis gene expression and adrenal function: In vivo experiments.

BACKGROUND: Many experimental data indicate interactions between peptides involved in the control of food intake, energy homeostasis and adrenocortical hormone release. Glucocorticoids stimulate or inhibit the secretion of orexigenic and anorexigenic peptides, which in turn are involved in the regulation of adrenal growth, structure and function. Galanin-like peptide (Galp) and alarin (Ala) are involved in the regulation of food intake. Galp and Ala mRNAs have already been shown to be present in the arcuate nucleus (ARC) of the hypothalamus in both rats and mice. OBJECTIVES: To investigate the expression of Ala, Galp and their receptors in the hypothalamus and pituitary and adrenal glands of the rat hypothalamic-pituitary-adrenal (HPA) axis after intraperitoneal administration of peptides in vivo. MATERIAL AND METHODS: Experimental in vivo models were used: acute and long-term exposure to peptides. RESULTS: The expression of Galp, Ala, their receptors, and steroidogenesis enzymes was analyzed using quantitative real-time polymerase chain reaction (qRT-PCR). Statistically significant expression changes were found in the hypothalamus and pituitary after 1-hour exposure to the peptides, such as a decrease in corticotropin-releasing hormone (CRH) expression after Ala, Galp and adrenocorticotropic hormone (ACTH) administration, and a decrease in the expression of receptors for galanin (Gal) (Galr1 and Galr2). In the pituitary, there was a statistically significant increase in the expression of Ala, Galr1, Galr2, and Galr3 receptors 1 h after Galp administration. In the adrenal glands, only a statistically significant decrease in Galr2 expression was observed after 1 h of Ala 0.5 administration. The mRNA expression of steroidogenesis enzymes also changed: for example, the expression of cholesterol desmolase increased 24 h after Ala peptide administration. CONCLUSIONS: The results indicate that the peptides tested under in vivo conditions can alter the expression of the peptides tested, as well as of Galp, Ala and Gal receptors and steroidogenesis enzymes - Cyp11a1 (cholesterol desmolase), Cyp11b1 (11ß-hydroxylase) and Cyp11b2 (aldosterone synthase).

Superoxide anions modulate the effects of alarin in the paraventricular nucleus on sympathetic activity and blood pressure in spontaneously hypertensive rats.

Neuropeptides are involved in the regulation of the sympathetic activity and blood pressure in the paraventricular nucleus of the hypothalamus (PVN). The present study was designed to determine how alarin modulates the renal sympathetic nerve activity (RSNA), arterial blood pressure and mean arterial pressure (MAP) in the PVN, and whether superoxide anions regulate the effects of alarin in the PVN of spontaneously hypertensive rats (SHRs). Acute experiment was carried out with male Wistar-Kyoto rats (WKY) and SHRs under anesthesia. RSNA, systolic blood pressure (SBP), diastolic blood pressure (DBP), and MAP were measured. Alarin microinjection into the PVN increased RSNA (7.8 ± 1.8 vs. 14.8 ± 2.3%), SBP (5.9 ± 1.4 vs. 12.1 ± 1.6 mmHg), DBP (5.1 ± 0.8 vs. 10.0 ± 1.1 mmHg), and MAP (5.4 ± 1.2 vs. 10.7 ± 1.3 mmHg) in WKY rats and SHRs,. Alarin antagonist ala6-25 Cys decreased RSNA, SBP, DBP, and MAP in SHRs, and inhibited the effects of alarin. The alarin level was increased in the PVN of SHR compared to WKY rats. (29.7 ± 4.9 vs. 14.6 ± 2.4 pg/mg protein). PVN microinjection of superoxide anion scavengers tempol and tiron, or NAD(P)H oxidase inhibitor apocynin, decreased RSNA, SBP, DBP, and MAP in SHRs, and inhibited the effects of alarin, but the superoxide dismutase inhibitor diethyldithiocarbamic acid potentiated the effects of alarin. Superoxide anions and NAD(P)H oxidase activity levels in the PVN were increased by alarin, but decreased by alarin antagonist ala6-25 Cys. The alarin-induced increases in superoxide anions and NAD(P)H oxidase activity levels were abolished by pre-treatment with ala6-25 Cys. The results suggest that alarin in the PVN increases sympathetic outflow and blood pressure. The enhanced activity of endogenous alarin in the PVN contributes to sympathetic activation in hypertension, and the superoxide anion is involved in these alarin-mediated processes in the PVN.

Expression profile of Galp, alarin and their receptors in rat adrenal gland.

BACKGROUND: Galanin-like peptide (Galp) and alarin (Ala) are 2 new members of the galanin peptide family. Galanin (Gal), the "parental" peptide of the entire family, is known to regulate numerous physiological processes, including energy and osmotic homeostasis, reproduction, food intake, and secretion of adrenocortical hormones. Galp and Ala are known to regulate food intake. In the rat, Galp mRNA has been found in the brain, exclusively in the hypothalamic arcuate nucleus (ARC) and median eminence, which are involved in the regulation of energy homeostasis. Alarin-like immunoreactivity is present in the locus coeruleus (LC) and the ARC of rats and mice. OBJECTIVES: The aim of the study was to investigate the expression of Ala, Galp and their receptors in the organs of the hypothalamo-pituitary-adrenal (HPA) axis of the rat. MATERIAL AND METHODS: The expression of the examined genes was measured in different models of adrenal growth of the rat in vivo (postnatal ontogenesis, compensatory adrenal growth, adrenocortical regeneration, adrenocorticotropic hormone (ACTH) administration). The expression was evaluated using the Affymetrix® microarray system or quantitative polymerase chain reaction (qPCR). RESULTS: The expression of Ala gene was observed in each organ of the HPA axis (the hypothalamus, hypophysis and adrenal gland). The elevated level of expression of this gene was observed in the pituitary of 2-day rats, while very low levels of Ala mRNA were observed in the adrenals. Galp mRNA expression was observed only in the hypothalamus and the hypophysis during postnatal ontogenesis. The expression of Gal receptors was demonstrated in the hypothalamus, the hypophysis and the adrenal gland. In different compartments of the adrenal glands of adult, intact male and female rats, the expression of Ala, Galp and galanin receptor 1 (Galr1) genes was negligible, but the expression of galanin receptor 2 (Galr2), galanin receptor 3 (Galr3) and neurotrophic receptor tyrosine kinase 2 (Ntrk2) genes was noticeable. CONCLUSIONS: The examined genes showed different expression levels within the studied HPA axis; some of them were neither expressed in the hypothalamus or the pituitary gland, nor in the adrenal gland.

Regulation of Feeding Behavior and Energy Metabolism by Galanin-like Peptide (GALP): A Novel Strategy to Fight Against Obesity.

Galanin-like peptide (GALP) is composed of 60 amino acid residues and its sequence is highly homologous across species. GALP is produced in the hypothalamic arcuate nucleus and has diverse physiological effects such as the regulation of feeding, energy metabolism, and reproductive behavior. GALP-containing neurons express leptin receptors and these neurons form networks in the hypothalamus that contain various peptides that regulate feeding behavior. Recent studies have revealed that GALP has a central anti-obesity action in addition to its role in food intake regulation. Furthermore, we have found that the respiratory quotient declines shortly after administration of GALP into the lateral ventricle. This suggests that lipid metabolism is accelerated by GALP administration, and identifies a new physiological action for this peptide. In this review article, we summarize our recent research focusing on the mechanism whereby GALP regulates feeding and energy metabolism. We concentrate on the mechanism of regulation of lipid metabolism in peripheral tissues via the autonomic nervous system and outline the effectiveness of the nasal administration of GALP and basic research towards its clinical application.

Brain and intestinal expression of galanin-like peptide (GALP), galanin receptor R1 and galanin receptor R2, and GALP regulation of food intake in goldfish (Carassius auratus).

Galanin-like peptide (GALP) is a 60 amino acid neuropeptide originally discovered from porcine hypothalamus, and is involved in the regulation of food intake in mammals. Since its discovery, GALP and its receptors (GALR1 and GALR2) have been characterized in mammals, but no publications are available on GALP in fish and other non-mammals. The present study aimed to characterize brain and intestinal GALP and its receptors using immunohistochemistry in a teleost, the goldfish (Carassius auratus), and to study its effects on feeding behavior. Immunostaining of brain sections shows the presence of GALP- and GALR1- and GALR2-like immunoreactive cells in different encephalic areas, including the telencephalon, some hypothalamic nuclei, the optic tectum, the torus longitudinalis and the cerebellum. Signal for GALP was also observed in the fasciculus retroflexus. In the gut, GALP-and GALR1 and GALR2 immunoreactive cells were detected in the mucosa. Results from the feeding study demonstrate that intracerebroventricular administration of GALP (1ng/g bodyweight) increases goldfish food intake at 1h post-injection. These observations form the first report on the presence of GALP in the fish brain and gut, and also on its modulatory role on fish feeding behavior. GALP, as in mammals, appears to be a functional neuropeptide in goldfish.

Autonomic nervous system-mediated effects of galanin-like peptide on lipid metabolism in liver and adipose tissue.

Galanin-like peptide (GALP) is a neuropeptide involved in the regulation of feeding behavior and energy metabolism in mammals. While a weight loss effect of GALP has been reported, its effects on lipid metabolism have not been investigated. The aim of this study was to determine if GALP regulates lipid metabolism in liver and adipose tissue via an action on the sympathetic nervous system. The respiratory exchange ratio of mice administered GALP intracerebroventricularly was lower than that of saline-treated animals, and fatty acid oxidation-related gene mRNA levels were increased in the liver. Even though the respiratory exchange ratio was reduced by GALP, this change was not significant when mice were treated with the sympatholytic drug, guanethidine. Lipolysis-related gene mRNA levels were increased in the adipose tissue of GALP-treated mice compared with saline-treated animals. These results show that GALP stimulates fatty acid ß-oxidation in liver and lipolysis in adipose tissue, and suggest that the anti-obesity effect of GALP may be due to anorexigenic actions and improvement of lipid metabolism in peripheral tissues via the sympathetic nervous system.

[Galanin-like peptide (GALP): localization, receptors and biological function]. / Peptyd galaninopodobny (GALP): wystepowanie, receptory i funkcja biologiczna.

Galanin-like peptide (GALP) was isolated from porcine hypothalamus in 1999 on the basis of its ability to activate galanin receptors in vitro. Extensive studies carried out since the discovery of GALP contributed to the significant progress in our knowledge regarding this neuropeptide. GALP is synthesized mainly in the neurons of the hypothalamic arcuate nucleus and in the pituicytes of the posterior pituitary. The effects of GALP are mediated by well-characterized G-protein coupled galanin receptor subtypes. The fact that GALP shares homology only with 13 amino acids of the galanin sequence suggests that it might also interact with its own specific receptor. This relatively small 60-amino acid peptide belongs to a growing list of neuropeptides that play a crucial role in the regulation of food intake, energy balance and the reproductive axis. This peptide appears to be involved in integrating energy balance control and reproduction. The paper presents the current state of knowledge about the biosynthesis, structure, localization of GALP and its receptors, with particular emphasis on its role. This review will attempt to summarize the significant body of in vitro and in vivo studies conducted so far, concerning the effects of GALP.

The regulative effect of galanin family members on link of energy metabolism and reproduction.

It is essential for the species survival that an efficient coordination between energy storage and reproduction through endocrine regulation. The neuropeptide galanin, one of the endocrine hormones, can potently coordinate energy metabolism and the activities of hypothalamic-pituitary-gonadal reproductive axis to adjust synthesis and release of metabolic and reproductive hormones in animals and humans. However, few papers have summarized the regulative effect of the galanin family members on the link of energy storage and reproduction as yet. To address this issue, this review attempts to summarize the current information available about the regulative effect of galanin, galanin-like peptide and alarin on the metabolic and reproductive events, with special emphasis on the interactions between galanin and hypothalamic gonadotropin-releasing hormone, pituitary luteinizing hormone and ovarian hormones. This research line will further deepen our understanding of the physiological roles of the galanin family in regulating the link of energy metabolism and reproduction.

Expression of alarin in ependymoma and choroid plexus tumors.

Alarin, a 25 amino acid splice variant of the galanin-like peptide, was originally discovered in gangliocytes of neuroblastic tumors and shown to be expressed in ganglioneuroblastoma and ganglioneuroma but not in undifferentiated neuroblastoma. Recently, in vivo studies have elucidated the physiological functions of alarin in the central nervous system (CNS). Alarin was shown to stimulate food intake, increase body weight, induce luteinizing hormone secretion and stimulate fos-expression in rats; the anatomical localization for these functions correlates well with the varied distribution of the alarin peptide in the brain. Because alarin was originally detected in neuroblastic tumors and is present in a wide range of nuclei in the CNS, we determined in the present study the expression of alarin in a variety of CNS tumors. Immunohistochemical analysis of 179 tumor samples resulted in different alarin-like immunoreactivity (alarin-LI) intensities, which were score-rated from 0 (no alarin stainin), 1 (low intensity), 2 (medium intensity) to 3 (high intensity). Immunohistochemical analyses revealed score 2 or 3 alarin-LI in all choroid plexus tumors (100 %, 7/7) and in the majority of ependymomas (90 %, 52/58), but only in a minority of astrocytomas (15 %, 5/33), meningiomas (14 %, 7/49) and tumors of the cranial nerves (7 %, 1/15). In oligodendrogliomas (0 %, 0/12) and oligoastrocytoma (0 %, 0/5) alarin-LI was not detectable. The high specificity (83 %) of alarin-LI suggests that it might be used as a diagnostic marker for ependymoma in differentiating them from other gliomas such as astrocytomas and oligodendrogliomas.

Positive allosteric modulators to peptide GPCRs: a promising class of drugs.

The task of finding selective and stable peptide receptor agonists with low molecular weight, desirable pharmacokinetic properties and penetrable to the blood-brain barrier has proven too difficult for many highly coveted drug targets, including receptors for endothelin, vasoactive intestinal peptide and galanin. These receptors and ligand-gated ion channels activated by structurally simple agonists such as glutamate, glycine and GABA present such a narrow chemical space that the design of subtype-selective molecules capable of distinguishing a dozen of glutamate and GABA receptor subtypes and possessing desirable pharmacokinetic properties has also been problematic. In contrast, the pharmaceutical industry demonstrates a remarkable success in developing 1,4-benzodiazepines, positive allosteric modulators (PMAs) of the GABAA receptor. They were synthesized over 50 years ago and discovered to have anxiolytic potential through an in vivo assay. As exemplified by Librium, Valium and Dormicum, these allosteric ligands of the receptor became the world's first blockbuster drugs. Through molecular manipulation over the past 2 decades, including mutations and knockouts of the endogenous ligands or their receptors, and by in-depth physiological and pharmacological studies, more peptide and glutamate receptors have become well-validated drug targets for which an agonist is sought. In such cases, the pursuit for PAMs has also intensified, and a working paradigm to identify drug candidates that are designed as PAMs has emerged. This review, which focuses on the general principles of finding PAMs of peptide receptors in the 21st century, describes the workflow and some of its resulting compounds such as PAMs of galanin receptor 2 that act as potent anticonvulsant agents.

Distribution of the regulatory peptide alarin in the eye of various species.

Alarin is a recently discovered regulatory peptide with vasoconstrictive properties in murine skin. Control of vasoconstriction/-relaxation is essential for ocular blood flow and hence the eye's homeostasis, and regulatory peptides are involved in regulation of ocular blood flow. Here we describe the existence and distribution of alarin in the eye of human and potential experimental animals (rat, mouse). Eyes of rat, mouse, and human were prepared for immunohistochemistry against murine and human alarin, respectively. Additionally, double staining experiments for alarin and CD31 were performed in human choroidal flat-mount preparations. For documentation, confocal laser scanning microscopy was used while quantitative real-time-PCR was applied to confirm immunohistochemical data and to detect alarin mRNA expression in human retina and choroid. Alarin-like immunoreactivity (alarin-LI) was detected in corneal epi- and endothelium of human, mouse, and rat, as well as in the conjunctiva of mouse and rat. Alarin-LI was found in the iris of all the species investigated and, in humans, was concentrated around blood vessels. All three species showed distinctive alarin-LI in the non-pigmented epithelium of the ciliary body. In the retina of mouse and rat, maximum signals were detected in the outer nuclear and ganglion cell layer, whereas in humans a strong alarin-LI was found around retinal blood vessels and in intrinsic choroidal neurons (ICN). Quantitative RT-PCR in human confirmed alarin mRNA expression retina and choroid. The existence of alarin in cornea and conjunctiva might indicate a role in immune defense, while its presence in the non-pigmented ciliary epithelium favors an involvement in aqueous humor production. Alarin around blood vessels/in ICN might indicate an involvement in ocular blood flow regulation. Since alarin is found widely distributed in the eyes of species investigated, we were able to establish the basis for further functional experiments.

Hypothalamic galanin-like peptide rescues the onset of puberty in food-restricted weanling rats.

Galanin-like peptide (GALP) is a known mediator of metabolism and reproduction; however, the role that GALP plays in the onset of puberty is unknown. First, we tested the hypothesis that central GALP administration could rescue puberty in food-restricted weanling rats. GALP treatment in food-restricted rats of both sexes rescued the timing of the onset of puberty to that seen in ad lib. fed controls. Second, we tested whether GALP translation knocked-down in ad lib. fed, prepubertal rats would alter the timing of puberty. Knock-down females, but not males, showed a significant (P < 0.01) delay in the onset of puberty compared to controls. Third, we sought evidence that the role of GALP in pubertal onset is mediated by the kisspeptin system. In situ hybridisation analyses showed a significant (P < 0.01) reduction in Kiss1 mRNA within the hypothalamic arcuate nucleus in food-restricted rats compared to ad lib. fed controls and this reduction was prevented with i.c.v. GALP administration. Furthermore, analyses of Fos-immunoreactivity (-IR) after i.c.v. GALP treatment did not elicit Fos-IR within any kisspeptin neurones, nor are GALP and kisspeptin peptides or mRNA colocalised. These data demonstrate that hypothalamic GALP infusion maintained the onset of puberty in food-restricted weanling rats, although probably not via direct innervation of kisspeptin neurones.

Effects of alarin on food intake, body weight and luteinizing hormone secretion in male mice.

Alarin is a member of the galanin family of neuropeptides that includes galanin and galanin-like peptide (GALP). Alarin is an alternate transcript of the GALP gene and is expressed in the brain and periphery. Recently, it was shown in male rats that alarin is an orexigenic peptide that also regulates reproductive hormone secretion. We hypothesized that alarin would also have similar central effects on feeding and luteinizing hormone (LH) secretion in mice as observed in rats. To test this hypothesis, we treated male mice with alarin intracerebroventricularly (i.c.v.) and measured its effects on food intake, body weight, body temperature, LH secretion, and Fos induction. We observed that i.c.v. injection of 1.0 nmol alarin significantly increased immediate food intake (p<0.01) from 30 to 120 min post-injection and relative body weight (p<0.05) after 24 h. Alarin had no effect on body temperature compared to controls. Alarin increased LH levels in male mice, an effect that was dependent on gonadotropin-Releasing-Hormone (GnRH) signaling. Furthermore, alarin-stimulated Fos immunoreactivity was observed in diencephalic nuclei, including the hypothalamic dorsomedial nucleus and the bed nucleus of the stria terminalis. Our studies demonstrated that alarin, like other members of the galanin peptide family, is a neuromediator of food intake and reproductive hormone secretion in male mice.

Distribution of alarin immunoreactivity in the mouse brain.

Alarin is a 25 amino acid peptide that belongs to the galanin peptide family. It is derived from the galanin-like peptide gene by a splice variant, which excludes exon 3. Alarin was first identified in gangliocytes of neuroblastic tumors and later shown to have a vasoactive function in the skin. Recently, alarin was demonstrated to stimulate food intake as well as the hypothalamic-pituitary-gonadal axis in rodents, suggesting that it might be a neuromodulatory peptide in the brain. However, the individual neurons in the central nervous system that express alarin have not been identified. Here, we determined the distribution of alarin-like immunoreactivity (alarin-LI) in the adult murine brain. The specificity of the antibody against alarin was demonstrated by the absence of labeling after pre-absorption of the antiserum with synthetic alarin peptide and in transgenic mouse brains lacking neurons expressing the GALP gene. Alarin-LI was observed in different areas of the murine brain. A high intensity of alarin-LI was detected in the accessory olfactory bulb, the medial preoptic area, the amygdala, different nuclei of the hypothalamus such as the arcuate nucleus and the ventromedial hypothalamic nucleus, the trigeminal complex, the locus coeruleus, the ventral chochlear nucleus, the facial nucleus, and the epithelial layer of the plexus choroideus. The distinct expression pattern of alarin in the adult mouse brain suggests potential functions in reproduction and metabolism.

Developmental overfeeding alters hypothalamic neuropeptide mRNA levels and response to a high-fat diet in adult mice.

It has been suggested that nutritional manipulations during the first weeks of life can alter the development of the hypothalamic circuits involved in energy homeostasis. We studied the expression of a large number of the hypothalamic neuropeptide mRNAs that control body weight in mice that were overfed during breastfeeding (mice grown in a small litter, SL) and/or during adolescence (adolescent mice fed a high-fat diet, AHF). We also investigated possible alterations in mRNA levels after 50 days of a high-fat diet (high-fat challenge, CHF) at 19 weeks of age. Both SL and AHF conditions caused overweight during the period of developmental overfeeding. During adulthood, all of the mouse groups fed a CHF significantly gained weight in comparison with mice fed a low-fat diet, but the mice that had undergone both breast and adolescent overfeeding (SL-AHF-CHF mice) gained significantly more weight than the control CHF mice. Of the ten neuropeptide mRNAs studied, only neuropeptide Y (NPY) expression was decreased in all of the groups of developmentally overfed adult mice, but CHF during adulthood by itself induced a decrease in NPY, agouti-related protein (AgRP) and orexin (Orx) mRNA levels. Moreover, in the developmentally overfed CHF mice NPY, AgRP, galanin (GAL) and galanin-like peptide (GalP) mRNA levels significantly decreased in comparison with the control CHF mice. These results show that, during adulthood, hypothalamic neuropeptide systems are altered (NPY) and/or abnormally respond to a high-fat diet (NPY, AgRP, GAL and GalP) in mice overfed during critical developmental periods.

Galanin-like peptide (GALP) is a hypothalamic regulator of energy homeostasis and reproduction.

Galanin-like peptide (GALP) was discovered in 1999 in the porcine hypothalamus and was found to be a 60 amino acid neuropeptide. GALP shares sequence homology to galanin (1-13) in position 9-21 and can bind to, as well as activate, the three galanin receptor subtypes (GalR1-3). GALP-expressing cells are limited, and are mainly found in the arcuate nucleus of the hypothalamus (ARC) and the posterior pituitary. GALP-positive neurons in the ARC project to several brain regions where they appear to make contact with multiple neuromodulators. These neuromodulators are involved in the regulation of energy homeostasis and reproduction, anatomical evidence that suggests a role for GALP in these physiological functions. In support of this idea, GALP gene expression is regulated by several factors that reflect metabolic state including the metabolic hormones leptin and insulin, thyroid hormones, and blood glucose. Considerable evidence now exists to support the hypothesis that GALP has a role in the regulation of energy homeostasis and reproduction; and, that GALP's role may be independent of the known galanin receptors. In this review, we (1) provide an overview of the distribution of GALP, and discuss the potential relationship between GALP and other neuromodulators of energy homeostasis and reproduction, (2) discuss the metabolic factors that regulate GALP expression, (3) review the evidence for the role of GALP in energy homeostasis and reproduction, (4) discuss the potential downstream mediators and mechanisms underlying GALP's effects, and (5) discuss the possibility that GALP may mediate its effects via an as yet unidentified GALP-specific receptor.

The galanin peptide family in inflammation.

The immune system defends the organism against invading pathogens. In recent decades it became evident that elimination of such pathogens, termination of inflammation, and restoration of host homeostasis all depend on bidirectional crosstalk between the immune system and the neuroendocrine system. This crosstalk is mediated by a complex network of interacting molecules that modulates inflammation and cell growth. Among these mediators are neuropeptides released from neuronal and non-neuronal components of the central and peripheral nervous systems, endocrine tissues, and cells of the immune system. Neuropeptide circuitry controls tissue inflammation and maintenance, and an imbalance of pro- and anti-inflammatory neuropeptides results in loss of host homeostasis and triggers inflammatory diseases. The galanin peptide family is undoubtedly involved in the regulation of inflammatory processes, and the aim of this review is to provide up-to-date knowledge from the literature concerning the regulation of galanin and its receptors in the nervous system and peripheral tissues in experimental models of inflammation. We also highlight the effects of galanin and other members of the galanin peptide family on experimentally induced inflammation and discuss these data in light of an anti-inflammatory role for this family of peptides.