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Lisa A Eckel - One of the best experts on this subject based on the ideXlab platform.
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the novel cannabinoid cb1 receptor agonist am11101 increases food intake in female rats
British Journal of Pharmacology, 2019Co-Authors: Sean B Ogden, Michael S Malamas, Alexandros Makriyannis, Lisa A EckelAbstract:BACKGROUND AND PURPOSE: Δ9 -tetrahydrocannabinol (THC) acts via cannabinoid CB1 receptors to increase feeding. Here, we assessed the Orexigenic effect of AM11101, a novel CB1 receptor agonist designed to have a more favourable pharmacodynamic profile than THC. EXPERIMENTAL APPROACH: The acute, Orexigenic effects of AM11101 and THC were compared in female rats. Food intake and meal patterns were also examined following once daily treatment with AM11101 and THC for 7 days. KEY RESULTS: AM11101 (0.01-0.1 mg·kg-1 ) increased food intake during the first hour following both acute and chronic treatments in pre-fed and freely feeding animals. This Orexigenic effect persisted for up to 4 hr, with no compensatory decrease in feeding during the subsequent 4-22 hr. THC (1 mg·kg-1 ) increased 1-hr food intake in pre-fed animals, but was less reliable than AM11101 in increasing 1-hr food intake in freely feeding animals following both acute and chronic administration. The Orexigenic effect of both compounds was due to an increase in meal size, not meal number. CONCLUSIONS AND IMPLICATIONS: Our study provides the first demonstration that AM11101 increases short-term food intake via a selective increase in meal size. AM11101 promotes a more reliable Orexigenic effect than THC in freely feeding animals, with no subsequent compensatory decrease in feeding. AM11101 may offer a greater efficacy than THC and its congeners in stimulating food intake in underweight clinical populations.
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Estradiol decreases the Orexigenic effect of neuropeptide Y, but not agouti-related protein, in ovariectomized rats.
Behavioural brain research, 2008Co-Authors: Jessica Santollo, Lisa A EckelAbstract:Available data suggest that estradiol exerts an inhibitory effect on food intake by modulating the actions of multiple gut- and brain-derived peptides implicated in the control of food intake. For example, recent studies have shown that estradiol decreases the Orexigenic effects of ghrelin and melanin-concentrating hormone. In the present study, we examined estradiol's ability to decrease the actions of two additional Orexigenic peptides, neuropeptide Y (NPY) and agouti-related protein (AgRP). Food intake was monitored following lateral ventricular infusions of 5 μg NPY, 10 μg AgRP, or saline vehicle in ovariectomized rats treated with either 1 μg estradiol or sesame oil vehicle. NPY increased food intake for 2 h in both oil- and estradiol-treated ovariectomized rats. During this interval, the Orexigenic effect of NPY was significantly greater in oil-treated rats, relative to estradiol-treated rats. In contrast to the short-term action of NPY, a single injection of AgRP increased food intake for 3 days in oil- and estradiol-treated rats. Meal pattern analysis revealed that the Orexigenic effect of AgRP is mediated by an increase in meal size, not meal number. Unlike that observed following NPY treatment, estradiol failed to modulate the magnitude by which AgRP increased food intake and meal size. We conclude that a physiological regimen of estradiol treatment decreases the Orexigenic effect of NPY, but not AgRP, in ovariectomized rats.
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The Orexigenic effect of melanin-concentrating hormone (MCH) is influenced by sex and stage of the estrous cycle
Physiology & Behavior, 2007Co-Authors: Jessica Santollo, Lisa A EckelAbstract:Recently, it was shown that the Orexigenic effect of melanin-concentrating hormone (MCH) is attenuated by estradiol treatment in ovariectomized (OVX) rats. This suggests that female rats may be less responsive than male rats to the behavioral effects of MCH. To investigate this hypothesis, the effects of lateral ventricular infusions of MCH on food intake, water intake, meal patterns, and running wheel activity were examined in male and female rats. To further characterize the impact of estradiol on MCH-induced food intake, female rats were OVX and tested with and without 17-β-estradiol benzoate (EB) replacement. In support of our hypothesis, food and water intakes following MCH treatment were greater in male rats, relative to female rats. Specifically, the Orexigenic effect of MCH was maximal in male rats and minimal in EB-treated OVX rats. In both sexes, the Orexigenic effect of MCH was mediated by a selective increase in meal size, which was attenuated in EB-treated OVX rats. MCH-induced a short-term (2 h) decrease in wheel running that, unlike its effects on ingestive behavior, was similar in males and females. Thus, estradiol decreases some, but not all, of the behavioral effects of MCH. To examine the influence of endogenous estradiol, food intake was monitored following MCH treatment in ovarian-intact, cycling rats. As predicted by our findings in OVX rats, the Orexigenic effect of MCH was attenuated in estrous rats, relative to diestrous rats. We conclude that the female rat's reduced sensitivity to the Orexigenic effect of MCH may contribute to sex- and estrous cycle-related differences in food intake.
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The Orexigenic effect of melanin-concentrating hormone (MCH) is influenced by sex and stage of the estrous cycle.
Physiology & behavior, 2007Co-Authors: Jessica Santollo, Lisa A EckelAbstract:Recently, it was shown that the Orexigenic effect of melanin-concentrating hormone (MCH) is attenuated by estradiol treatment in ovariectomized (OVX) rats. This suggests that female rats may be less responsive than male rats to the behavioral effects of MCH. To investigate this hypothesis, the effects of lateral ventricular infusions of MCH on food intake, water intake, meal patterns, and running wheel activity were examined in male and female rats. To further characterize the impact of estradiol on MCH-induced food intake, female rats were OVX and tested with and without 17-beta-estradiol benzoate (EB) replacement. In support of our hypothesis, food and water intakes following MCH treatment were greater in male rats, relative to female rats. Specifically, the Orexigenic effect of MCH was maximal in male rats and minimal in EB-treated OVX rats. In both sexes, the Orexigenic effect of MCH was mediated by a selective increase in meal size, which was attenuated in EB-treated OVX rats. MCH-induced a short-term (2 h) decrease in wheel running that, unlike its effects on ingestive behavior, was similar in males and females. Thus, estradiol decreases some, but not all, of the behavioral effects of MCH. To examine the influence of endogenous estradiol, food intake was monitored following MCH treatment in ovarian-intact, cycling rats. As predicted by our findings in OVX rats, the Orexigenic effect of MCH was attenuated in estrous rats, relative to diestrous rats. We conclude that the female rat's reduced sensitivity to the Orexigenic effect of MCH may contribute to sex- and estrous cycle-related differences in food intake.
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Estradiol decreases the Orexigenic effect of NPY, but not AgRP, in ovariectomized rats.
Appetite, 2007Co-Authors: Jessica Santollo, Lisa A EckelAbstract:Available data suggest that estradiol exerts its inhibitory effect on food intake by modulating the actions of multiple anOrexigenic and Orexigenic gut- and brain-derived peptides. For example, recent studies have shown that estradiol decreases the Orexigenic effect of ghrelin and melanin-concentrating hormone (MCH) in ovariectomized and cycling female rats. In the present study, we examined estradiol's ability to decrease the strength of two additional Orexigenic peptides, neuropeptide Y (NPY) and agouti-related protein (AgRP). Food intake and meal patterns were monitored following lateral ventricular (icv) infusions of 5 μg NPY, 10 μg AgRP, or saline vehicle in ovariectomized rats who received a physiological regimen of either 1 μg estradiol or sesame oil vehicle treatment. NPY increased light-phase food intake for 2 h in both oil- and estradiol-treated rats. During this interval, the Orexigenic effect of NPY was, however, greater in oil-treated rats, relative to estradiol-treated rats (2.7 ± 0.4 g vs. 1.4 ± 0.4 g, respectively, P
Miguel López - One of the best experts on this subject based on the ideXlab platform.
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the Orexigenic effect of orexin a revisited dependence of an intact growth hormone axis
Endocrinology, 2013Co-Authors: Mayte Alvarezcrespo, Carlos Dieguez, Noelia Martinezsanchez, Francisco Ruizpino, Montserrat Garcialavandeira, Clara V Alvarez, Manuel Tenasempere, Ruben Nogueiras, Miguel LópezAbstract:Fifteen years ago orexins were identified as central regulators of energy homeostasis. Since then, that concept has evolved considerably and orexins are currently considered, besides Orexigenic neuropeptides, key modulators of sleep-wake cycle and neuroendocrine function. Little is known, however, about the effect of the neuroendocrine milieu on orexins' effects on energy balance. We therefore investigated whether hypothalamic-pituitary axes have a role in the central Orexigenic action of orexin A (OX-A) by centrally injecting hypophysectomized, adrenalectomized, gonadectomized (male and female), hypothyroid, and GH-deficient dwarf rats with OX-A. Our data showed that the Orexigenic effect of OX-A is fully maintained in adrenalectomized and gonadectomized (females and males) rats, slightly reduced in hypothyroid rats, and totally abolished in hypophysectomized and dwarf rats when compared with their respective vehicle-treated controls. Of note, loss of the OX-A effect on feeding was associated with a blun...
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The Orexigenic Effect of Orexin-A Revisited: Dependence of an Intact Growth Hormone Axis
Endocrinology, 2013Co-Authors: Mayte Alvarez-crespo, Carlos Dieguez, Clara V Alvarez, Ruben Nogueiras, Noelia Martínez-sánchez, Francisco Ruiz-pino, Montserrat Garcia-lavandeira, Manuel Tena-sempere, Miguel LópezAbstract:Fifteen years ago orexins were identified as central regulators of energy homeostasis. Since then, that concept has evolved considerably and orexins are currently considered, besides Orexigenic neuropeptides, key modulators of sleep-wake cycle and neuroendocrine function. Little is known, however, about the effect of the neuroendocrine milieu on orexins' effects on energy balance. We therefore investigated whether hypothalamic-pituitary axes have a role in the central Orexigenic action of orexin A (OX-A) by centrally injecting hypophysectomized, adrenalectomized, gonadectomized (male and female), hypothyroid, and GH-deficient dwarf rats with OX-A. Our data showed that the Orexigenic effect of OX-A is fully maintained in adrenalectomized and gonadectomized (females and males) rats, slightly reduced in hypothyroid rats, and totally abolished in hypophysectomized and dwarf rats when compared with their respective vehicle-treated controls. Of note, loss of the OX-A effect on feeding was associated with a blunted OX-A-induced increase in the expression of either neuropeptide Y or its putative regulator, the transcription factor cAMP response-element binding protein, as well as its phosphorylated form, in the arcuate nucleus of the hypothalamus of hypophysectomized and dwarf rats. Overall, this evidence suggests that the Orexigenic action of OX-A depends on an intact GH axis and that this neuroendocrine feedback loop may be of interest in the understanding of orexins action on energy balance and GH deficiency.
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Hypothalamic Ceramide Levels Regulated by CPT1C Mediate the Orexigenic Effect of Ghrelin
Diabetes, 2013Co-Authors: Sara Ramírez, Luís Martins, Jordi Jacas, Patricia Carrasco, Macarena Pozo, Josep Clotet, Dolors Serra, Fausto G. Hegardt, Carlos Dieguez, Miguel LópezAbstract:Recent data suggest that ghrelin exerts its Orexigenic action through regulation of hypothalamic AMP-activated protein kinase pathway, leading to a decline in malonyl-CoA levels and desinhibition of carnitine palmitoyltransferase 1A (CPT1A), which increases mitochondrial fatty acid oxidation and ultimately enhances the expression of the Orexigenic neuropeptides agouti-related protein (AgRP) and neuropeptide Y (NPY). However, it is unclear whether the brain-specific isoform CPT1C, which is located in the endoplasmic reticulum of neurons, may play a role in this action. Here, we demonstrate that the Orexigenic action of ghrelin is totally blunted in CPT1C knockout (KO) mice, despite having the canonical ghrelin signaling pathway activated. We also demonstrate that ghrelin elicits a marked upregulation of hypothalamic C18:0 ceramide levels mediated by CPT1C. Notably, central inhibition of ceramide synthesis with myriocin negated the Orexigenic action of ghrelin and normalized the levels of AgRP and NPY, as well as their key transcription factors phosphorylated cAMP-response element–binding protein and forkhead box O1. Finally, central treatment with ceramide induced food intake and Orexigenic neuropeptides expression in CPT1C KO mice. Overall, these data indicate that, in addition to formerly reported mechanisms, ghrelin also induces food intake through regulation of hypothalamic CPT1C and ceramide metabolism, a finding of potential importance for the understanding and treatment of obesity.
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Hypothalamic mTOR signaling mediates the Orexigenic action of ghrelin.
PloS one, 2012Co-Authors: Luís Martins, María J. Vázquez, Miguel López, Ruben Nogueiras, Manuel Tena-sempere, Marta G. Novelle, Diana Fernández-mallo, Carlos DieguezAbstract:Current evidence suggests that ghrelin, a stomach derived peptide, exerts its Orexigenic action through specific modulation of Sirtuin1 (SIRT1)/p53 and AMP-activated protein kinase (AMPK) pathways, which ultimately increase the expression of agouti-related protein (AgRP) and neuropeptide Y (NPY) in the arcuate nucleus of the hypothalamus (ARC). However, there is a paucity of data about the possible action of ghrelin on alternative metabolic pathways at this level. Here, we demonstrate that ghrelin elicits a marked upregulation of the hypothalamic mammalian target of rapamycin (mTOR) signaling pathway. Of note, central inhibition of mTOR signaling with rapamycin decreased ghrelin’s Orexigenic action and normalized the mRNA expression of AgRP and NPY, as well as their key downstream transcription factors, namely cAMP response-element binding protein (pCREB) and forkhead box O1 (FoxO1, total and phosphorylated). Taken together, these data indicate that, in addition to previous reported mechanisms, ghrelin also promotes feeding through modulation of hypothalamic mTOR pathway.
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Acute effects of Orexigenic antipsychotic drugs on lipid and carbohydrate metabolism in rat
Psychopharmacology, 2011Co-Authors: Goran Jassim, María J. Vázquez, Carlos Dieguez, Silje Skrede, Hege Wergedal, Audun Osland Vik-mo, Niclas Lunder, Antonio Vidal-puig, Rolf K. Berge, Miguel LópezAbstract:Objective This study aims to investigate whether Orexigenic antipsychotic drugs may induce dyslipidemia and glucose disturbances in female rats through direct perturbation of metabolically active peripheral tissues, independent of prior weight gain.
Akio Inui - One of the best experts on this subject based on the ideXlab platform.
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central prostaglandin d2 stimulates food intake via the neuropeptide y system in mice
FEBS Letters, 2008Co-Authors: Kousaku Ohinata, Kuniko Takagi, Akihiro Asakawa, Kyoko Biyajima, Yoko Fujiwara, Shingo Fukumoto, Naomi Eguchi, Yoshihiro Urade, Mineko Fujimiya, Akio InuiAbstract:We found that prostaglandin (PG) D2, the most abundant PG in the central nervous system, stimulates food intake after intracerebroventricular administration in mice. The Orexigenic effect of PGD2 was mimicked by a selective agonist for the DP1 receptor among two receptor subtypes for PGD2, and abolished by its antagonist. Central administration of an antagonist or antisense oligodeoxynucleotide for the DP1 receptor remarkably decreased food intake, body weight and fat mass. Hypothalamic mRNA levels of lipocalin-type PGD synthase were up-regulated after fasting. The Orexigenic activity of PGD2 was also abolished by an antagonist for neuropeptide Y (NPY) Y1 receptor. Taken together, PGD2 may stimulate food intake through central DP1 receptor coupled to the NPY system.
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ghrelin treatment causes increased food intake and retention of lean body mass in a rat model of cancer cachexia
Endocrinology, 2007Co-Authors: Mark D Deboer, Akio Inui, Peter R Levasseur, Michael M Meguid, Susumu Suzuki, John E Taylor, Heather A Halem, Jesse Z Dong, Rakesh Datta, Michael D CullerAbstract:Cancer cachexia is a debilitating syndrome of anorexia and loss of lean body mass that accompanies many malignancies. Ghrelin is an Orexigenic hormone with a short half-life that has been shown to improve food intake and weight gain in human and animal subjects with cancer cachexia. We used a rat model of cancer cachexia and administered human ghrelin and a synthetic ghrelin analog BIM-28131 via continuous infusion using sc osmotic minipumps. Tumor-implanted rats receiving human ghrelin or BIM-28131 exhibited a significant increase in food consumption and weight gain vs. saline-treated animals. We used dual-energy x-ray absorptiometry scans to show that the increased weight was due to maintenance of lean mass vs. a loss of lean mass in saline-treated animals. Also, BIM-28131 significantly limited the loss of fat mass normally observed in tumor-implanted rats. We further performed real-time PCR analysis of the hypothalami and brainstems and found that ghrelin-treated animals exhibited a significant increase in expression of Orexigenic peptides agouti-related peptide and neuropeptide Y in the hypothalamus and a significant decrease in the expression of IL-1 receptor-I transcript in the hypothalamus and brainstem. We conclude that ghrelin and a synthetic ghrelin receptor agonist improve weight gain and lean body mass retention via effects involving Orexigenic neuropeptides and antiinflammatory changes.
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Eating behavior in anorexia nervosa--an excess of both Orexigenic and anOrexigenic signalling?
Molecular psychiatry, 2001Co-Authors: Akio InuiAbstract:Anorexia nervosa (AN) is a disorder characterized by abnormal eating behavior, weight regulation, and disturbances in attitudes and perceptions toward body weight and shape. Although progress has been made in the treatment of AN, a substantial portion of patients have a limited response to treatment. Multiple endocrine and metabolic changes occur after prolonged starvation, conserving energy and protein. A number of the endocrine findings in patients with AN may be secondary to adaptive mechanisms. However, AN differs from simple starvation in that excess of both feeding-stimulatory (Orexigenic) and feeding-inhibitory (anOrexigenic) signalling is characteristic, producing the ‘mixed’ signal about satiety and desire to feed. This leads to a failure of the adaptive feeding response that is initiated by a decrease in leptin, an adiposity signal from fat tissue, and the resultant increase and decrease of Orexigenic and anOrexigenic signalling, respectively. The hypothesis of unbalanced shift of feeding-regulatory circuitry places anOrexigenic corticotropin-releasing factor and Orexigenic neuropeptide Y in the final common neurobiological substrate for AN. Therapeutic intervention using such receptor antagonists may lead to more successful and targeted psychopharmacological treatment.
Thierry Groblewski - One of the best experts on this subject based on the ideXlab platform.
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The receptor for the Orexigenic peptide melanin-concentrating hormone is a G-protein-coupled receptor.
Nature cell biology, 1999Co-Authors: Lembo Paola, Eric Grazzini, Jack Cao, Douglas A. Hubatsch, Manon Pelletier, Cyrla Hoffert, Stephane St-onge, Chantevy Pou, Jean Labrecque, Thierry GroblewskiAbstract:The receptor for the Orexigenic peptide melanin-concentrating hormone is a G-protein-coupled receptor
Toshihiko Yada - One of the best experts on this subject based on the ideXlab platform.
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optogenetic activation of leptin and glucose regulated gabaergic neurons in dorsomedial hypothalamus promotes food intake via inhibitory synaptic transmission to paraventricular nucleus of hypothalamus
Molecular metabolism, 2016Co-Authors: Zesemdorj Otgonuul, Shigetomo Suyama, Hiroshi Onodera, Toshihiko YadaAbstract:Objective The dorsomedial hypothalamus (DMH) has been considered an Orexigenic nucleus, since the DMH lesion reduced food intake and body weight and induced resistance to diet-induced obesity. The DMH expresses feeding regulatory neuropeptides and receptors including neuropeptide Y (NPY), cocaine- and amphetamine-regulated transcript (CART), cholecystokinin (CCK), leptin receptor, and melanocortin 3/4 receptors. However, the principal neurons generating the Orexigenic function in the DMH remain to be defined. This study aimed to clarify the role of the DMH GABAergic neurons in feeding regulation by using optogenetics and electrophysiological techniques.
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Optogenetic activation of leptin- and glucose-regulated GABAergic neurons in dorsomedial hypothalamus promotes food intake via inhibitory synaptic transmission to paraventricular nucleus of hypothalamus
Elsevier, 2016Co-Authors: Zesemdorj Otgon-uul, Hiroshi Onodera, Shigetomo Suyama, Toshihiko YadaAbstract:Objective: The dorsomedial hypothalamus (DMH) has been considered an Orexigenic nucleus, since the DMH lesion reduced food intake and body weight and induced resistance to diet-induced obesity. The DMH expresses feeding regulatory neuropeptides and receptors including neuropeptide Y (NPY), cocaine- and amphetamine-regulated transcript (CART), cholecystokinin (CCK), leptin receptor, and melanocortin 3/4 receptors. However, the principal neurons generating the Orexigenic function in the DMH remain to be defined. This study aimed to clarify the role of the DMH GABAergic neurons in feeding regulation by using optogenetics and electrophysiological techniques. Methods: We generated the mice expressing ChRFR-C167A, a bistable chimeric channelrhodopsin, selectively in GABAergic neurons of DMH via locally injected adeno-associated virus 2. Food intake after optogenetic activation of DMH GABAergic neurons was measured. Electrophysiological properties of DMH GABAergic neurons were measured using slice patch clamp. Results: Optogenetic activation of DMH GABAergic neurons promoted food intake. Leptin hyperpolarized and lowering glucose depolarized half of DMH GABAergic neurons, suggesting their Orexigenic property. Optical activation of axonal terminals of DMH GABAergic neurons at the paraventricular nucleus of hypothalamus (PVN), where anOrexigenic neurons are localized, increased inhibitory postsynaptic currents on PVN neurons and promoted food intake. Conclusion: DMH GABAergic neurons are regulated by metabolic signals leptin and glucose and, once activated, promote food intake via inhibitory synaptic transmission to PVN. Keywords: Dorsomedial hypothalamus, GABAergic neuron, Feeding, Leptin, Glucose, Optogenetic
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Galanin-like peptide and ghrelin increase cytosolic Ca2+ in neurons containing growth hormone-releasing hormone in the arcuate nucleus.
Regulatory peptides, 2005Co-Authors: Motoki Kuramochi, Daisuke Kohno, Tatsushi Onaka, Satoshi Kato, Toshihiko YadaAbstract:Galanin-like peptide (GALP), discovered in the porcine hypothalamus, is expressed predominantly in the arcuate nucleus (ARC), a feeding-controlling center. Intracerebroventricular injection of GALP has been shown to stimulate food intake in the rats. However, the mechanisms underlying the Orexigenic effect of GALP are unknown. The present study aimed to determine the target neurons of GALP in the ARC. We investigated the effects of GALP on cytosolic free Ca2+ concentration ([Ca2+]i) in the neurons isolated from the rat ARC, followed by neurochemical identification of these neurons by immunocytochemistry using antisera against growth hormone-releasing hormone (GHRH), neuropeptide Y (NPY) and proopiomelanocortin (POMC), the peptides localized in the ARC. GALP at 10(-10) M increased [Ca2+]i in 11% of single neurons of the ARC, while ghrelin, an Orexigenic and GH-releasing peptide, at 10(-10) M increased [Ca2+]i in 35% of the ARC neurons. Some of these GALP- and/or ghrelin-responsive neurons were proved to contain GHRH. In contrast, NPY- and POMC-containing neurons did not respond to GALP. These results indicate that GALP directly targets GHRH neurons, but not NPY and POMC neurons, and that ghrelin directly targets GHRH neurons in the ARC. The former action may be involved in the Orexigenic effect of GALP and the latter in the GH-releasing and/or Orexigenic effects ghrelin.