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      Differential Orexigenic Effects of Hexarelin and Its Analogs in the Rat Hypothalamus: Indication for Multiple Growth Hormone Secretagogue Receptor Subtypes

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          We have previously reported that hexarelin and some of its analogs, including EP 50885, stimulated GH secretion and feeding after systemic administration in the rat, whereas EP 40904 selectively stimulated food intake and EP 40737 only GH release. The precise mechanism of growth hormone-releasing peptides (GHRPs) actions is still unclear, but the integrity of the arcuate nucleus of the hypothalamus (ARC) appears crucial for their endocrine effects. To better characterize the site(s) and mechanisms(s) of the orexigenic action of GHRPs, we have investigated their effects after infusion into the arcuate, paraventricular, ventromedial and medial preoptic areas of the hypothalamus. Food intake was measured for 60 min following injection of the test compound (2 µg/rat). Hexarelin, EP 40904 and EP 50885 had significant orexigenic effects after injection into the ARC. A specific NPY antagonist significantly inhibited the effect of hexarelin, whereas a GHRH antagonist was ineffective. In the paraventricular nucleus, only EP 50885 stimulated feeding, whereas all peptides were ineffective in the ventromedial nucleus and medial preoptic area. Taken altogether, these results demonstrate that GHRPs are endowed with site-specific orexigenic actions and that endogenous NPY, but not GHRH, mediates these effects. The additional orexigenic action of EP 50885 in the paraventricular nucleus suggests the existence of a GHRP receptor subtype different from the already cloned one.

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          Most cited references 7

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          Co-Localization of Growth Hormone Secretagogue Receptor and NPY mRNA in the Arcuate Nucleus of the Rat

          Growth hormone secretagogues (GHS) are small, synthetic compounds which have the potential of releasing growth hormone (GH) from the pituitary. The mechanism of action of GHS has not been fully elucidated. A specific GHS receptor (GHS-R) is expressed in the pituitary gland and in several areas of the brain including the hypothalamus. We have characterized the GHS-R-mRNA-expressing neurons with respect to co-expression of selected neurotransmitters in the hypothalamus. This was done by dual chromogenic and autoradiographic in situ hybridization with riboprobes for GHS-R mRNA and neuropeptide Y (NPY), pro-opiomelanocortin (POMC), somatostatin (SRIH) or GH-releasing hormone (GHRH) mRNA. In the arcuate nucleus, GHS-R mRNA was expressed in 94 ± 1% of the neurons expressing NPY, 8 ± 2% of those expressing POMC and 30 ± 6% expressing SRIH mRNA. 20–25% of the GHRH- mRNA-expressing neurons contained GHS-R mRNA, whereas the vast majority of the arcuate GHS-R-mRNA-containing cells did not contain GHRH mRNA. The finding of a significant co-expression of GHS-R and NPY mRNA in the arcuate nucleus is in accordance with the previous demonstration by Dickson et al. that c-Fos is induced in NPY neurons following GHS administration. These results indicate that GHS have other effects on neuroendocrine regulation than GH release via GHRH neurons. Stimulation of the arcuate NPY neurons via GHS-R may explain the increased appetite and the cortisol release seen after administration of some GHS compounds.
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            Interacting Appetite-Regulating Pathways in the Hypothalamic Regulation of Body Weight

             S P Kalra (1999)
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              An arcuato-paraventricular and -dorsomedial hypothalamic neuropeptide Y-containing system which lacks noradrenaline in the rat.

              The origins of neuropeptide Y-like immunoreactive (NPYI) fibers in the paraventricular and dorsomedial hypothalamic nuclei of the rat were examined using immunohistochemistry. Destruction of the arcuate nucleus resulted in a marked decrease of NPYI fibers ipsilaterally in these nuclei, suggesting that most of NPYI fibers in these nuclei originate from NPYI neurons in the arcuate nucleus. These NPYI systems did not contain noradrenalin.

                Author and article information

                S. Karger AG
                December 2000
                22 December 2000
                : 72
                : 6
                : 327-332
                aDepartment of Experimental and Environmental Medicine and Biotechnologies, University of Milano-Bicocca, bDepartment of Neuroscience, University of Cagliari, Italy; cEuropeptides, Argenteuil, France; dDepartment of Pharmacology, University of Milano, Italy
                54601 Neuroendocrinology 2000;72:327–332
                © 2000 S. Karger AG, Basel

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                Page count
                Figures: 4, Tables: 1, References: 35, Pages: 6
                Regulation of Growth Hormone and Food Intake


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