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      α-melanocyte stimulating hormone modulates the central acyl ghrelin-induced stimulation of feeding, gastrointestinal motility, and colonic secretion

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          Acyl ghrelin-induced intake depends on hypothalamic neuropeptide Y and agouti-related protein (AgRP) neurotransmitters. Intracerebroventricular (ICV) injection of AgRP increases feeding through competitive antagonism at melanocortin receptors. ICV administration of α-melanocyte stimulating hormone (α-MSH), a natural antagonist of AgRP, may modulate the acyl ghrelin-induced orexigenic effect.


          This study aimed to investigate the modulating effect of α-MSH on the central acyl ghrelin-induced food intake, gastrointestinal motility, and colonic secretion in rats.

          Methods and procedures

          We examined the effects of α-MSH and acyl ghrelin on food intake, gastric emptying, small intestinal transit, colonic motility, and secretion in conscious rats with a chronic implant of ICV catheters.


          ICV injection of O- n-octanoylated ghrelin (0.1 nmol/rat) significantly increased the cumulative food intake up to 8 h ( P<0.01), enhanced non-nutrient semi-liquid gastric emptying ( P<0.001), increased the geometric center and running percentage of small intestinal transit ( P<0.001), accelerated colonic transit time ( P<0.05), and increased fecal pellet output ( P<0.01) and total fecal weight ( P<0.01). Pretreatment with ICV injection of α-MSH (1.0 and 2.0 nmol/rat) attenuated the acyl ghrelin-induced hyperphagic effect, fecal pellet output, and total fecal weight, while higher dose of α-MSH (2.0 nmol/rat) attenuated the increase in the geometric center of small intestinal transit ( P<0.01). However, neither dose of α-MSH altered acyl ghrelin-stimulated gastroprokinetic effect, increase in the running percentage of small intestinal transit, nor accelerated colonic transit time.


          α-MSH is involved in central acyl ghrelin-elicited feeding, small intestinal transit, fecal pellet output, and fecal weight. α-MSH does not affect central acyl ghrelin-induced acceleration of gastric emptying and colonic transit time in rats.

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          Most cited references 54

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          Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein.

          Expression of Agouti protein is normally limited to the skin where it affects pigmentation, but ubiquitous expression causes obesity. An expressed sequence tag was identified that encodes Agouti-related protein, whose RNA is normally expressed in the hypothalamus and whose levels were increased eightfold in ob/ob mice. Recombinant Agouti-related protein was a potent, selective antagonist of Mc3r and Mc4r, melanocortin receptor subtypes implicated in weight regulation. Ubiquitous expression of human AGRP complementary DNA in transgenic mice caused obesity without altering pigmentation. Thus, Agouti-related protein is a neuropeptide implicated in the normal control of body weight downstream of leptin signaling.
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            Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin.

            : Ghrelin, an endogenous ligand for growth hormone secretagogue receptor, was recently identified in the rat stomach. We examined the effects of the gastric peptide ghrelin on energy balance in association with leptin and vagal nerve activity. : Food intake, oxygen consumption, gastric emptying, and hypothalamic neuropeptide Y (NPY) messenger RNA expression were measured after intra-third cerebroventricular or intraperitoneal injections of ghrelin in mice. The gastric vagal nerve activity was recorded after intravenous administration in rats. Gastric ghrelin gene expression was assessed by Northern blot analysis. Repeated coadministration of ghrelin and interleukin (IL)-1 beta was continued for 5 days. : Ghrelin exhibited gastroprokinetic activity with structural resemblance to motilin and potent orexigenic activity through action on the hypothalamic neuropeptide Y (NPY) and Y(1) receptor, which was lost after vagotomy. Ghrelin decreased gastric vagal afferent discharge in contrast to other anorexigenic peptides that increased the activity. Ghrelin gene expression in the stomach was increased by fasting and in ob/ob mice, and was decreased by administration of leptin and IL-1 beta. Peripherally administered ghrelin blocked IL-1 beta-induced anorexia and produced positive energy balance by promoting food intake and decreasing energy expenditure. : Ghrelin, which is negatively regulated by leptin and IL-1 beta, is secreted by the stomach and increases arcuate NPY expression, which in turn acts through Y(1) receptors to increase food intake and decrease energy expenditure. Gastric peptide ghrelin may thus function as part of the orexigenic pathway downstream from leptin and is a potential therapeutic target not only for obesity but also for anorexia and cachexia.
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              Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2 and PI 3-kinase/AKT

              Ghrelin is an acyl-peptide gastric hormone acting on the pituitary and hypothalamus to stimulate growth hormone (GH) release, adiposity, and appetite. Ghrelin endocrine activities are entirely dependent on its acylation and are mediated by GH secretagogue (GHS) receptor (GHSR)-1a, a G protein–coupled receptor mostly expressed in the pituitary and hypothalamus, previously identified as the receptor for a group of synthetic molecules featuring GH secretagogue (GHS) activity. Des-acyl ghrelin, which is far more abundant than ghrelin, does not bind GHSR-1a, is devoid of any endocrine activity, and its function is currently unknown. Ghrelin, which is expressed in heart, albeit at a much lower level than in the stomach, also exerts a cardio protective effect through an unknown mechanism, independent of GH release. Here we show that both ghrelin and des-acyl ghrelin inhibit apoptosis of primary adult and H9c2 cardiomyocytes and endothelial cells in vitro through activation of extracellular signal–regulated kinase-1/2 and Akt serine kinases. In addition, ghrelin and des-acyl ghrelin recognize common high affinity binding sites on H9c2 cardiomyocytes, which do not express GHSR-1a. Finally, both MK-0677 and hexarelin, a nonpeptidyl and a peptidyl synthetic GHS, respectively, recognize the common ghrelin and des-acyl ghrelin binding sites, inhibit cell death, and activate MAPK and Akt. These findings provide the first evidence that, independent of its acylation, ghrelin gene product may act as a survival factor directly on the cardiovascular system through binding to a novel, yet to be identified receptor, which is distinct from GHSR-1a.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                16 August 2017
                : 11
                : 2377-2386
                [1 ]Institute of Clinical Medicine, National Yang-Ming University of Medicine
                [2 ]Department of Emergency Medicine, Taipei Veterans General Hospital
                [3 ]Aging and Health Research Center, National Yang-Ming University
                [4 ]Center for Geriatrics and Gerontology, Taipei Veterans General Hospital
                [5 ]Institute of Physiology, National Yang-Ming University School of Medicine
                [6 ]Institute of Emergency and Critical Medicine, National Yang-Ming University School of Medicine
                [7 ]Department of Chest Medicine, Taipei Veterans General Hospital
                [8 ]Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital
                [9 ]Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei
                [10 ]Taiwan Association for the Study of Small Intestinal Diseases, Guishan, Taiwan
                Author notes
                Correspondence: Chih-Yen Chen, Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, 201, Sec. 2, Shih-Pai Road, Taipei 112, Taiwan, Tel +886 22 871 2121 ext 3763, Fax +886 22 871 1058, Email chency@ 123456vghtpe.gov.tw
                © 2017 Huang et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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