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      Ghrelin: Central and Peripheral Implications in Anorexia Nervosa

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          Abstract

          Increasing clinical and therapeutic interest in the neurobiology of eating disorders reflects their dramatic impact on health. Chronic food restriction resulting in severe weight loss is a major symptom described in restrictive anorexia nervosa (AN) patients, and they also suffer from metabolic disturbances, infertility, osteopenia, and osteoporosis. Restrictive AN, mostly observed in young women, is the third largest cause of chronic illness in teenagers of industrialized countries. From a neurobiological perspective, AN-linked behaviors can be considered an adaptation that permits the endurance of reduced energy supply, involving central and/or peripheral reprograming. The severe weight loss observed in AN patients is accompanied by significant changes in hormones involved in energy balance, feeding behavior, and bone formation, all of which can be replicated in animals models. Increasing evidence suggests that AN could be an addictive behavior disorder, potentially linking defects in the reward mechanism with suppressed food intake, heightened physical activity, and mood disorder. Surprisingly, the plasma levels of ghrelin, an orexigenic hormone that drives food-motivated behavior, are increased. This increase in plasma ghrelin levels seems paradoxical in light of the restrained eating adopted by AN patients, and may rather result from an adaptation to the disease. The aim of this review is to describe the role played by ghrelin in AN focusing on its central vs. peripheral actions. In AN patients and in rodent AN models, chronic food restriction induces profound alterations in the « ghrelin » signaling that leads to the development of inappropriate behaviors like hyperactivity or addiction to food starvation and therefore a greater depletion in energy reserves. The question of a transient insensitivity to ghrelin and/or a potential metabolic reprograming is discussed in regard of new clinical treatments currently investigated.

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          Most cited references327

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          Reward, dopamine and the control of food intake: implications for obesity.

          The ability to resist the urge to eat requires the proper functioning of neuronal circuits involved in top-down control to oppose the conditioned responses that predict reward from eating the food and the desire to eat the food. Imaging studies show that obese subjects might have impairments in dopaminergic pathways that regulate neuronal systems associated with reward sensitivity, conditioning and control. It is known that the neuropeptides that regulate energy balance (homeostatic processes) through the hypothalamus also modulate the activity of dopamine cells and their projections into regions involved in the rewarding processes underlying food intake. It is postulated that this could also be a mechanism by which overeating and the resultant resistance to homoeostatic signals impairs the function of circuits involved in reward sensitivity, conditioning and cognitive control. Published by Elsevier Ltd.
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            A receptor in pituitary and hypothalamus that functions in growth hormone release.

            Small synthetic molecules termed growth hormone secretagogues (GHSs) act on the pituitary gland and the hypothalamus to stimulate and amplify pulsatile growth hormone (GH) release. A heterotrimeric GTP-binding protein (G protein)-coupled receptor (GPC-R) of the pituitary and arcuate ventro-medial and infundibular hypothalamus of swine and humans was cloned and was shown to be the target of the GHSs. On the basis of its pharmacological and molecular characterization, this GPC-R defines a neuroendocrine pathway for the control of pulsatile GH release and supports the notion that the GHSs mimic an undiscovered hormone.
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              Ghrelin octanoylation mediated by an orphan lipid transferase.

              The peptide hormone ghrelin is the only known protein modified with an O-linked octanoyl side group, which occurs on its third serine residue. This modification is crucial for ghrelin's physiological effects including regulation of feeding, adiposity, and insulin secretion. Despite the crucial role for octanoylation in the physiology of ghrelin, the lipid transferase that mediates this novel modification has remained unknown. Here we report the identification and characterization of human GOAT, the ghrelin O-acyl transferase. GOAT is a conserved orphan membrane-bound O-acyl transferase (MBOAT) that specifically octanoylates serine-3 of the ghrelin peptide. Transcripts for both GOAT and ghrelin occur predominantly in stomach and pancreas. GOAT is conserved across vertebrates, and genetic disruption of the GOAT gene in mice leads to complete absence of acylated ghrelin in circulation. The occurrence of ghrelin and GOAT in stomach and pancreas tissues demonstrates the relevance of GOAT in the acylation of ghrelin and further implicates acylated ghrelin in pancreatic function.
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                Author and article information

                Journal
                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrinol.
                Frontiers in Endocrinology
                Frontiers Media S.A.
                1664-2392
                10 November 2012
                26 February 2013
                2013
                : 4
                : 15
                Affiliations
                [1] 1UMR INSERM 837, Development and Plasticity of Postnatal Brain Lille, France
                [2] 2Pathophysiology of inflammatory of bone diseases, Université Lille Nord de France-ULCO – Lille 2 Boulogne sur Mer, France
                [3] 3Department of Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg Gothenburg, Sweden
                [4] 4Department of Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg Gothenburg, Sweden
                [5] 5Université Lille Nord de France – Université d’Artois Liévin, France
                [6] 6Université Lille Nord de France-USTL (Lille 1) Villeneuve d’Ascq, France
                Author notes

                Edited by: Hubert Vaudry, University of Rouen, France

                Reviewed by: Masamitsu Nakazato, University of Miyazaki, Japan; Paolo Magni, Università degli Studi di Milano, Italy

                *Correspondence: Odile Viltart, Development and Plasticity of the Postnatal Brain, Team 2, Jean-Pierre Aubert Research Center, UMR INSERM 837, Bât Biserte, 1 place de Verdun, 59,045 Lille cedex, France. e-mail: odile.viltart@ 123456univ-lille1.fr

                Christophe Chauveau and Odile Viltart have contributed equally to this work.

                This article was submitted to Frontiers in Neuroendocrine Science, a specialty of Frontiers in Endocrinology.

                Article
                10.3389/fendo.2013.00015
                3581855
                23549309
                09566647-7f85-41aa-b01d-949ee2556999
                Copyright © 2013 Méquinion, Langlet, Zgheib, Dickson, Dehouck, Chauveau and Viltart.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

                History
                : 15 October 2012
                : 01 February 2013
                Page count
                Figures: 4, Tables: 6, Equations: 0, References: 376, Pages: 27, Words: 27565
                Categories
                Endocrinology
                Review Article

                Endocrinology & Diabetes
                animal models,anorexia,central alterations,energy balance,food intake,ghrelin,peripheral alterations,reward

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