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      Anti-ghrelin immunoglobulins modulate ghrelin stability and its orexigenic effect in obese mice and humans

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          Abstract

          Obese individuals often have increased appetite despite normal plasma levels of the main orexigenic hormone ghrelin. Here we show that ghrelin degradation in the plasma is inhibited by ghrelin-reactive IgG immunoglobulins, which display increased binding affinity to ghrelin in obese patients and mice. Co-administration of ghrelin together with IgG from obese individuals, but not with IgG from anorectic or control patients, increases food intake in rats. Similarly, chronic injections of ghrelin together with IgG from ob/ob mice increase food intake, meal frequency and total lean body mass of mice. These data reveal that in both obese humans and mice, IgG with increased affinity for ghrelin enhances ghrelin’s orexigenic effect, which may contribute to increased appetite and overeating.

          Abstract

          Obesity is often associated with increased appetite and food intake, despite normal blood levels of the hunger hormone ghrelin. Here the authors show that ghrelin-reactive antibodies in the blood of obese mice and humans enhance the orexigenic effect of ghrelin by protecting it from degradation.

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          Ghrelin octanoylation mediated by an orphan lipid transferase.

          Jesus A Gutierrez, Patricia J Solenberg, Douglas R Perkins … (2008)
          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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            Deciphering a neuronal circuit that mediates appetite.

            Qi Wu, Richard D. Palmiter, Lynn Clark (2012)
            Hypothalamic neurons that co-express agouti-related protein (AgRP), neuropeptide Y and γ-aminobutyric acid (GABA) are known to promote feeding and weight gain by integration of various nutritional, hormonal, and neuronal signals. Ablation of these neurons in mice leads to cessation of feeding that is accompanied by activation of Fos in most regions where they project. Previous experiments have indicated that the ensuing starvation is due to aberrant activation of the parabrachial nucleus (PBN) and it could be prevented by facilitating GABA(A) receptor signalling in the PBN within a critical adaptation period. We speculated that loss of GABA signalling from AgRP-expressing neurons (AgRP neurons) within the PBN results in unopposed excitation of the PBN, which in turn inhibits feeding. However, the source of the excitatory inputs to the PBN was unknown. Here we show that glutamatergic neurons in the nucleus tractus solitarius (NTS) and caudal serotonergic neurons control the excitability of PBN neurons and inhibit feeding. Blockade of serotonin (5-HT(3)) receptor signalling in the NTS by either the chronic administration of ondansetron or the genetic inactivation of Tph2 in caudal serotonergic neurons that project to the NTS protects against starvation when AgRP neurons are ablated. Likewise, genetic inactivation of glutamatergic signalling by the NTS onto N-methyl D-aspartate-type glutamate receptors in the PBN prevents starvation. We also show that suppressing glutamatergic output of the PBN reinstates normal appetite after AgRP neuron ablation, whereas it promotes weight gain without AgRP neuron ablation. Thus we identify the PBN as a hub that integrates signals from several brain regions to bidirectionally modulate feeding and body weight.
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              Ghrelin increases food intake in obese as well as lean subjects.

              Gregory Bloom, J. Park, Eliza Small … (2005)
              To investigate whether effects on food intake are seen in obese subjects receiving exogenous administration of ghrelin. Randomised, double-blind, placebo-controlled study of intravenous ghrelin at doses 1 pmol/kg/min and 5 pmol/kg/min. In all, 12 healthy lean subjects (mean body mass index (BMI) 20.5+/-0.17 kg/m(2)) and 12 healthy overweight and obese subjects (mean BMI 31.9+/-1.02 kg/m(2)). Food intake, appetite and palatability of food, ghrelin and other obesity-related hormones, growth hormone. Low-dose infusion of ghrelin increased ad libitum energy intake at a buffet meal in the obese group only (mean increase 36.6+/-9.4%, P<0.01.) High-dose ghrelin infusion increased energy intake in both groups (mean increase 20.1+/-10.6% in the lean and 70.1+/-15.5% in the obese, P<0.01 in both cases.) Ghrelin infusion increased palatability of food in the obese group. Ghrelin increases food intake in obese as well as lean subjects. Obese people are sensitive to the appetite-stimulating effects of ghrelin and inhibition of circulating ghrelin may be a useful therapeutic target in the treatment of obesity.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Nat Commun
                Journal ID (iso-abbrev): Nat Commun
                Title: Nature Communications
                Publisher: Nature Pub. Group
                ISSN (Electronic): 2041-1723
                Publication date (Electronic): 25 October 2013
                Volume: 4
                Electronic Location Identifier: 2685
                Affiliations
                [1 ]Inserm UMR1073, Nutrition, Gut and Brain Laboratory , Rouen 76183, France
                [2 ]Institute for Research and Innovation in Biomedicine (IRIB), Rouen University, Normandy University , Rouen 76183, France
                [3 ]Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences , Kagoshima 890-8520, Japan
                [4 ]Rouen University Hospital, CHU Charles Nicolle , Rouen 76183, France
                [5 ]Animal Behavior Platform (SCAC), IRIB , Rouen 76183, France
                [6 ]These authors contributed equally to this work
                Author notes
                Article
                Publisher Item ID: ncomms3685
                DOI: 10.1038/ncomms3685
                PMC ID: 3826639
                PubMed ID: 24158035
                SO-VID: 17057d28-9992-4b2c-9cab-b6816ef23854
                Copyright © Copyright © 2013, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.
                License:

                This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

                History
                Date received : 08 August 2013
                Date accepted : 30 September 2013
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                Subject: Article

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