FP08-2 The Orphan G Protein Coupled Receptor 83 (GPR83) Modulates Ghrelin Receptor Signaling in Vitro and in Vivo

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: FP08-Obesity: Novel Mechanisms of Body Weight Regulation
Saturday, June 15, 2013: 11:00 AM-11:30 AM
Presentation Start Time: 11:05 AM
Room 301 (Moscone Center)

Poster Board SAT-649
Anne Müller*1, Timo D. Müller2, Kirk Habegger3, Carolin Leonie Piechowski1, Chun-Xia Yi2, Richard DiMarchi4, Heiko Krude1, Paul T. Pfluger2, Gunnar Kleinau1, Matthias H. Tschöp2 and Heike Biebermann1
1Charité - Universitätsmedizin Berlin, Berlin, Germany, 2Helmholtz Center Munich, Munich, Germany, 3University of Cincinnati, Cincinnati, 4Indiana University, Bloomington
Signaling of the ghrelin receptor (GHSR1a) is of upmost importance for energy metabolism. Recently it was shown that the GHSR1a can interact with a variety of other G protein coupled receptors (GPCRs) including the melanocortin 3 receptor, dopamin 1 receptor and serotonin 2c receptor. Here we investigated the role of the orphan G protein coupled receptor 83 (GPR83) in modulating the function of GHSR1a. The GPR83 is an orphan GPCR that is expressed widely in the brain, including in hypothalamic nuclei governing energy balance. We show that hypothalamic expression of GPR83 is decreased in diet-induced obese (DIO) mice compared to lean mice. Furthermore, hypothalamic expression is reduced following fasting and increased upon re-feeding. GPR83 is co-localized with GHSR1a in the arcuate nucleus (ARC), and in vitro studies indicate that GPR83 forms heterodimers with GHSR1a, leading to reduced activation of GHSR1a by its ligand ghrelin. Studies in GPR83-knockout mice show that loss of GPR83 potentiates the effect of central and peripheral ghrelin treatment on food intake and adiposity. GPR83-knockout mice have normal body weight and glucose tolerance when fed a regular chow diet. However, glucose intolerance and obesity were not observed in response to high-fat diet despite relative hyperphagia. Taken together, these data suggest that the orphan GPR83 acts as a modulator of ghrelin action in response to nutrient availability and might act also through other pathways to regulate systemic metabolism in response to high-fat diet. Our data support the notion that GHSR1a is part of a hypothalamic GPCR interactome which have to be unravelled when GHSR1a is used as target to combat obesity.

Nothing to Disclose: AM, TDM, KH, CLP, CXY, RD, HK, PTP, GK, MHT, HB

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