Central treatment with ghrelin increases body weight and fat accumulation. Here we explore the pharmacological effect of a combined central (ICV) infusion of ghrelin (0.3 nmol/day) and a recently developed ghrelin receptor (GHS-R1A) antagonist (JMV2959, 100 nmol/day) on food intake and body composition. The effect of ghrelin infusion for 14 days to increase body weight (20.7±0.9% vs 34.3±3.1%, saline vs ghrelin, P<0.001) was blocked by co-infusion with JMV2959 (34.3±3.1% vs 24.8±2.5%, ghrelin vs JMV2959+ghrelin, P<0.05). The higher food intake (rat chow; 333.4±6.8 g vs 407.4±16.4 g, saline vs ghrelin, P<0.005) and the increase of food efficiency (17.9±0.5% vs 24±1.4%, saline vs ghrelin, P<0.05) in ghrelin treated rats was not suppressed by the antagonist (407.4±16.4 g vs 368.3±13.4 g and 24±1.4% vs 19.8±1.6%. Body composition analysis (DEXA) showed that ghrelin treatment increased delta lean mass (9.4±1.4% vs 12.9±1.2%, saline vs ghrelin) and delta fat mass (0.27±0.5% vs 2.6±0.6%, saline vs ghrelin, P<0.001) but only the latter was blocked by JMV2959 (2.6±0.6% vs −2.1±0.3%, ghrelin vs ghrelin+JMV, P<0.001). Ghrelin induced an increase in the weight of all dissected fat pads (retroperinotenal, inguinal, reproductive and mesenteric as well as the intracapsular brown adipose (iBAT) tissue) but only the effects on retroperitoneal, inguinal and iBAT depots were suppressed by the antagonist.
Thus, the ghrelin antagonist JMV2959 suppresses the weight gain and fat accumulation induced by central ghrelin administration. These antagonist effects are not mediated by changes in food intake and food efficiency and future studies will elucidate whether this is due to an influence on metabolic rate. Supported by EC 6th LSHM-CT-2003-503041.
03 - 07 May 2008
European Society of Endocrinology