Altered metabolism in the melatonin-related receptor (GPR50) knockout mouse

1 Faculty of Life Sciences, University of Manchester, Manchester; 2 Cardiovascular and Gastrointestinal Department Discovery, AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield; and 3 Molecular Endocrinology Group, Division of Obesity and Metabolic Health and Aberdeen Centre for Energy Regulation and Obesity, Rowett Research Institute, Aberdeen, United Kingdom Submitted 30 March 2007 ; accepted in final form 23 October 2007 The X-linked orphan receptor GPR50 shares 45% homology with the melatonin receptors, yet its ligand and physiological function remain unknown. Here we report that mice lacking functional GPR50 through insertion of a lacZ gene into the coding sequence of GPR50 exhibit an altered metabolic phenotype. GPR50 knockout mice maintained on normal chow exhibit lower body weight than age-matched wild-type littermates by 10 wk of age. Furthermore, knockout mice were partially resistant to diet-induced obesity. When placed on a high-energy diet (HED) for 5 wk, knockout mice consumed significantly more food per unit body weight yet exhibited an attenuated weight gain and reduced body fat content compared with wild-type mice. Wheel-running activity records revealed that, although GPR50 knockout mice showed no alteration of circadian period, the overall levels of activity were significantly increased over wild types in both nocturnal and diurnal phases. In line with this, basal metabolic rate (O 2 consumption, CO 2 production, and respiratory quotient) was found to be elevated in knockout mice. Using in situ hybridization (wild-type mice) and β-galactosidase activity (from LacZ insertion element in knockout mice), brain expression of GPR50 was found to be restricted to the ependymal layer of the third ventricle and dorsomedial nucleus of the hypothalamus. GPR50 expression was highly responsive to energy status, showing a significantly reduced expression following both fasting and 5 wk of HED. These data implicate GPR50 as an important regulator of energy metabolism. dorsomedial hypothalamus; metabolic rate; obesity; tanycyte Address for reprint requests and other correspondence: A. Loudon, Faculty of Life Sciences, Univ. of Manchester, 1.124 Stopford Bldg., Oxford Road, Manchester, UK, M13 9PT (e-mail: andrew.loudon{at}manchester.ac.uk )