title: Disruption of Gpr45 causes reduced hypothalamic POMC expression and obesity.
abstract: A rise in the occurrence of obesity has driven exploration of its underlying genetic basis and potential targets for intervention. GWAS studies have identified obesity susceptibility pathways involving several neuropeptides that control energy homeostasis, suggesting that variations in the genes that regulate food intake and energy expenditure may contribute to obesity. In this study, we identified 5 additional obesity loci, including a neuronal orphan GPCR called Gpr45, in a forward genetic screen of mutant mice generated by piggyBac insertional mutagenesis. Disruption of Gpr45 led to increased adiposity at the time of weaning and increases in body mass, fat content, glucose intolerance, and hepatic steatosis with advancing age. Mice with disruptions in Gpr45 also displayed a reduction in expression of the metabolic regulator POMC and less energy expenditure prior to the onset of obesity. Mechanistically, we determined that GPR45 regulates POMC expression via the JAK/STAT pathway in a cell-autonomous manner. Consistent with this finding, intraventricular administration of melanotan-2, an analog of the POMC derivative α-MSH, suppressed adult obesity in Gpr45 mutants. These results reveal that GPR45 is a regulator of POMC signaling and energy expenditure, which suggests that it may be a potential intervention target to combat obesity.
authors: Jing
authors: J
authors: Cui
authors: Yi
authors: Y
authors: Ding
authors: Shu
authors: S
authors: Chen
authors: Xiaoqiang
authors: X
authors: Zhu
authors: Yichen
authors: Y
authors: Wu
authors: Mingliang
authors: M
authors: Zhang
authors: Yaxin
authors: Y
authors: Zhao
authors: Tong-Ruei R
authors: TR
authors: Li
authors: Ling V
authors: LV
authors: Sun
authors: Shimin
authors: S
authors: Zhao
authors: Yuan
authors: Y
authors: Zhuang
authors: Weiping
authors: W
authors: Jia
authors: Lei
authors: L
authors: Xue
authors: Min
authors: M
authors: Han
authors: Tian
authors: T
authors: Xu
authors: Xiaohui
authors: X
authors: Wu
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D004594:Electrophysiology; D005234:Fatty Liver / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D016296:Mutagenesis; D009154:Mutation; D009479:Neuropeptides / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*; D010641:Phenotype; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics* / Q000378:metabolism
chemical_list: C000622726:Gpr45 protein, mouse; D009479:Neuropeptides; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; D011333:Pro-Opiomelanocortin; D005947:Glucose