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- Title
Disruption of Gpr45 causes reduced hypothalamic POMC expression and obesity.
- Authors
Jing Cui; Yi Ding; Shu Chen; Xiaoqiang Zhu; Yichen Wu; Mingliang Zhang; Yaxin Zhao; Li, Tong-Ruei R.; Sun, Ling V.; Shimin Zhao; Yuan Zhuang; Weiping Jia; Lei Xue; Min Han; Tian Xu; Xiaohui Wu; Cui, Jing; Ding, Yi; Chen, Shu; Zhu, Xiaoqiang
- 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.
- Subjects
PROOPIOMELANOCORTIN; G protein coupled receptors; OBESITY; NEUROPEPTIDES; BODY mass index; GLUCOSE metabolism; ANIMAL behavior; ANIMAL experimentation; BIOLOGICAL models; CELL receptors; ELECTROPHYSIOLOGY; FATTY liver; GENES; HYPOTHALAMUS; LIVER; MICE; GENETIC mutation; PROTEIN precursors; RESEARCH funding; PHENOTYPES
- Publication
Journal of Clinical Investigation, 2016, Vol 126, Issue 9, p3192
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI85676