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Disruption of Gpr45 causes reduced hypothalamic POMC expression and obesity
Jing Cui, … , Tian Xu, Xiaohui Wu
Jing Cui, … , Tian Xu, Xiaohui Wu
Published August 8, 2016
Citation Information: J Clin Invest. 2016;126(9):3192-3206. https://doi.org/10.1172/JCI85676.
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Research Article Endocrinology

Disruption of Gpr45 causes reduced hypothalamic POMC expression and obesity

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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 Cui, Yi Ding, Shu Chen, Xiaoqiang Zhu, Yichen Wu, Mingliang Zhang, Yaxin Zhao, Tong-Ruei R. Li, Ling V. Sun, Shimin Zhao, Yuan Zhuang, Weiping Jia, Lei Xue, Min Han, Tian Xu, Xiaohui Wu

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Figure 4

Obesity is the primary defect in Gpr45 mutants.

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Obesity is the primary defect in Gpr45 mutants.
(A) Daily fat/lean ratio...
(A) Daily fat/lean ratio of female (+/+, n = 9; PB1/+, n = 18; PB1/PB1, n = 8) and male (+/+, n = 9; PB1/+, n = 18; PB1/PB1, n = 8) mice revealed early-onset obesity before weaning. Data from wild-type mice were used as the control for the P value calculation. (B) Bar graphs showing similar plasma leptin levels found in 2-week-old mutant and wild-type mice. At least 7 female or 6 male mice were analyzed for each genotype. (C) Bar graphs showing higher plasma leptin levels in 4-week-old mutant mice than those in wild-type littermates. Number of mice: female, +/+, 7; PB1/+, 11; PB1/PB1, 11; male +/+, 7; PB1/+, 8; PB1/PB1, 6. (D) Oil red O and hematoxylin staining detecting no hepatic steatosis in a 4-week-old male mouse. Scale bar: 0.05 mm. (E) Bar graphs showing normal plasma insulin levels in 4-week-old mutant mice. Number of mice: female, +/+, n = 7; PB1/+, n = 11; PB1/PB1, n = 10; male, +/+, n = 5; PB1/+, n = 4; PB1/PB1, n = 6. (F) Bar graphs showing no difference in fasted plasma glucose (FPG) levels of 9-week-old female (+/+, n = 5; PB1/PB1, n = 4) and male (+/+, n = 5; PB1/PB1, n = 4) mice. All data are shown as the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001 by Student’s t test; ###P < 0.001, PB1/+ versus +/+ in A.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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