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Disruption of Gpr45 causes reduced hypothalamic POMC expression and obesity.

Publication ,  Journal Article
Cui, J; Ding, Y; Chen, S; Zhu, X; Wu, Y; Zhang, M; Zhao, Y; Li, T-RR; Sun, LV; Zhao, S; Zhuang, Y; Jia, W; Xue, L; Han, M; Xu, T; Wu, X
Published in: J Clin Invest
September 1, 2016

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.

Duke Scholars

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Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

September 1, 2016

Volume

126

Issue

9

Start / End Page

3192 / 3206

Location

United States

Related Subject Headings

  • Receptors, Lysophosphatidic Acid
  • Receptors, G-Protein-Coupled
  • Pro-Opiomelanocortin
  • Phenotype
  • Obesity
  • Neuropeptides
  • Mutation
  • Mutagenesis
  • Mice
  • Male
 

Citation

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Cui, J., Ding, Y., Chen, S., Zhu, X., Wu, Y., Zhang, M., … Wu, X. (2016). Disruption of Gpr45 causes reduced hypothalamic POMC expression and obesity. J Clin Invest, 126(9), 3192–3206. https://doi.org/10.1172/JCI85676
Cui, Jing, Yi Ding, Shu Chen, Xiaoqiang Zhu, Yichen Wu, Mingliang Zhang, Yaxin Zhao, et al. “Disruption of Gpr45 causes reduced hypothalamic POMC expression and obesity.J Clin Invest 126, no. 9 (September 1, 2016): 3192–3206. https://doi.org/10.1172/JCI85676.
Cui J, Ding Y, Chen S, Zhu X, Wu Y, Zhang M, et al. Disruption of Gpr45 causes reduced hypothalamic POMC expression and obesity. J Clin Invest. 2016 Sep 1;126(9):3192–206.
Cui, Jing, et al. “Disruption of Gpr45 causes reduced hypothalamic POMC expression and obesity.J Clin Invest, vol. 126, no. 9, Sept. 2016, pp. 3192–206. Pubmed, doi:10.1172/JCI85676.
Cui J, Ding Y, Chen S, Zhu X, Wu Y, Zhang M, Zhao Y, Li T-RR, Sun LV, Zhao S, Zhuang Y, Jia W, Xue L, Han M, Xu T, Wu X. Disruption of Gpr45 causes reduced hypothalamic POMC expression and obesity. J Clin Invest. 2016 Sep 1;126(9):3192–3206.

Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

September 1, 2016

Volume

126

Issue

9

Start / End Page

3192 / 3206

Location

United States

Related Subject Headings

  • Receptors, Lysophosphatidic Acid
  • Receptors, G-Protein-Coupled
  • Pro-Opiomelanocortin
  • Phenotype
  • Obesity
  • Neuropeptides
  • Mutation
  • Mutagenesis
  • Mice
  • Male