Study summary · research use only
Disruption of Gpr45 causes reduced hypothalamic POMC expression and obesity
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
In this mouse study, researchers used a forward genetic screen of piggyBac insertional mutants and identified 5 additional obesity loci, including a neuronal orphan GPCR called Gpr45. Disrupting Gpr45 was associated with increased adiposity at weaning and, with age, increases in body mass, fat content, glucose intolerance, and hepatic steatosis, along with reduced expression of the metabolic regulator POMC and less energy expenditure before obesity onset. The authors report that GPR45 regulates POMC expression via the JAK/STAT pathway in a cell-autonomous manner, and that intraventricular administration of melanotan-2, an analog of the POMC derivative α-MSH, suppressed adult obesity in Gpr45 mutant mice.
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.
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