Disruption of Gpr45 causes reduced hypothalamic POMC expression and obesity
Disruption of Gpr45 causes reduced hypothalamic POMC expression and obesity
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Gpr45 的破坏导致下丘脑 POMC 表达减少和肥胖
DOI：
10.1172/jci85676
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发表时间：
2016-09-01
影响因子：
15.9
通讯作者：
Wu, Xiaohui
中科院分区：
文献类型：
--
作者：
Cui, Jing;Ding, Yi;Wu, Xiaohui
肥胖症发病率的上升促使人们探索其潜在的遗传基础和潜在的干预目标。Gwas的研究已经确定了肥胖易感性途径，涉及几种控制能量稳态的神经肽，这表明调节食物摄入量和能量消耗的基因变异可能导致肥胖。在这项研究中，我们在由iggyBac插入突变产生的突变小鼠的正向遗传筛查中发现了另外5个肥胖基因座，包括一个名为GPR45的神经元孤儿GPCR。GPR45基因的缺失导致断奶时肥胖增加，随着年龄的增长，体重、脂肪含量、糖耐量和肝脏脂肪变性增加。在肥胖开始之前，GPR45基因突变的小鼠也表现出代谢调节因子POMC表达的减少和能量消耗的减少。从机制上讲，我们确定GPR45以细胞自主的方式通过JAK/STAT途径调节POMC的表达。与这一发现一致的是，脑室内给予黑色素-2，一种POMC衍生物α-MSH的类似物，抑制了GPR45突变体中的成年肥胖症。这些结果表明GPR45是POMC信号和能量消耗的调节者，这表明它可能是一个潜在的抗击肥胖的干预靶点。
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 alpha-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.