Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America.
PLoS One. 2012;7(7):e40764. doi: 10.1371/journal.pone.0040764. Epub 2012 Jul 16.
G-protein coupled receptor 26 (GPR26) is a brain-specific orphan GPCR with high expression in the brain region that controls satiety. Depletion of GPR26 has been shown to increase fat storage in C. elegans, whereas GPR26 deficiency in the hypothalamus is associated with high genetic susceptibility to the onset of obesity in mice. However, the metabolic function of GPR26 in mammals remains elusive. Herein, we investigated a role of GPR26 in regulating energy homeostasis by generating mice with targeted deletion of the GPR26 gene. We show that GPR26 deficiency causes hyperphagia and hypometabolism, leading to early onset of diet-induced obesity. Accordingly, GPR26 deficiency also caused metabolic complications commonly associated with obesity, including glucose intolerance, hyperinsulinemia, and dyslipidemia. Moreover, consistent with hyperphagia in GPR26 null mice, GPR26 deficiency significantly increased hypothalamic activity of AMPK, a key signaling event that stimulates appetite. In further support of a regulatory role of GPR26 in satiety, GPR26 knockout mice also demonstrate hypersensitivity to treatment of rimonabant, an endocannabinoid receptor-1 antagonist commonly used to treat obesity by suppressing appetite in humans. Together, these findings identified a key role of GPR26 as a central regulator of energy homeostasis though modulation of hypothalamic AMPK activation.
G 蛋白偶联受体 26（GPR26）是一种大脑特异性孤儿 GPCR，在控制饱腹感的大脑区域表达水平较高。研究表明，GPR26 耗竭会增加秀丽隐杆线虫的脂肪储存，而下丘脑 GPR26 缺乏与小鼠肥胖发病的高遗传易感性相关。然而，GPR26 在哺乳动物中的代谢功能仍不清楚。在此，我们通过生成靶向敲除 GPR26 基因的小鼠，研究了 GPR26 在调节能量平衡中的作用。结果表明，GPR26 缺失会导致多食和代谢率降低，从而导致饮食诱导肥胖的早期发生。相应地，GPR26 缺失还会导致与肥胖相关的代谢并发症，包括葡萄糖不耐受、高胰岛素血症和血脂异常。此外，与 GPR26 缺失小鼠的多食一致，GPR26 缺失显著增加了 AMPK 的下丘脑活性，AMPK 是一种刺激食欲的关键信号事件。进一步支持 GPR26 在饱腹感中的调节作用，GPR26 敲除小鼠对 rimonabant 的治疗也表现出超敏反应，rimonabant 是一种内源性大麻素受体-1 拮抗剂，常用于通过抑制人类食欲来治疗肥胖。综上所述，这些发现确定了 GPR26 作为通过调节下丘脑 AMPK 激活来调节能量平衡的中枢调节剂的关键作用。
