Obesity is one of the diseases with severe health consequences and rapidly increasing worldwide prevalence. Understanding the complex network of food intake and energy balance regulation is an essential prerequisite for pharmacological intervention with obesity. G protein-coupled receptors (GPCRs) are among the main modulators of metabolism and energy balance. They, for instance, regulate appetite and satiety in certain hypothalamic neurons, as well as glucose and lipid metabolism and hormone secretion from adipocytes. Mutations in some GPCRs, such as the melanocortin receptor type 4 (MC4R), have been associated with early-onset obesity. Here, we identified the adhesion GPCR latrophilin 1 (ADGRL1/LPHN1) as a member of the regulating network governing food intake and the maintenance of energy balance. Deficiency of the highly conserved receptor in mice results in increased food consumption and severe obesity, accompanied by dysregulation of glucose homeostasis. Consistently, we identified a partially inactivating mutation in human ADGRL1/LPHN1 in a patient suffering from obesity. Therefore, we propose that LPHN1 dysfunction is a risk factor for obesity development.

肥胖是一种对健康造成严重后果且全球患病率迅速上升的疾病之一。了解食物摄入和能量平衡调节的复杂网络是药物干预肥胖的重要先决条件。 G 蛋白偶联受体 (GPCR) 是代谢和能量平衡的主要调节剂之一。例如，它们调节某些下丘脑神经元的食欲和饱腹感，以及葡萄糖和脂质代谢以及脂肪细胞的激素分泌。一些 GPCR 的突变，例如 4 型黑皮质素受体 (MC4R)，与早发性肥胖有关。在这里，我们将粘附 GPCR latrophilin 1 (ADGRL1/LPHN1) 确定为控制食物摄入和维持能量平衡的调节网络的成员。小鼠体内高度保守的受体缺乏会导致食物消耗增加和严重肥胖，并伴有葡萄糖稳态失调。一致地，我们在一名肥胖患者体内发现了人类 ADGRL1/LPHN1 的部分失活突变。因此，我们认为LPHN1功能障碍是肥胖发生的危险因素。