GPR101 loss promotes insulin resistance and diet-induced obesity risk

G-protein-coupled receptors (GPCRs) represent targets for improved low-side-effect therapies to tackle the evolving Western obesity epidemic. The orphan (o) GPCR GPR101 emerged as an attractive candidate in this regard. Expressed on cells in brain areas regulating energy homeostasis, including the hunger-suppressing proopiomelanocortin (POMC) + neurons, it is minimally expressed outside the brain. To understand the function of this receptor in vivo, we herein generated and comprehensively characterized a Gpr101 knockout mouse line, either under standard feeding conditions or with chronic high-fat diet (HFD) access (16 weeks). GPR101 loss accelerated the risk for diet-induced obesity (DIO), hyperinsulinemia and disrupted glucose homeostasis. Hypothalamic transcriptomic analysis revealed also decreased Pomc activation with HFD suggesting impaired hunger suppression. Moreover, on a standard diet, there was a molecular signature of downregulated tristetrapolin (TTP) pathway gene activation suggesting impaired inflammation resolution and one of aberrant microglial phagocytosis and lipid metabolism on HFD. Morphometry revealed altered hypothalamic arcuate nucleus microglial morphology consistent with the transcriptomic profile. We discuss how the GPR101 specialized pro-resolving mediator (SPM) receptor capacity likely underlies the aberrant microglial function and contributes to DIO risk. Thus, this evidence shows that GPR101 is a potential therapeutic target for DIO through, among other factors, effects on hypothalamic inflammation resolution. We analysed hypothalamic tissue of Gpr101 knock-out and control mice treated with high-fat or control dietsG蛋白偶联受体（G-protein-coupled receptors, GPCRs）是开发低副作用疗法的潜在靶点，可用于应对日益严峻的西方肥胖流行趋势。孤儿GPCR GPR101在此领域成为极具吸引力的候选靶点。该受体在调控能量稳态的脑区细胞中表达，包括抑制饥饿的阿黑皮素原（proopiomelanocortin, POMC）阳性神经元，且在脑外的表达量极低。 为解析该受体在体内的功能，本研究构建并全面表征了Gpr101基因敲除小鼠品系，分别在标准喂食条件与慢性高脂饮食（high-fat diet, HFD）暴露16周的场景下开展实验。研究发现，GPR101缺失会加剧饮食诱导肥胖（diet-induced obesity, DIO）、高胰岛素血症的发生风险，并破坏葡萄糖稳态。下丘脑转录组分析显示，高脂饮食条件下POMC的激活水平下调，提示饥饿抑制功能受损。 此外，在标准饮食条件下，小鼠呈现出三联体激蛋白（tristetrapolin, TTP）通路基因激活下调的分子特征，提示炎症消退功能受损；而在高脂饮食条件下，则出现小胶质细胞吞噬异常与脂质代谢紊乱的分子特征。形态计量分析显示，下丘脑弓状核的小胶质细胞形态发生改变，与转录组学分析结果相符。 本文讨论了GPR101作为特异性促炎症消退介质（specialized pro-resolving mediator, SPM）受体的功能特性，如何介导异常小胶质细胞功能，并进而增加饮食诱导肥胖风险。综上，本研究结果表明，GPR101是治疗饮食诱导肥胖的潜在靶点，其作用机制包括影响下丘脑炎症消退过程等多个方面。 本研究分析了经高脂饮食或对照饮食处理的Gpr101基因敲除小鼠与对照小鼠的下丘脑组织。