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. Overall design: We analysed hypothalamic tissue of Gpr101 knock-out and control mice treated with high-fat or control diets