Central regulation of feeding and body weight by ciliary GPR75

Variants of the G protein-coupled receptor 75 (GPR75) are associated with lower BMI in large-scale human exome sequencing studies. However, how GPR75 regulates body weight remains poorly understood. Using random germline mutagenesis in mice, we identified a missense allele (Thinner) of Gpr75 that resulted in a lean phenotype and verified the decreased body weight and fat weight in Gpr75 knockout (Gpr75–/–) mice. Gpr75–/– mice displayed reduced food intake under a high-fat diet (HFD), and pair-feeding normalized their body weight. The endogenous GPR75 protein was exclusively expressed in the brains of 3xFlag tagged Gpr75 knock-in (3xFlag-Gpr75) mice, with consistent expression across different brain regions. GPR75 interacted with Gaq to activate various signaling pathways after HFD feeding. Additionally, GPR75 was localized in the primary cilia of hypothalamic cells, whereas the Thinner mutation (L144P) and human GPR75 variants with lower BMI failed to localize in the cilia. Loss of GPR75 selectively inhibited weight gain in HFD-fed mice but failed to suppress the development of obesity in Leptin ob mice and Adenylate cyclase 3 (Adcy3) mutant mice on a chow diet. Our data reveal that GPR75 is a ciliary protein expressed in the brain and plays an important role in regulating food intake. Overall design: To gain insights into the role of GPR75 in the central regulation of feeding, we performed a transcriptomics analysis (RNA-seq) of the hypothalamus from wild-type (WT) and Gpr75-/- (Gpr75 KO) mice under a chow diet or 2 weeks of high-fat diet (HFD) since 6 weeks of age. There are four groups in total (chow_wt, chow_75ko, hfd_wt, hfd_75ko) with three age-matched male mice were used in each group, resulting a total of 12 samples.