FASEB J. 2026 Feb 28. 40(4):
e71579
Sakib Hossain,
Elizabeth Villegas,
Catherine Liapes,
Nahid Sultana,
Dorina Krasniqi,
Danielle Diegisser,
Ana Castro,
Comfort Williams,
Artiom Gruzdev,
Darryl C Zeldin,
Victor Garcia,
Michal Laniado Schwartzman.
Loss of function G-protein coupled receptor 75 (GPR75) variants in humans are associated with leanness, and Gpr75 null mice are protected from diet-induced obesity (DIO). However, the mechanisms underlying this protection are largely unknown. Here, we investigated the contribution of adipocyte-derived Gpr75 to DIO. Adipocyte-specific Gpr75 knockout (adipo-Gpr75-/-) male and female mice and their wild-type (WT) littermates were placed on a high-fat diet (HFD) for 14 weeks. Metabolic parameters including body weight, energy intake and expenditure, activity, and glucose metabolism were monitored before and after diet feeding. While WT mice obtained a diabetogenic phenotype on HFD, the adipo-Gpr75-/- counterparts were protected. This protection showed sexual dimorphism. Female adipo-Gpr75-/- mice displayed a 50% (p < 0.001) decrease in weight gain and adiposity compared to WT, whereas male adipo-Gpr75-/- gained weight like WT mice. Interestingly, both male and female adipo-Gpr75-/- mice exhibited improved glucose handling compared to WT, which was correlated to decreased adiposity, abrogated adipose tissue inflammation, and increased insulin sensitivity in skeletal muscle. Importantly, no differences in food intake were observed; however, adipo-Gpr75-/- mice exhibited increased activity and energy expenditure, regardless of sex. Taken together, these findings demonstrate that deletion of GPR75 specifically in adipocytes is sufficient to confer protection against DIO and suggest that adipocyte-derived GPR75 contributes importantly to the pathogenesis of DIO potentially by mechanisms that may include promotion of inflammation, impairment of insulin signaling, and disruption of metabolic homeostasis.
Keywords: GLP‐1; GPR75; diabetes; insulin sensitivity; obesity; sex differences