244-LB: GPR75 Ablation Protects against Diet-Induced Obesity, Inflammation, and Insulin Resistance

Obesity related conditions including atherosclerosis and type 2 diabetes mellitus (T2DM) have a profound effect on cardiovascular health and morbidity. Recent reports by Akbari et. al. indicate that truncated loss of function variants of the orphan G-protein coupled receptor, GPR75, are associated with 5.3 kg lower bodyweight and 54% lower odds of obesity in heterozygous individuals (Science, 2021) . Based on these findings, we hypothesized that whole body deletion of Gpr75 protects against diet-induced obesity (DIO) and the resulting insulin resistance. Wild-type and Gpr75 null mice were subjected to 14 weeks of regular chow or high-fat diet (HFD) feeding. Body weight, intraperitoneal glucose and insulin tolerance tests, and pro-inflammatory cytokine gene expressions were measured initially and at week 14. There were no significant differences in body weight, glucose homeostasis, and tumor necrosis factor alpha (TNF-α) expression between wild-type (WT) and Gpr75^-/- (KO) mice at baseline. However, WT mice obtained a diabetogenic phenotype after HFD-feeding while the KO counterparts were protected as indicated by reduced body weight, (45.32 ± 1.387 grams vs. 28.29 ± 1.47 grams) and increased sensitivity to insulin (blood glucose 30 min after insulin injection as percent change, -28.5 ± 4.41% vs. -50.68 ± 4.15%, p<0.0001) . This correlated with a 1.98-fold decrease in brown adipose tissue (BAT) and 2.31-fold decrease in subcutaneous adipose tissue (SAT) TNF-α mRNA expression in KO compared to WT mice. Furthermore, there was a 3.19-fold reduction in circulating chemokine ligand 5 (CCL5) in KO compared to WT mice. This data may provide a potential novel target for the control of obesity-driven disorders such as inflammation and insulin resistance.