GPR75 Deficiency Protects Against High‐Fat Diet Induced Obesity

Abstract

The CDC estimates the prevalence of obesity in the United States to be over 42.5% in 2021. With obesity related conditions including hypertension, heart disease, and type 2 diabetes, therapeutic approaches to treat obesity are necessary to prevent premature death. Recent studies have identified the orphan G‐protein coupled receptor, GPR75, as a possible target. For example, Akbari et. al., (Science, 2021) found that truncated loss of function variants of GPR75 were associated with 5.3 kg lower bodyweight and 54% lower odds of obesity in heterozygous individuals. Based on these findings, we hypothesized that global deletion of Gpr75 protects against diet‐induced obesity (DIO) and insulin resistance. Wild‐type and Gpr75null mice were subjected to 14 weeks of regular chow or high‐fat diet (HFD) feeding. Body composition, intraperitoneal glucose and insulin tolerance tests, and oxygen consumption were measured initially and at week 14. There were no significant differences in body composition, glucose homeostasis, and oxygen consumption between wild‐type (WT), Gpr75‐/‐ (KO) and Gpr75+/‐ (HET) mice initially. However, WT mice obtained a diabetogenic phenotype after HFD‐feeding while KO and HET counterparts were robustly protected as indicated by reduced body weight, (45.32 ± 1.387 grams, 28.29 ± 1.47 grams, and 36.60 ± 1.8 grams respectively) and increased sensitivity to insulin (blood glucose 30 min after insulin injection as percent change, ‐28.5 ± 4.41%, ‐50.68 ± 4.15% and ‐39.07 ± 1.79% respectively, p<0.0001). Weekly energy intake calculated from food consumption showed no significant differences between all three groups. However, oxygen consumption measured over 60 minutes indicated an increase in energy expenditure in KO compared to WT mice (73.76 ml/min/kg vs. 44.61 ml/min/kg respectively, p<0.0001). This correlated with a 2.63‐fold increase in brown adipose tissue (BAT) UCP1 mRNA expression in KO compared to WT mice. While the abundance of BAT is low in humans compared to mice, our findings suggest that improved glucose homeostasis as a result of GPR75 deficiency is linked to increased BAT thermogenesis. This may provide a potential novel route for the control of metabolism to combat obesity‐driven metabolic disorders.