Sexual Dimorphism in the Immunometabolic Role of Gpr183 in Mice.

Abstract

Excessive eating and intake of a Western diet negatively affect the intestinal immune system, resulting in compromised glucose homeostasis and lower gut bacterial diversity. The G protein-coupled receptor GPR183 regulates immune cell migration and intestinal immune response and has been associated with tuberculosis, type 1 diabetes, and inflammatory bowel diseases. We hypothesized that with these implications, GPR183 has an important immunometabolic role and investigated this using a global Gpr183 knockout mouse model. Wild-type (WT) and Gpr183-deficient (Gpr183-/-) mice were fed a high-fat, high-sucrose diet (HFSD) for 15 weeks. We investigated changes in weight, body composition, fecal immunoglobulin A (IgA) levels, fecal microbiome, and glucose tolerance before and after the diet. Macrophage infiltration into visceral fat was determined by flow cytometry, and hepatic gene expression was measured. A sexual dimorphism was discovered, whereby female Gpr183-/- mice showed adverse metabolic outcomes compared to WT counterparts with inferior glucose tolerance, lower fecal IgA levels, and increased macrophage infiltration in visceral fat. In contrast, male Gpr183-/- mice had significantly lower fasting blood glucose after diet than male WT mice. Liver gene expression showed reduced inflammation and macrophage markers in Gpr183-/- livers, regardless of sex, while the pancreatic islet area did not differ between the groups. No conclusive differences were found after microbiome sequencing. Gpr183 maintains metabolic homeostasis in female but not in male mice independent of diet. If confirmed in humans, future therapy targeting GPR183 should consider this sexual dimorphism.