Prostaglandin Pge2 Receptor Ep4 Signaling Deficiency In Microglia Reduces Weight Gain With Transient Glucose Improvements In Diet-Induced Obesity

High fat diet (HFD) triggers a microglial inflammatory response in the mediobasal hypothalamus that is associated with weight gain and glucose dysregulation. Microglia depletion or selective disruption of the NFkB signaling pathway in microglia during HFD prevents the inflammatory response, and reduces food intake and weight gain. Here, we investigated the role of microglial prostaglandin PGE2 receptor 4 (EP4) signaling on the inflammatory response to HFD and metabolic outcomes. Compared to their wildtype counterparts, microglia-specific EP4 knockout (MG EP4-KO) mice on HFD showed reduced weight gain and improved glucose tolerance at 5 weeks. However, the two groups did not differ in glucose tolerance at 12 weeks, despite the MG EP4-KO mice maintaining lower body weight. This decoupling of body weight and glucose impairment indicates a progressive deterioration of glucose homeostasis associated with EP4 deficiency in microglia. Overall, these findings unravel a complex and dynamic interplay between EP4 signaling in microglia, weight gain and glucose imbalance in HFD. Disclosure A. Niraula: None. R. Fasnacht: None. K.M. Ness: None. J. Frey: None. M.D. Dorfman: None. J. Thaler: None. Funding National Institutes of Health (R01DK119754)