OR23-1 FXR Regulates the Expansion and Metabolic Function of Adipose Tissue Upon Caloric Excess

Abstract Obesity is a major risk factor for developing metabolic diseases. Adipose tissue stores excess calories during obesity. Nuclear receptor Farnesoid X receptor (FXR) is expressed in various tissues and transcriptionally regulates lipid and glucose metabolism. However, the role of FXR in regulating adipose expansion is unknown. We showed that Fxr transcript is expressed in mature adipocytes isolated from both white (WAT) and brown (BAT) adipose tissues. In adipocyte-specific Fxr knockout (Ad-FxrKO) mice, we found enlarged adipocytes and decreased expression of lipolytic genes upon 60% high fat diet (HFD) or high fat/high sucrose western diet challenge. Transcriptomic analysis of WAT from Ad-FxrKO and control mice upon chow or HFD revealed that many genes involved in glucose and lipid homeostasis are misregulated in Ad-FxrKO mice with distinct patterns under normal and obese conditions. Since WAT stores fat and BAT generates heat, we examined both these depots in Ad-FxrKO mice and found reductions in the expression of mitochondrial genes and energy expenditure. Intriguingly, we found ectopic fat accumulation in the liver and systemic glucose intolerance in Ad-FxrKO compared to the control mice during obesity. Overall, these findings implicate that FXR may regulate lipid metabolism and mitochondrial functions in the adipose tissue, which consequently impacts whole-body energy homeostasis. Presentation: Monday, June 13, 2022 11:15 a.m. - 11:30 a.m.