SUN-675 - Loss of Brown Adipocyte FXR Differentially Alters Mitochondrial Function and Energy Metabolism in Normal and Obese Conditions

Adipose tissue stores and mobilizes energy and is extensively remodeled in obesity. While white adipose tissue (WAT) stores excess calories, brown adipose tissue (BAT) is rich in mitochondria and specialized for energy expenditure through generating heat. The discovery of functional BAT in adult humans and its beneficial effects on metabolic health have developed it as a potential therapeutic target for obesity and metabolic disorders. Farnesoid X receptor (FXR) is a nuclear receptor that transcriptionally regulates bile acid, glucose, and lipid homeostasis in various tissues. Recently, we have revealed a role of FXR in regulating endocannabinoid metabolites in the WAT. However, the exact function of FXR in the BAT still remains elusive. Therefore, we recently generated the first brown adipocyte-specific Fxr knockout (BAT-FxrKO) mice using Ucp1-Cre. To recapitulate diet-induced obesity, we challenged BAT-FxrKO and control mice with either normal chow or 60% high fat diet (HFD) for 8 weeks. We were intrigued to find that BAT-FxrKO mice displayed loss of body weight and white fat mass, higher energy expenditure, and increased brown adipose mitochondrial respiration compared to control mice even under chow-fed basal conditions. These results suggest that loss of brown adipose FXR expression may be beneficial as it induces mitochondrial function and energy metabolism. However, when we challenged BAT-FxrKO mice with HFD, it showed an unexpected result with higher body weight and brown fat gain, lower energy expenditure, decreased BAT mitochondrial DNA copy number, and slightly reduced BAT mitochondrial respiration compared to controls. Overall, these findings reveal that brown adipocyte FXR may have distinct roles in regulating mitochondrial function and numbers along with overall energy metabolism under normal and obese states.

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