Bile Acid Excess Impairs Thermogenic Function in Brown Adipose Tissue

Obesity is a major epidemic and is associated with metabolic dysfunction leading to excess accumulation of fat. Bile acids (BAs) are body's natural detergents that facilitate fat digestion. Additionally, BAs act as signaling molecules regulating metabolism and can protect against obesity. Despite, several studies have demonstrated that elevated BAs promote energy expenditure, it remains unknown if BAs are present in brown adipose tissue (BAT) and can they directly affect BAT function. Here, we show that BAs, BA transporters and de novo synthetic enzymes are detected in BAT. Notably, the global farnesoid X receptor; small heterodimer partner double knockout (DKO) mice, a model for BA overload, exhibit higher BAs levels in BAT than the control mice. DKO mice exhibit lower body temperature, decreased mitochondrial DNA content, and altered activities of oxidative phosphorylation enzyme complexes. Consistent with this phenotype, we find that excess BAs impair BAT mitochondrial function and can cause thermogenic dysfunction. Importantly, when low physiological BA levels are used to treat brown adipocytes, we do not find mitochondrial defects. However, upon treatment with pathological BA concentrations, differentiated primary brown adipocytes in vitro show reduced mitochondrial membrane potential and concomitant reduction in thermogenic gene expression profile. We have shown that DKO mice are resistant to fat accumulation both on normal chow and when challenged with a high‐fat diet. This protection is significantly lost when the mice are housed at thermoneutral conditions indicating that by having leaky mitochondria and poor thermoregulation, DKO mice are protected against accumulating fat. Overall, we show for the first time the presence of BA metabolic machinery in the BAT and identify that elevated levels of BAs can cause thermogenic dysfunctions. Weinan Zhou and Philip VanDuyne contributed equally to this work. Support or Funding Information Startup funds from the University of Illinois at Urbana‐Champaign, and R01 DK113080 from NIDDK. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .