FXR regulates metabolic function of fat depots during obesity

Abstract

Obesity is a major epidemic and is associated with excess calorie intake leading to adipose tissue expansion and metabolic dysfunction. Farnesoid X receptor (FXR) is a nuclear receptor that transcriptionally regulates lipid and glucose metabolism. Despite several studies revealing FXR expression in the adipose tissue, its exact role in this tissue remains elusive. We determined that both primary pre‐ and post‐differentiated adipocytes from inguinal white (WAT) and brown (BAT) adipose tissue express Fxr transcripts. Notably, adipose‐specific Fxr knockout (Ad‐FxrKO) mice recently generated in our laboratory exhibit glucose intolerance, increased fat accumulation and concomitant reduction in the expression of lipolytic genes in both WAT and BAT when challenged with a high‐fat diet. These data suggest that adipose‐specific FXR may play a crucial role in regulating fat accumulation and subsequent glucose homeostasis during diet‐induced obesity. Since BAT is specialized for non‐shivering thermogenesis by generating heat through uncoupled mitochondrial respiration, we investigated the role for FXR in brown adipocyte mitochondrial function. We found that when Fxr is deleted, genes involved in BAT mitochondrial β‐oxidation, biosynthesis and respiratory chain complex are down‐regulated. Conversely, FXR activation by its endogenous bile acid ligand, chenodeoxycholic acid increases mitochondrial membrane potential of primary differentiated brown adipocytes in vitro, suggesting a key role for FXR in controlling brown adipocyte mitochondrial function and a potential role in thermogenesis. Overall, we demonstrate that FXR can modulate fat break down and regulate mitochondrial functions in the adipose tissue.Support or Funding InformationSupported by R01 DK113080 from NIDDK, and UIUC Start Up Funds.