Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance

Nat Med. 2015 Feb;21(2):159-65. doi: 10.1038/nm.3760. Epub 2015 Jan 5.


The systemic expression of the bile acid (BA) sensor farnesoid X receptor (FXR) has led to promising new therapies targeting cholesterol metabolism, triglyceride production, hepatic steatosis and biliary cholestasis. In contrast to systemic therapy, bile acid release during a meal selectively activates intestinal FXR. By mimicking this tissue-selective effect, the gut-restricted FXR agonist fexaramine (Fex) robustly induces enteric fibroblast growth factor 15 (FGF15), leading to alterations in BA composition, but does so without activating FXR target genes in the liver. However, unlike systemic agonism, we find that Fex reduces diet-induced weight gain, body-wide inflammation and hepatic glucose production, while enhancing thermogenesis and browning of white adipose tissue (WAT). These pronounced metabolic improvements suggest tissue-restricted FXR activation as a new approach in the treatment of obesity and metabolic syndrome.

MeSH terms

  • Adipose Tissue, Brown / drug effects*
  • Adipose Tissue, Brown / metabolism
  • Adipose Tissue, White / drug effects
  • Adipose Tissue, White / metabolism
  • Animals
  • Benzene Derivatives / pharmacology*
  • Bile Acids and Salts / metabolism*
  • Fibroblast Growth Factors / drug effects*
  • Fibroblast Growth Factors / metabolism
  • Glucose Clamp Technique
  • Insulin Resistance*
  • Intestinal Mucosa / metabolism*
  • Mice
  • Obesity / metabolism*
  • Receptors, Cytoplasmic and Nuclear / agonists*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Weight Gain / drug effects*


  • Benzene Derivatives
  • Bile Acids and Salts
  • Receptors, Cytoplasmic and Nuclear
  • fexaramine
  • fibroblast growth factor 15, mouse
  • farnesoid X-activated receptor
  • Fibroblast Growth Factors

Associated data

  • SRA/SRP048631