Intestinally-biased FXR agonism browns white adipose tissue preventing obesity and insulin resistance. Mus musculus breed:C57Bl/6

The distributed expression of bile acid (BA) sensor Farnesoid X receptor (FXR) has led to new therapies targeting cholesterol metabolism, triglyceride production, hepatic steatosis and biliary cholestasis. In contrast to the effects of system-wide drugs, we posited that selective activation of intestinal FXR might mimic the restricted bile acid response linked to feeding. Like systemic drugs, the gut-specific FXR agonist Fexaramine robustly induces enteric FGF15 leading to alterations in BA composition but does so without activating FXR target genes in the liver. Unlike systemic drugs, we find Fexaramine reduces diet-induced weight gain, body-wide inflammation and hepatic glucose production, while enhancing thermogenesis and browning of white adipose tissue. These pronounced metabolic improvements suggest tissue-restricted FXR activation as a new approach in the treatment of obesity and metabolic syndrome.