The distributed expression of bile acid (BA) sensor Farnesoid X receptor (FXR) has led to new therapies targeting cholesterol metabolism, triglyceride production, 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 enteral FGF15 leading to alterations in BA composition but does so without activating hepatic FXR target genes. Unlike systemic drugs, we find Fexaramine protects mice against diet-induced weight gain, reduces body-wide inflammation, enhances thermogenesis, promotes browning of white adipose tissue and suppresses hepatic glucose production. These pronounced metabolic improvements suggest tissue-restricted FXR activation as a new approach in the treatment of obesity and metabolic disease.