By using TBC, an intestinal-selective PXR activator, we first provide evidence that selective activation of PXR in the intestine ameliorated HFD-induced obesity and insulin resistance, suggesting a protective role of intestinal PXR in metabolic disorders, which is depart from the deleterious effect of hepatic PXR. The gene discussed is NR1I2; the disease is obesity due to melanocortin 4 receptor deficiency.