Given that long-term activation of FXR is reported to induce obesity [17] and that activation of TGR5 alone has a limited effect on lipid metabolism, our data suggest that targeting both FXR and TGR5 is a more attractive strategy for treatment of common metabolic disorders, such as obesity, NAFLD, and atherosclerosis. The gene discussed is GPBAR1; the disease is obesity due to melanocortin 4 receptor deficiency.