RT Journal Article SR Electronic T1 Farnesoid X Receptor Deficiency Improves Glucose Homeostasis in Mouse Models of Obesity JF Diabetes JO Diabetes FD American Diabetes Association SP 1861 OP 1871 DO 10.2337/db11-0030 VO 60 IS 7 A1 Prawitt, Janne A1 Abdelkarim, Mouaadh A1 Stroeve, Johanna H.M. A1 Popescu, Iuliana A1 Duez, Helene A1 Velagapudi, Vidya R. A1 Dumont, Julie A1 Bouchaert, Emmanuel A1 van Dijk, Theo H. A1 Lucas, Anthony A1 Dorchies, Emilie A1 Daoudi, Mehdi A1 Lestavel, Sophie A1 Gonzalez, Frank J. A1 Oresic, Matej A1 Cariou, Bertrand A1 Kuipers, Folkert A1 Caron, Sandrine A1 Staels, Bart YR 2011 UL http://diabetes.diabetesjournals.org/content/60/7/1861.abstract AB OBJECTIVE Bile acids (BA) participate in the maintenance of metabolic homeostasis acting through different signaling pathways. The nuclear BA receptor farnesoid X receptor (FXR) regulates pathways in BA, lipid, glucose, and energy metabolism, which become dysregulated in obesity. However, the role of FXR in obesity and associated complications, such as dyslipidemia and insulin resistance, has not been directly assessed.RESEARCH DESIGN AND METHODS Here, we evaluate the consequences of FXR deficiency on body weight development, lipid metabolism, and insulin resistance in murine models of genetic and diet-induced obesity.RESULTS FXR deficiency attenuated body weight gain and reduced adipose tissue mass in both models. Surprisingly, glucose homeostasis improved as a result of an enhanced glucose clearance and adipose tissue insulin sensitivity. In contrast, hepatic insulin sensitivity did not change, and liver steatosis aggravated as a result of the repression of β-oxidation genes. In agreement, liver-specific FXR deficiency did not protect from diet-induced obesity and insulin resistance, indicating a role for nonhepatic FXR in the control of glucose homeostasis in obesity. Decreasing elevated plasma BA concentrations in obese FXR-deficient mice by administration of the BA sequestrant colesevelam improved glucose homeostasis in a FXR-dependent manner, indicating that the observed improvements by FXR deficiency are not a result of indirect effects of altered BA metabolism.CONCLUSIONS Overall, FXR deficiency in obesity beneficially affects body weight development and glucose homeostasis.