Farnesoid X Receptor Deficiency Improves Glucose Homeostasis in Mouse Models of Obesity

作者：Prawitt Janne; Abdelkarim Mouaadh; Stroeve Johanna H M; Popescu Iuliana; Duez Helene; Velagapudi Vidya R; Dumont Julie; Bouchaert Emmanuel; van Dijk Theo H; Lucas Anthony; Dorchies Emilie; Daoudi Mehdi; Lestavel Sophie; Gonzalez Frank J; Oresic Matej; Cariou Bertrand; Kuipers Folkert; Caron Sandrine; Staels Bart^*

来源：Diabetes, 2011, 60(7): 1861-1871.

DOI：10.2337/db11-0030

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 beta-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 colesevelarn 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.Diabetes 60:1861-1871, 2011

• 出版日期2011-7