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

  1. Bart Staels1
  1. 1University of Lille Nord de France, INSERM UMR1011; UDSL; Institut Pasteur de Lille, Lille, France
  2. 2Center for Liver, Digestive and Metabolic Diseases, Laboratory of Pediatrics, University Medical Center Groningen, Groningen, the Netherlands
  3. 3VTT Technical Research Centre of Finland, Espoo, Finland
  4. 4Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
  5. 5INSERM U915; Faculty of Medicine, University of Nantes, Thorax Institute; Clinic of Endocrinology, University Hospital Center Nantes, Nantes, France
  1. Corresponding author: Bart Staels, bart.staels{at}pasteur-lille.fr.

Abstract

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.

Footnotes

  • Received January 11, 2011.
  • Accepted April 3, 2011.

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  1. Diabetes vol. 60 no. 7 1861-1871
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