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Farnesoid X receptor deficiency improves glucose homeostasis in mouse models of obesity
University of Lille Nord de France, Lille, France; Institut national de la santé et de la recherche médicale (INSERM), unité mixte de recherche (UMR)1011, Lille, France; UDSL, Lille, France; Institut Pasteur de Lille, Lille, France.
University of Lille Nord de France, Lille, France; INSERM UMR1011, Lille, France; UDSL, Lille, France; Institut Pasteur de Lille, Lille, France.
Center for Liver, Digestive and Metabolic Diseases, Laboratory of Pediatrics, University Medical Center Groningen, Groningen, Netherlands.
University of Lille Nord de France, Lille, France; INSERM UMR1011, Lille, France; UDSL, Lille, France; Institut Pasteur de Lille, Lille, France.
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2011 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 60, no 7, p. 1861-1871Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
American Diabetes Association , 2011. Vol. 60, no 7, p. 1861-1871
National Category
Endocrinology and Diabetes
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URN: urn:nbn:se:oru:diva-63648DOI: 10.2337/db11-0030ISI: 000292425800007PubMedID: 21593203Scopus ID: 2-s2.0-79960838523OAI: oai:DiVA.org:oru-63648DiVA, id: diva2:1169212
Note

Funding agencies:

European Union 018734 

Agence Nationale de la Recherche A05056GS 

COST Action BM0602 

Available from: 2017-12-22 Created: 2017-12-22 Last updated: 2018-09-12Bibliographically approved

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Oresic, Matej

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