Farnesoid X receptor deficiency improves glucose homeostasis in mouse models of obesity

Janne Prawitt, Mouaadh Abdelkarim, Johanna H.M. Stroeve, Iuliana Popescu, Helene Duez, Vidya Velagapudi, Julie Dumont, Emmanuel Bouchaert, Theo H. van Dijk, Anthony Lucas, Emilie Dorchies, Mehdi Daoudi, Sophia Lestavel, Frank J. Gonzalez, Matej Orešič, Bertrand Cariou, Folkert Kuipers, Sandrine Caron, Bert Staels (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

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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.
Original languageEnglish
Pages (from-to)1861-1871
JournalDiabetes
Volume60
Issue number7
DOIs
Publication statusPublished - 2011
MoE publication typeA1 Journal article-refereed

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Bile Acids and Salts
Homeostasis
Obesity
Insulin Resistance
Glucose
Body Weight
Lipid Metabolism
Adipose Tissue
Diet
Liver
Genetic Models
Fatty Liver
Dyslipidemias
Energy Metabolism
Weight Gain
Maintenance
Genes

Cite this

Prawitt, J., Abdelkarim, M., Stroeve, J. H. M., Popescu, I., Duez, H., Velagapudi, V., ... Staels, B. (2011). Farnesoid X receptor deficiency improves glucose homeostasis in mouse models of obesity. Diabetes, 60(7), 1861-1871. https://doi.org/10.2337/db11-0030
Prawitt, Janne ; Abdelkarim, Mouaadh ; Stroeve, Johanna H.M. ; Popescu, Iuliana ; Duez, Helene ; Velagapudi, Vidya ; Dumont, Julie ; Bouchaert, Emmanuel ; van Dijk, Theo H. ; Lucas, Anthony ; Dorchies, Emilie ; Daoudi, Mehdi ; Lestavel, Sophia ; Gonzalez, Frank J. ; Orešič, Matej ; Cariou, Bertrand ; Kuipers, Folkert ; Caron, Sandrine ; Staels, Bert. / Farnesoid X receptor deficiency improves glucose homeostasis in mouse models of obesity. In: Diabetes. 2011 ; Vol. 60, No. 7. pp. 1861-1871.
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title = "Farnesoid X receptor deficiency improves glucose homeostasis in mouse models of obesity",
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.",
author = "Janne Prawitt and Mouaadh Abdelkarim and Stroeve, {Johanna H.M.} and Iuliana Popescu and Helene Duez and Vidya Velagapudi and Julie Dumont and Emmanuel Bouchaert and {van Dijk}, {Theo H.} and Anthony Lucas and Emilie Dorchies and Mehdi Daoudi and Sophia Lestavel and Gonzalez, {Frank J.} and Matej Orešič and Bertrand Cariou and Folkert Kuipers and Sandrine Caron and Bert Staels",
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Prawitt, J, Abdelkarim, M, Stroeve, JHM, Popescu, I, Duez, H, Velagapudi, V, Dumont, J, Bouchaert, E, van Dijk, TH, Lucas, A, Dorchies, E, Daoudi, M, Lestavel, S, Gonzalez, FJ, Orešič, M, Cariou, B, Kuipers, F, Caron, S & Staels, B 2011, 'Farnesoid X receptor deficiency improves glucose homeostasis in mouse models of obesity', Diabetes, vol. 60, no. 7, pp. 1861-1871. https://doi.org/10.2337/db11-0030

Farnesoid X receptor deficiency improves glucose homeostasis in mouse models of obesity. / Prawitt, Janne; Abdelkarim, Mouaadh; Stroeve, Johanna H.M.; Popescu, Iuliana; Duez, Helene; Velagapudi, Vidya; Dumont, Julie; Bouchaert, Emmanuel; van Dijk, Theo H.; Lucas, Anthony; Dorchies, Emilie; Daoudi, Mehdi; Lestavel, Sophia; Gonzalez, Frank J.; Orešič, Matej; Cariou, Bertrand; Kuipers, Folkert; Caron, Sandrine; Staels, Bert (Corresponding Author).

In: Diabetes, Vol. 60, No. 7, 2011, p. 1861-1871.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Farnesoid X receptor deficiency improves glucose homeostasis in mouse models of obesity

AU - Prawitt, Janne

AU - Abdelkarim, Mouaadh

AU - Stroeve, Johanna H.M.

AU - Popescu, Iuliana

AU - Duez, Helene

AU - Velagapudi, Vidya

AU - Dumont, Julie

AU - Bouchaert, Emmanuel

AU - van Dijk, Theo H.

AU - Lucas, Anthony

AU - Dorchies, Emilie

AU - Daoudi, Mehdi

AU - Lestavel, Sophia

AU - Gonzalez, Frank J.

AU - Orešič, Matej

AU - Cariou, Bertrand

AU - Kuipers, Folkert

AU - Caron, Sandrine

AU - Staels, Bert

PY - 2011

Y1 - 2011

N2 - 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.

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.

U2 - 10.2337/db11-0030

DO - 10.2337/db11-0030

M3 - Article

VL - 60

SP - 1861

EP - 1871

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 7

ER -

Prawitt J, Abdelkarim M, Stroeve JHM, Popescu I, Duez H, Velagapudi V et al. Farnesoid X receptor deficiency improves glucose homeostasis in mouse models of obesity. Diabetes. 2011;60(7):1861-1871. https://doi.org/10.2337/db11-0030