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Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction

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  • Changtao Jiang

    (Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health
    School of Basic Medical Sciences, Peking University, and the Key Laboratory of Molecular Cardiovascular Science, Ministry of Education)

  • Cen Xie

    (Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health)

  • Ying Lv

    (School of Basic Medical Sciences, Peking University, and the Key Laboratory of Molecular Cardiovascular Science, Ministry of Education)

  • Jing Li

    (Peking University People's Hospital)

  • Kristopher W. Krausz

    (Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health)

  • Jingmin Shi

    (Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health)

  • Chad N. Brocker

    (Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health)

  • Dhimant Desai

    (College of Medicine, The Pennsylvania State University)

  • Shantu G. Amin

    (College of Medicine, The Pennsylvania State University)

  • William H. Bisson

    (Oregon State University)

  • Yulan Liu

    (Peking University People's Hospital)

  • Oksana Gavrilova

    (Mouse Metabolism Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health)

  • Andrew D. Patterson

    (The Pennsylvania State University)

  • Frank J. Gonzalez

    (Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health)

Abstract

The farnesoid X receptor (FXR) regulates bile acid, lipid and glucose metabolism. Here we show that treatment of mice with glycine-β-muricholic acid (Gly-MCA) inhibits FXR signalling exclusively in intestine, and improves metabolic parameters in mouse models of obesity. Gly-MCA is a selective high-affinity FXR inhibitor that can be administered orally and prevents, or reverses, high-fat diet-induced and genetic obesity, insulin resistance and hepatic steatosis in mice. The high-affinity FXR agonist GW4064 blocks Gly-MCA action in the gut, and intestine-specific Fxr-null mice are unresponsive to the beneficial effects of Gly-MCA. Mechanistically, the metabolic improvements with Gly-MCA depend on reduced biosynthesis of intestinal-derived ceramides, which directly compromise beige fat thermogenic function. Consequently, ceramide treatment reverses the action of Gly-MCA in high-fat diet-induced obese mice. We further show that FXR signalling in ileum biopsies of humans positively correlates with body mass index. These data suggest that Gly-MCA may be a candidate for the treatment of metabolic disorders.

Suggested Citation

  • Changtao Jiang & Cen Xie & Ying Lv & Jing Li & Kristopher W. Krausz & Jingmin Shi & Chad N. Brocker & Dhimant Desai & Shantu G. Amin & William H. Bisson & Yulan Liu & Oksana Gavrilova & Andrew D. Patt, 2015. "Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction," Nature Communications, Nature, vol. 6(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms10166
    DOI: 10.1038/ncomms10166
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    Cited by:

    1. Yuanyuan Lei & Li Tang & Qiao Chen & Lingyi Wu & Wei He & Dianji Tu & Sumin Wang & Yuyang Chen & Shuang Liu & Zhuo Xie & Hong Wei & Shiming Yang & Bo Tang, 2022. "Disulfiram ameliorates nonalcoholic steatohepatitis by modulating the gut microbiota and bile acid metabolism," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Qi Zhao & Man-Yun Dai & Ruo-Yue Huang & Jing-Yi Duan & Ting Zhang & Wei-Min Bao & Jing-Yi Zhang & Shao-Qiang Gui & Shu-Min Xia & Cong-Ting Dai & Ying-Mei Tang & Frank J. Gonzalez & Fei Li, 2023. "Parabacteroides distasonis ameliorates hepatic fibrosis potentially via modulating intestinal bile acid metabolism and hepatocyte pyroptosis in male mice," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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