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

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. Patterson () and Frank J. Gonzalez ()
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Changtao Jiang: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health
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

Nature Communications, 2015, vol. 6, issue 1, 1-18

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms10166

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