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

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https://ir.library.oregonstate.edu/concern/articles/zc77sr91c

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  • The farnesoid X receptor (FXR) regulates bile acid, lipid and glucose metabolism. Here we show that treatment of mice with glycine-b-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.
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  • Jiang, C., Xie, C., Lv, Y., Li, J., Krausz, K. W., & Gonzalez, F. J. (2015). ntestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction. Nature Communications, 6, 10166. doi:10.1038/ncomms10166
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  • 6
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  • This work was supported by the Intramural Research Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, and by the National Institutes of Environmental Health Sciences (ES022186 (A.D.P.)). This project was funded in part by grants from the National Natural Science Foundation of China (31401011 to C.J. and 81200626 to J.L.) and in part by a grant with the Pennsylvania Department of Health using Tobacco CURE Funds (to A.D.P.).
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file details BissonWilliamEnvironMoleToxIntestineSelectiveFarnesoid(Supplementary Figures 1-17, Supplementary Tables 1-3 and Supplementary Reference).pdf 07/26/2017 Public