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

http://ir.library.oregonstate.edu/concern/articles/f1881n69g

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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-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.
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  • Jiang, C., Xie, C., Lv, Y., Li, J., Krausz, K. W., Shi, J., ... & Gonzalez, F. J. (2015). Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction. Nature Communications, 6, 10166. doi:10.1038/ncomms10166
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  • description.provenance : Made available in DSpace on 2016-01-22T17:17:04Z (GMT). No. of bitstreams: 3 license_rdf: 1370 bytes, checksum: cd1af5ab51bcc7a5280cf305303530e9 (MD5) BissonWilliamEnvironMoleToxIntestineSelectiveFarnesoid.pdf: 2888981 bytes, checksum: 9915b74551589e3c93142d1e77d87974 (MD5) BissonWilliamEnvironMoleToxIntestineSelectiveFarnesoid(Supplement).pdf: 16936805 bytes, checksum: 7877fdd521ba22c062faf91763311ee6 (MD5) Previous issue date: 2015-12
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