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, Frank J. Gonzalez

Research output: Contribution to journalArticlepeer-review

235 Scopus citations

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.

Original languageEnglish (US)
Article number10166
JournalNature communications
Volume6
DOIs
StatePublished - Dec 15 2015

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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