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

Nat Commun. 2015 Dec 15;6:10166. doi: 10.1038/ncomms10166.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Animals
  • Ceramides / biosynthesis
  • Cholic Acids / pharmacology*
  • Diet, High-Fat
  • Fatty Liver / metabolism*
  • Female
  • Glycine / pharmacology*
  • Humans
  • Ileum / metabolism*
  • Insulin Resistance / genetics
  • Intestinal Mucosa / metabolism
  • Isoxazoles / pharmacology
  • Liver / drug effects*
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Mice
  • Middle Aged
  • Obesity / metabolism*
  • Receptors, Cytoplasmic and Nuclear / agonists
  • Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors*
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Young Adult

Substances

  • Ceramides
  • Cholic Acids
  • Isoxazoles
  • Receptors, Cytoplasmic and Nuclear
  • farnesoid X-activated receptor
  • muricholic acid
  • GW 4064
  • Glycine