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

  • Nat Commun. 2015 Dec 15;6:10166. doi: 10.1038/ncomms10166.
Changtao Jiang  1  2 ,  Cen Xie  1 ,  Ying Lv  2 ,  Jing Li  3 ,  Kristopher W Krausz  1 ,  Jingmin Shi  1 ,  Chad N Brocker  1 ,  Dhimant Desai  4 ,  Shantu G Amin  4 ,  William H Bisson  5 ,  Yulan Liu  3 ,  Oksana Gavrilova  6 ,  Andrew D Patterson  7 ,  Frank J Gonzalez  1
Affiliations
  • 1. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
  • 2. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and the Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, China.
  • 3. Department of Gastroenterology, Peking University People's Hospital, Beijing 100044, China.
  • 4. Department of Pharmacology, College of Medicine, The Pennsylvania State University, Hershey, Pennsylvania 17033, USA.
  • 5. Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon 97331, USA.
  • 6. Mouse Metabolism Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
  • 7. Department of Veterinary and Biomedical Sciences and the Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
PMID: 26670557 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.

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