2. Academic Validation
  3. Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction

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

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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