title: Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction.
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.
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.|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.
authors.forename: Changtao
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Cen
authors.initials: C
authors.lastname: Xie
authors.affiliation: 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.
authors.forename: Ying
authors.initials: Y
authors.lastname: Lv
authors.affiliation: Department of Gastroenterology, Peking University People's Hospital, Beijing 100044, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Kristopher W
authors.initials: KW
authors.lastname: Krausz
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Jingmin
authors.initials: J
authors.lastname: Shi
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Chad N
authors.initials: CN
authors.lastname: Brocker
authors.affiliation: Department of Pharmacology, College of Medicine, The Pennsylvania State University, Hershey, Pennsylvania 17033, USA.
authors.forename: Dhimant
authors.initials: D
authors.lastname: Desai
authors.affiliation: Department of Pharmacology, College of Medicine, The Pennsylvania State University, Hershey, Pennsylvania 17033, USA.
authors.forename: Shantu G
authors.initials: SG
authors.lastname: Amin
authors.affiliation: Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon 97331, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Bisson
authors.affiliation: Department of Gastroenterology, Peking University People's Hospital, Beijing 100044, China.
authors.forename: Yulan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Mouse Metabolism Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Oksana
authors.initials: O
authors.lastname: Gavrilova
authors.affiliation: Department of Veterinary and Biomedical Sciences and the Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Patterson
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Frank J
authors.identifier: http://orcid.org/0000-0002-7990-2140
authors.initials: FJ
authors.lastname: Gonzalez
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D002518:Ceramides / Q000096:biosynthesis; D002793:Cholic Acids / Q000494:pharmacology*; D059305:Diet, High-Fat; D005234:Fatty Liver / Q000378:metabolism*; D005260:Female; D005998:Glycine / Q000494:pharmacology*; D006801:Humans; D007082:Ileum / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D009765:Obesity / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D055815:Young Adult; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D002518:Ceramides; D002793:Cholic Acids; D005998:Glycine; D007555:Isoxazoles; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C004821:muricholic acid; C412815:GW 4064