title: Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance.
abstract: The systemic expression of the bile acid (BA) sensor farnesoid X receptor (FXR) has led to promising new therapies targeting cholesterol metabolism, triglyceride production, hepatic steatosis and biliary cholestasis. In contrast to systemic therapy, bile acid release during a meal selectively activates intestinal FXR. By mimicking this tissue-selective effect, the gut-restricted FXR agonist fexaramine (Fex) robustly induces enteric fibroblast growth factor 15 (FGF15), leading to alterations in BA composition, but does so without activating FXR target genes in the liver. However, unlike systemic agonism, we find that Fex reduces diet-induced weight gain, body-wide inflammation and hepatic glucose production, while enhancing thermogenesis and browning of white adipose tissue (WAT). These pronounced metabolic improvements suggest tissue-restricted FXR activation as a new approach in the treatment of obesity and metabolic syndrome.
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA.
authors.forename: Sungsoon
authors.initials: S
authors.lastname: Fang
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA.
authors.forename: Jae Myoung
authors.initials: JM
authors.lastname: Suh
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Reilly
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Yu
authors.affiliation: Department of Medicine, University of California San Diego, San Diego, California, USA.
authors.forename: Olivia
authors.initials: O
authors.lastname: Osborn
authors.affiliation: Department of Medicine, University of California San Diego, San Diego, California, USA.
authors.forename: Denise
authors.initials: D
authors.lastname: Lackey
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA.
authors.forename: Eiji
authors.initials: E
authors.lastname: Yoshihara
authors.affiliation: Metabolic Signaling, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Federale de Lausanne, Switzerland.
authors.forename: Alessia
authors.initials: A
authors.lastname: Perino
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Jacinto
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA.
authors.forename: Yelizaveta
authors.initials: Y
authors.lastname: Lukasheva
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA.
authors.forename: Annette R
authors.initials: AR
authors.lastname: Atkins
authors.affiliation: ChemDiv, Inc., San Diego, California, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Khvat
authors.affiliation: Department of Medicine, University of California San Diego, San Diego, California, USA.
authors.forename: Bernd
authors.initials: B
authors.lastname: Schnabl
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA.
authors.forename: Ruth T
authors.identifier: 0000000295279627
authors.initials: RT
authors.lastname: Yu
authors.affiliation: Department of Medicine, University of California San Diego, San Diego, California, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Brenner
authors.affiliation: Storr Liver Unit, Westmead Millennium Institute, Sydney Medical School, University of Sydney, Australia.
authors.forename: Sally
authors.initials: S
authors.lastname: Coulter
authors.affiliation: Storr Liver Unit, Westmead Millennium Institute, Sydney Medical School, University of Sydney, Australia.
authors.forename: Christopher
authors.initials: C
authors.lastname: Liddle
authors.affiliation: Metabolic Signaling, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Federale de Lausanne, Switzerland.
authors.forename: Kristina
authors.initials: K
authors.lastname: Schoonjans
authors.affiliation: Department of Medicine, University of California San Diego, San Diego, California, USA.
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Olefsky
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Saltiel
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Downes
authors.affiliation: 1] Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA. [2] Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, California, USA.
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
mesh_terms: D002001:Adipose Tissue, Brown / Q000187:drug effects* / Q000378:metabolism; D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001555:Benzene Derivatives / Q000494:pharmacology*; D001647:Bile Acids and Salts / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000187:drug effects* / Q000378:metabolism; D015309:Glucose Clamp Technique; D007333:Insulin Resistance; D007413:Intestinal Mucosa / Q000378:metabolism*; D051379:Mice; D009765:Obesity / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001555:Benzene Derivatives; D001647:Bile Acids and Salts; D005346:Fibroblast Growth Factors; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C474615:fexaramine; C108526:fibroblast growth factor 15, mouse