title: Lowering bile acid pool size with a synthetic farnesoid X receptor (FXR) agonist induces obesity and diabetes through reduced energy expenditure.
abstract: We evaluated the metabolic impact of farnesoid X receptor (FXR) activation by administering a synthetic FXR agonist (GW4064) to mice in which obesity was induced by a high fat diet. Administration of GW4064 accentuated body weight gain and glucose intolerance induced by the high fat diet and led to a pronounced worsening of the changes in liver and adipose tissue. Mechanistically, treatment with GW4064 decreased bile acid (BA) biosynthesis, BA pool size, and energy expenditure, whereas reconstitution of the BA pool in these GW4064-treated animals by BA administration dose-dependently reverted the metabolic abnormalities. Our data therefore suggest that activation of FXR with synthetic agonists is not useful for long term management of the metabolic syndrome, as it reduces the BA pool size and subsequently decreases energy expenditure, translating as weight gain and insulin resistance. In contrast, expansion of the BA pool size, which can be achieved by BA administration, could be an interesting strategy to manage the metabolic syndrome.
authors.affiliation: Department of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan. wmitsu@sc.itc.keio.ac.jp
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Watanabe
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Horai
authors.forename: Sander M
authors.initials: SM
authors.lastname: Houten
authors.forename: Kohkichi
authors.initials: K
authors.lastname: Morimoto
authors.forename: Taichi
authors.initials: T
authors.lastname: Sugizaki
authors.forename: Eri
authors.initials: E
authors.lastname: Arita
authors.forename: Chikage
authors.initials: C
authors.lastname: Mataki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sato
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Tanigawara
authors.forename: Kristina
authors.initials: K
authors.lastname: Schoonjans
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Itoh
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D001835:Body Weight / Q000187:drug effects; D003920:Diabetes Mellitus / Q000139:chemically induced* / Q000378:metabolism; D004041:Dietary Fats / Q000009:adverse effects* / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects*; D007555:Isoxazoles / Q000009:adverse effects* / Q000494:pharmacology; D024821:Metabolic Syndrome / Q000188:drug therapy; D051379:Mice; D009765:Obesity / Q000139:chemically induced* / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D004041:Dietary Fats; D007555:Isoxazoles; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C412815:GW 4064