Lowering bile acid pool size with a synthetic farnesoid X receptor (FXR) agonist induces obesity and diabetes through reduced energy expenditure

Mitsuhiro Watanabe, Yasushi Horai, Sander M. Houten, Kohkichi Morimoto, Taichi Sugizaki, Eri Arita, Chikage Mataki, Hiroyuki Sato, Yusuke Tanigawara, Kristina Schoonjans, Hiroshi Itoh, Johan Auwerx

Research output: Contribution to journalArticle

149 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)26913-26920
Number of pages8
JournalJournal of Biological Chemistry
Volume286
Issue number30
DOIs
Publication statusPublished - 2011 Jul 29

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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