FXR is a molecular target for the effects of vertical sleeve gastrectomy

Research output: Contribution to journalJournal articleResearchpeer-review

  • Karen K Ryan
  • Valentina Tremaroli
  • Clemmensen, Christoffer
  • Petia Kovatcheva-Datchary
  • Andriy Myronovych
  • Rebekah Karns
  • Hilary E Wilson-Pérez
  • Darleen A Sandoval
  • Rohit Kohli
  • Fredrik Bäckhed
  • Randy J Seeley

Bariatric surgical procedures, such as vertical sleeve gastrectomy (VSG), are at present the most effective therapy for the treatment of obesity, and are associated with considerable improvements in co-morbidities, including type-2 diabetes mellitus. The underlying molecular mechanisms contributing to these benefits remain largely undetermined, despite offering the potential to reveal new targets for therapeutic intervention. Substantial changes in circulating total bile acids are known to occur after VSG. Moreover, bile acids are known to regulate metabolism by binding to the nuclear receptor FXR (farsenoid-X receptor, also known as NR1H4). We therefore examined the results of VSG surgery applied to mice with diet-induced obesity and targeted genetic disruption of FXR. Here we demonstrate that the therapeutic value of VSG does not result from mechanical restriction imposed by a smaller stomach. Rather, VSG is associated with increased circulating bile acids, and associated changes to gut microbial communities. Moreover, in the absence of FXR, the ability of VSG to reduce body weight and improve glucose tolerance is substantially reduced. These results point to bile acids and FXR signalling as an important molecular underpinning for the beneficial effects of this weight-loss surgery.

Original languageEnglish
JournalNature
Volume509
Issue number7499
Pages (from-to)183-8
Number of pages6
ISSN0028-0836
DOIs
Publication statusPublished - 8 May 2014

    Research areas

  • Animals, Bariatric Surgery, Bile Acids and Salts, Body Composition, Cecum, Feeding Behavior, Gastrectomy, Glucose Intolerance, Glucose Tolerance Test, Male, Mice, Mice, Inbred C57BL, Obesity, Receptors, Cytoplasmic and Nuclear, Signal Transduction, Stomach, Weight Loss, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't

ID: 182328338