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Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance

Sungsoon Fang1, Jae Myoung Suh1, Shannon M Reilly2

  • 1Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA.

Nature Medicine
|January 7, 2015
PubMed

Insights

A gut-restricted farnesoid X receptor (FXR) agonist, fexaramine, mimics natural bile acid signaling to improve metabolic health. This targeted approach reduces weight gain, inflammation, and hepatic glucose production without liver FXR activation.

Area of Science:

  • Metabolic disease research
  • Gastroenterology
  • Endocrinology

Background:

  • Bile acid (BA) signaling via farnesoid X receptor (FXR) is crucial for metabolic regulation.
  • Systemic FXR activation offers therapeutic potential but can cause off-target effects.
  • Intestinal FXR activation by BAs during meals is tissue-selective.

Purpose of the Study:

  • To investigate the metabolic effects of a gut-restricted FXR agonist, fexaramine (Fex).
  • To determine if tissue-selective intestinal FXR activation can yield metabolic benefits without hepatic side effects.
  • To explore Fex as a potential therapeutic strategy for obesity and metabolic syndrome.

Main Methods:

  • Administration of the gut-restricted FXR agonist fexaramine (Fex).
  • Assessment of fibroblast growth factor 15 (FGF15) induction in the gut.
  • Analysis of changes in bile acid composition.
  • Evaluation of hepatic gene expression and metabolic parameters (weight gain, inflammation, glucose production, thermogenesis, adipose tissue browning).

Main Results:

  • Fex robustly induced enteric FGF15, altering BA composition.
  • Fex did not activate FXR target genes in the liver.
  • Fex reduced diet-induced weight gain, systemic inflammation, and hepatic glucose production.
  • Fex enhanced thermogenesis and promoted the browning of white adipose tissue (WAT).

Conclusions:

  • Tissue-restricted activation of intestinal FXR by Fex provides significant metabolic benefits.
  • This targeted approach avoids hepatic side effects associated with systemic FXR agonism.
  • Gut-restricted FXR activation represents a promising new therapeutic avenue for obesity and metabolic syndrome.

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