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

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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.
Publisher
NATURE PUBLISHING GROUP
Issue Date
2015-02
Language
English
Article Type
Article
Keywords

FARNESOID-X-RECEPTOR; BILE-ACID RECEPTOR; UNCOUPLING PROTEIN-1 GENE; FATTY LIVER-DISEASE; NUCLEAR RECEPTOR; GLUCOSE-HOMEOSTASIS; FEEDBACK-REGULATION; ENERGY-EXPENDITURE; MOUSE-LIVER; MICE

Citation

NATURE MEDICINE, v.21, no.2, pp.71 - 77

ISSN
1078-8956
DOI
10.1038/nm.3760
URI
http://hdl.handle.net/10203/198254
Appears in Collection
MSE-Journal Papers(저널논문)
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