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

Abstract	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.
Authors	Sungsoon Fang, Jae Myoung Suh, Shannon M Reilly, Elizabeth Yu, Olivia Osborn, Denise Lackey, Eiji Yoshihara, Alessia Perino, Sandra Jacinto, Yelizaveta Lukasheva, Annette R Atkins, Alexander Khvat, Bernd Schnabl, Ruth T Yu, David A Brenner, Sally Coulter, Christopher Liddle, Kristina Schoonjans, Jerrold M Olefsky, Alan R Saltiel, Michael Downes, Ronald M Evans
Journal	Nature medicine (Nat Med) Vol. 21 Issue 2 Pg. 159-65 (Feb 2015) ISSN: 1546-170X [Electronic] United States
PMID	25559344 (Publication Type: Journal Article)
Chemical References	Benzene Derivatives Bile Acids and Salts Receptors, Cytoplasmic and Nuclear fexaramine fibroblast growth factor 15, mouse farnesoid X-activated receptor Fibroblast Growth Factors
Topics	Adipose Tissue, Brown (drug effects, metabolism) Adipose Tissue, White (drug effects, metabolism) Animals Benzene Derivatives (pharmacology) Bile Acids and Salts (metabolism) Fibroblast Growth Factors (drug effects, metabolism) Glucose Clamp Technique Insulin Resistance Intestinal Mucosa (metabolism) Mice Obesity (metabolism) Receptors, Cytoplasmic and Nuclear (agonists, metabolism) Weight Gain (drug effects)

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