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

Journal: 
Nat Med
Publication Year: 
2015
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
PubMed link: 
25559344
Public Summary: 
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.
Scientific 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.