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Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction
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Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction
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Journal Article
Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction
2015
Overview
The farnesoid X receptor (FXR) regulates bile acid, lipid and glucose metabolism. Here we show that treatment of mice with glycine-β-muricholic acid (Gly-MCA) inhibits FXR signalling exclusively in intestine, and improves metabolic parameters in mouse models of obesity. Gly-MCA is a selective high-affinity FXR inhibitor that can be administered orally and prevents, or reverses, high-fat diet-induced and genetic obesity, insulin resistance and hepatic steatosis in mice. The high-affinity FXR agonist GW4064 blocks Gly-MCA action in the gut, and intestine-specific
Fxr
-null mice are unresponsive to the beneficial effects of Gly-MCA. Mechanistically, the metabolic improvements with Gly-MCA depend on reduced biosynthesis of intestinal-derived ceramides, which directly compromise beige fat thermogenic function. Consequently, ceramide treatment reverses the action of Gly-MCA in high-fat diet-induced obese mice. We further show that FXR signalling in ileum biopsies of humans positively correlates with body mass index. These data suggest that Gly-MCA may be a candidate for the treatment of metabolic disorders.
The nuclear farnesoid X receptor (FXR) is activated by bile acids and influences energy metabolism. Here, the authors report a small molecule inhibitor of FXR, glycine-ß-muricholic acid, which inhibits FXR in the intestine and improves metabolic homeostasis by repressing intestinal ceramide synthesis.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 13/109
/ 38/77
/ 38/90
/ 64/60
/ 82/58
/ 82/6
/ Acids
/ Adult
/ Aged
/ Animals
/ Bile
/ Biopsy
/ Diabetes
/ Female
/ Genes
/ Humanities and Social Sciences
/ Humans
/ Insulin Resistance - genetics
/ Intestinal Mucosa - metabolism
/ Male
/ Mice
/ Obesity
/ Receptors, Cytoplasmic and Nuclear - agonists
/ Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors
/ Receptors, Cytoplasmic and Nuclear - genetics
/ Receptors, Cytoplasmic and Nuclear - metabolism
/ Science
