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Intestine-selective Farnesoid X Receptor Inhibition Improves Obesity-Related Metabolic Dysfunction

Intestine-selective Farnesoid X Receptor Inhibition Improves Obesity-Related Metabolic Dysfunction

Changtao Jiang, Cen Xie, Ying Lv, Jing Li, Kristopher W Krausz, Jingmin Shi, Chad N Brocker, Dhimant Desai, Shantu G Amin, William H Bisson, Yulan Liu, Oksana Gavrilova, Andrew D Patterson, Frank J Gonzalez

Nat Commun. 2015 Dec 15;6:10166.

PMID: 26670557

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP278779309	GW4064		278779-30-9	Price

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