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

doi:10.1038/ncomms10166

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

Research output: Contribution to journal › Article › peer-review

366 Scopus citations

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.

Original language	English (US)
Article number	10166
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms10166
State	Published - Dec 15 2015

All Science Journal Classification (ASJC) codes

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/ncomms10166

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@article{dc8c1f51bcdd43cbabb8d14eb0c2aa3c,

title = "Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction",

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.",

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

note = "Funding Information: We thank Linda G. Byrd and John Buckley for technical assistance with the mouse studies. We thank Paul A. Dawson, Makoto Miyazaki and Kristina Schoonjans for recombinant plasmids and Jerry T. Thompson for assistance with the FXR reporter assays. This work was supported by the Intramural Research Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, and by the National Institutes of Environmental Health Sciences (ES022186 (A.D.P.)). This project was funded in part by grants from the National Natural Science Foundation of China (31401011 to C.J. and 81200626 to J.L.) and in part by a grant with the Pennsylvania Department of Health using Tobacco CURE Funds (to A.D.P.). The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations or conclusions of this work.",

year = "2015",

month = dec,

day = "15",

doi = "10.1038/ncomms10166",

language = "English (US)",

volume = "6",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

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TY - JOUR

T1 - Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction

AU - Jiang, Changtao

AU - Xie, Cen

AU - Lv, Ying

AU - Li, Jing

AU - Krausz, Kristopher W.

AU - Shi, Jingmin

AU - Brocker, Chad N.

AU - Desai, Dhimant

AU - Amin, Shantu G.

AU - Bisson, William H.

AU - Liu, Yulan

AU - Gavrilova, Oksana

AU - Patterson, Andrew D.

AU - Gonzalez, Frank J.

N1 - Funding Information: We thank Linda G. Byrd and John Buckley for technical assistance with the mouse studies. We thank Paul A. Dawson, Makoto Miyazaki and Kristina Schoonjans for recombinant plasmids and Jerry T. Thompson for assistance with the FXR reporter assays. This work was supported by the Intramural Research Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, and by the National Institutes of Environmental Health Sciences (ES022186 (A.D.P.)). This project was funded in part by grants from the National Natural Science Foundation of China (31401011 to C.J. and 81200626 to J.L.) and in part by a grant with the Pennsylvania Department of Health using Tobacco CURE Funds (to A.D.P.). The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations or conclusions of this work.

PY - 2015/12/15

Y1 - 2015/12/15

N2 - 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.

AB - 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.

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U2 - 10.1038/ncomms10166

DO - 10.1038/ncomms10166

M3 - Article

C2 - 26670557

AN - SCOPUS:84949932843

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 10166

ER -

Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction

Abstract

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