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

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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.

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Figure 1: Orally delivered Fex is an intestine-restricted FXR agonist.
Figure 2: Fex prevents diet-induced obesity and improves metabolic homeostasis.
Figure 3: Fex increases oxidative phosphorylation to enhance metabolic rate in BAT.
Figure 4: Fex increases endogenous Fgf15 signaling and alters serum BA composition.
Figure 5: Fex reduces inflammation and increases lipolysis in adipose tissues.
Figure 6: Fex treatment improves glucose homeostasis.

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Acknowledgements

We thank H. Juguilon, L. Chong, Y. Yin, J. Alvarez, Y. Dai, S. Kaufman and B. Collins for technical assistance, and L. Ong and C. Brondos for administrative assistance. R.M.E. is an Investigator of the Howard Hughes Medical Institute (HHMI) at the Salk Institute and March of Dimes Chair in Molecular and Developmental Biology, and is supported by National Institutes of Health (NIH) grants (DK057978, DK090962, HL088093, HL105278 and ES010337), the Glenn Foundation for Medical Research, the Leona M. and Harry B. Helmsley Charitable Trust, Ipsen/Biomeasure, California Institute for Regenerative Medicine and The Ellison Medical Foundation. C.L. and M.D. are funded by grants from the National Health and Medical Research Council of Australia Project Grants 512354, 632886 and 1043199; J.M.O. is supported by NIH grants (DK033651, DK074868, T32-DK007494, DK063491 and P01-DK054441-14A1) and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development/NIH through cooperative agreement of U54-HD-012303-25 as part of the specialized Cooperative Centers Program in Reproduction and Infertility Research; A.R.S. is supported by NIH grants (DK60597 and DK61618). R.M.E., J.M.O., A.R.S. and D.A.B. are supported by NIH grant R24DK090962.

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S.F., J.M.S., M.D. and R.M.E. designed and supervised the research. S.F., J.M.S., S.M.R., E. Yoshihara, O.O., D.L., E. Yu, S.J., S.C. and Y.L. performed research. K.S., A.K., and A.P. performed research and analyzed data. S.F., J.M.S., S.M.R., E. Yoshihara, O.O., D.L., E. Yu, R.T.Y., S.C., C.L., A.R.A., B.S., D.A.B., J.M.O., A.R.S., M.D. and R.M.E. analyzed data. S.F., J.M.S., A.R.A., B.S., D.A.B., C.L., J.M.O., A.R.S., M.D. and R.M.E. wrote the manuscript.

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Correspondence to Michael Downes or Ronald M Evans.

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Competing interests

S.F., J.M.S., A.R.A., A.R.S., M.D. and R.M.E. are co-inventors of FXR molecules and methods of use and may be entitled to royalties.

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Fang, S., Suh, J., Reilly, S. et al. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med 21, 159–165 (2015). https://doi.org/10.1038/nm.3760

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