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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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.

Author information


  1. Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA.

    • Sungsoon Fang
    • , Jae Myoung Suh
    • , Elizabeth Yu
    • , Eiji Yoshihara
    • , Sandra Jacinto
    • , Yelizaveta Lukasheva
    • , Annette R Atkins
    • , Ruth T Yu
    • , Michael Downes
    •  & Ronald M Evans
  2. Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA.

    • Shannon M Reilly
    •  & Alan R Saltiel
  3. Department of Medicine, University of California San Diego, San Diego, California, USA.

    • Olivia Osborn
    • , Denise Lackey
    • , Bernd Schnabl
    • , David A Brenner
    •  & Jerrold M Olefsky
  4. Metabolic Signaling, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Federale de Lausanne, Switzerland.

    • Alessia Perino
    •  & Kristina Schoonjans
  5. ChemDiv, Inc., San Diego, California, USA.

    • Alexander Khvat
  6. Storr Liver Unit, Westmead Millennium Institute, Sydney Medical School, University of Sydney, Australia.

    • Sally Coulter
    •  & Christopher Liddle
  7. Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, California, USA.

    • Ronald M Evans


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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.

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.

Corresponding authors

Correspondence to Michael Downes or Ronald M Evans.

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