Journal
NATURE MEDICINE
Volume 21, Issue 2, Pages 159-165Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.3760
Keywords
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Funding
- National Institutes of Health (NIH) [DK057978, DK090962, HL088093, HL105278, ES010337]
- Glenn Foundation for Medical Research
- Leona M. and Harry B. Helmsley Charitable Trust
- Ipsen/Biomeasure
- California Institute for Regenerative Medicine
- Ellison Medical Foundation
- National Health and Medical Research Council of Australia Project [512354, 632886, 1043199]
- NIH [DK033651, DK074868, T32-DK007494, DK063491, P01-DK054441-14A1, DK60597, DK61618, R24DK090962]
- Eunice Kennedy Shriver National Institute of Child Health and Human Development/NIH, Cooperative Centers Program in Reproduction and Infertility Research [U54-HD-012303-25]
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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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