Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance
Open accessAbstract
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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Fexaramine reduces diet-induced weight gain, body-wide inflammation, and hepatic glucose production.
“The gut-restricted FXR agonist fexaramine robustly induces enteric FGF15, leading to alterations in BA composition, without activating FXR target genes in the liver and reducing diet-induced weight gain, body-wide inflammation, hepatic glucose production, while enhancing thermogenesis and browning of white adipose tissue [255].”
From Gut-pancreas-liver Axis as a target for treatment of NAFLD/NASH (2020) · cites this paper as [255]
Fexaramine alters bile acid composition.
“The gut-restricted FXR agonist fexaramine robustly induces enteric FGF15, leading to alterations in BA composition, without activating FXR target genes in the liver and reducing diet-induced weight gain, body-wide inflammation, hepatic glucose production, while enhancing thermogenesis and browning of white adipose tissue [255].”
From Gut-pancreas-liver Axis as a target for treatment of NAFLD/NASH (2020) · cites this paper as [255]
Fexaramine enhances thermogenesis and browning of white adipose tissue.
“The gut-restricted FXR agonist fexaramine robustly induces enteric FGF15, leading to alterations in BA composition, without activating FXR target genes in the liver and reducing diet-induced weight gain, body-wide inflammation, hepatic glucose production, while enhancing thermogenesis and browning of white adipose tissue [255].”
From Gut-pancreas-liver Axis as a target for treatment of NAFLD/NASH (2020) · cites this paper as [255]
The gut-restricted FXR agonist fexaramine robustly induces enteric FGF15.
“The gut-restricted FXR agonist fexaramine robustly induces enteric FGF15, leading to alterations in BA composition, without activating FXR target genes in the liver and reducing diet-induced weight gain, body-wide inflammation, hepatic glucose production, while enhancing thermogenesis and browning of white adipose tissue [255].”
From Gut-pancreas-liver Axis as a target for treatment of NAFLD/NASH (2020) · cites this paper as [255]
Fexaramine does not activate FXR target genes in the liver.
“The gut-restricted FXR agonist fexaramine robustly induces enteric FGF15, leading to alterations in BA composition, without activating FXR target genes in the liver and reducing diet-induced weight gain, body-wide inflammation, hepatic glucose production, while enhancing thermogenesis and browning of white adipose tissue [255].”
From Gut-pancreas-liver Axis as a target for treatment of NAFLD/NASH (2020) · cites this paper as [255]
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- Authors
- Fang, S., Suh, J. M., Reilly, S. M., Yu, E., Osborn, O., Lackey, D., Yoshihara, E., Perino, A., Jacinto, S., Lukasheva, Y., Atkins, A. R., Khvat, A., Schnabl, B., Yu, R. T., Brenner, D. A., Coulter, S., Liddle, C., Schoonjans, K., Olefsky, J. M., Saltiel, A. R., Downes, M., & Evans, R. M.
- Affiliations
- Salk Institute for Biological Studies (US)
- University of Michigan (US)
- University of California San Diego (US)
- École Polytechnique Fédérale de Lausanne (CH)
- ChemDiv (United States) (US)
- The University of Sydney (AU)
- Corresponding author
- Downes, Michael
- Evans, Ronald M
- ORCID
- Venue
- Nature Medicine
- Published
- 2015-01-05
- Volume
- 21
- Issue
- 2
- Pages
- 159-165
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC4320010
- OpenAlex
- W2107051699
- Cited by
- 738
- References
- 50
- Citations by year
- 2026: 36 · 2025: 56 · 2024: 70 · 2023: 70 · 2022: 72 · 2021: 73 · 2020: 59 · 2019: 58 · 2018: 58 · 2017: 72 · 2016: 69 · 2015: 44
- FWCI
- 59.69
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Funders
- Howard Hughes Medical Institute
- National Heart, Lung, and Blood Institute (R01HL105278, P01HL088093)
- National Cancer Institute (P30CA014195)
- National Institute of Diabetes and Digestive and Kidney Diseases (R37DK057978, P01DK054441, T32DK007494, R01DK061618, R01DK057978, R37DK033651, R24DK090962, P01DK074868, R01DK060591, R01DK060597, R01DK033651, P30DK063491)
- National Institute of Environmental Health Sciences (P42ES010337)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD012303)
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Keywords
- farnesoid X receptor, bile acids, FGF15, white adipose tissue browning, thermogenesis, obesity, insulin resistance, hepatic glucose production, metabolic syndrome, inflammation
- MeSH terms
- Receptor, Farnesoid X-Activated, Animals, Benzene Derivatives, Bile Acids and Salts, Adipose Tissue, Brown, Fibroblast Growth Factors, Insulin Resistance, Intestinal Mucosa, Obesity, Glucose Clamp Technique, Weight Gain, Receptors, Cytoplasmic and Nuclear, Mice, Adipose Tissue, White
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