The TMAO-Producing Enzyme Flavin-Containing Monooxygenase 3 Regulates Obesity and the Beiging of White Adipose Tissue
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Emerging evidence suggests that microbes resident in the human intestine represent a key environmental factor contributing to obesity-associated disorders. Here, we demonstrate that the gut microbiota-initiated trimethylamine N-oxide (TMAO)-generating pathway is linked to obesity and energy metabolism. In multiple clinical cohorts, systemic levels of TMAO were observed to strongly associate with type 2 diabetes. In addition, circulating TMAO levels were associated with obesity traits in the different inbred strains represented in the Hybrid Mouse Diversity Panel. Further, antisense oligonucleotide-mediated knockdown or genetic deletion of the TMAO-producing enzyme flavin-containing monooxygenase 3 (FMO3) conferred protection against obesity in mice. Complimentary mouse and human studies indicate a negative regulatory role for FMO3 in the beiging of white adipose tissue. Collectively, our studies reveal a link between the TMAO-producing enzyme FMO3 and obesity and the beiging of white adipose tissue.
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Elevated levels of TMAO induce vascular inflammation and a direct prothrombotic effect by increasing platelet hyper-responsiveness to multiple agonists in both rodents and humans.
“Elevated level of TMAO induces vascular inflammation and a direct prothrombotic effect by increasing platelet hyper-responsiveness to multiple agonists in both rodents and humans, and might be involved in the pathogenesis of obesity and type 2 diabetes (90,91).”
From Health Benefits of the Mediterranean Diet: Metabolic and Molecular Mechanisms (2018) · cites this paper as [91]
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- Authors
- Schugar, R. C., Shih, D. M., Warrier, M., Helsley, R. N., Burrows, A., Ferguson, D., Brown, A. L., Gromovsky, A. D., Heine, M., Chatterjee, A., Li, L., Li, X. S., Wang, Z., Willard, B., Meng, Y., Kim, H., Che, N., Pan, C., Lee, R. G., Crooke, R. M., Graham, M. J., Morton, R. E., Langefeld, C. D., Das, S. K., Rudel, L. L., Zein, N., McCullough, A. J., Dasarathy, S., Tang, W. H. W., Erokwu, B. O., Flask, C. A., Laakso, M., Civelek, M., Naga Prasad, S. V., Heeren, J., Lusis, A. J., Hazen, S. L., & Brown, J. M.
- Affiliations
- Cleveland Clinic (US)
- University of California, Los Angeles (US)
- University Medical Center Hamburg-Eppendorf (DE)
- Ionis Pharmaceuticals (United States) (US)
- Wake Forest University Health Sciences (US)
- Case Western Reserve University (US)
- University of Eastern Finland (FI)
- University of Virginia (US)
- Corresponding author
- Brown, J. Mark
- ORCID
- Schugar, Rebecca C.
- Shih, Diana M.
- Helsley, Robert N.
- Burrows, Amy
- Ferguson, Daniel
- Brown, Amanda L.
- Heine, Markus
- Li, Lin
- Li, Xinmin S.
- Wang, Zeneng
- Willard, Belinda
- Meng, YongHong
- Pan, Calvin
- Lee, Richard G.
- Morton, Richard E.
- Langefeld, Carl D.
- Das, Swapan K.
- McCullough, Arthur J.
- Dasarathy, Srinivasan
- Tang, W.H. Wilson
- Flask, Chris A.
- Laakso, Markku
- Civelek, Mete
- Lusis, Aldons J.
- Hazen, Stanley L.
- Brown, J. Mark
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2017-06
- Volume
- 19
- Issue
- 12
- Pages
- 2451-2461
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC5672822
- OpenAlex
- W2710428763
- Cited by
- 291
- References
- 46
- Citations by year
- 2026: 23 · 2025: 28 · 2024: 39 · 2023: 29 · 2022: 37 · 2021: 46 · 2020: 27 · 2019: 27 · 2018: 28 · 2017: 7
- FWCI
- 9.95
- Type
- journal article
- Language
- en
- Update notices
- erratum (2017-07-05)
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- NIH (R00 HL096166, R01 HL122283, P50 AA024333, R01 HL103866, R01 HL126827, R01 DK106000, R01 HL130819, R01 DK090111, R00 HL12172, P01 HL028481, P01 HL030568-31A1, P01 HL49373)
- Deutsche Forschungsgemeinschaft (SFB841)
- Academy of Finland
- Finnish Cardiovascular Research Foundation
- American Heart Association (15POST2535000, 14POST18700001, 17POST3285000)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- trimethylamine N-oxide, FMO3, gut microbiota, obesity, white adipose tissue browning, type 2 diabetes, energy metabolism, Hybrid Mouse Diversity Panel, antisense oligonucleotide knockdown, microbial metabolites
- MeSH terms
- Adipocytes, Beige, Animals, Diabetes Mellitus, Type 2, Female, Humans, Male, Methylamines, Mice, Inbred C57BL, Obesity, Oxygenases, Gene Expression, Mice, Knockout, Subcutaneous Fat, Mice
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