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Nat Commun. 2015 Apr 7;6:6498. doi: 10.1038/ncomms7498.

Flavin-containing monooxygenase 3 as a potential player in diabetes-associated atherosclerosis.

Author information

1
Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
2
Isis Pharmaceuticals, Carlsbad, California, USA.
3
Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
4
Metabolic Disease Program and Diabetes and Obesity Center, Sanford-Burnham Medical Research Institute, Orlando, Florida, USA.
5
Broad Institute, Cambridge, Massachusetts, USA.
6
1] Department of Endocrinology and Nutrition, Hospital Carlos III, Madrid 28029, Spain [2] Instituto de Investigación Sanitaria del Hospital Universitario La Paz (IdiPAZ), Madrid 28046, Spain.

Abstract

Despite the well-documented association between insulin resistance and cardiovascular disease, the key targets of insulin relevant to the development of cardiovascular disease are not known. Here, using non-biased profiling methods, we identify the enzyme flavin-containing monooxygenase 3 (Fmo3) to be a target of insulin. FMO3 produces trimethylamine N-oxide (TMAO), which has recently been suggested to promote atherosclerosis in mice and humans. We show that FMO3 is suppressed by insulin in vitro, increased in obese/insulin resistant male mice and increased in obese/insulin-resistant humans. Knockdown of FMO3 in insulin-resistant mice suppresses FoxO1, a central node for metabolic control, and entirely prevents the development of hyperglycaemia, hyperlipidemia and atherosclerosis. Taken together, these data indicate that FMO3 is required for FoxO1 expression and the development of metabolic dysfunction.

PMID:
25849138
PMCID:
PMC4391288
DOI:
10.1038/ncomms7498
[Indexed for MEDLINE]
Free PMC Article

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