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

Ji Miao, Alisha V. Ling, Praveen V. Manthena, Mary E. Gearing, Mark J. Graham, Rosanne M. Crooke, Kevin J. Croce, Ryan M. Esquejo, Clary B. Clish, David Vicent and Sudha B. Biddinger ()
Additional contact information
Ji Miao: Boston Children’s Hospital, Harvard Medical School
Alisha V. Ling: Boston Children’s Hospital, Harvard Medical School
Praveen V. Manthena: Boston Children’s Hospital, Harvard Medical School
Mary E. Gearing: Boston Children’s Hospital, Harvard Medical School
Mark J. Graham: Isis Pharmaceuticals
Rosanne M. Crooke: Isis Pharmaceuticals
Kevin J. Croce: Brigham and Women’s Hospital, Harvard Medical School
Ryan M. Esquejo: Metabolic Disease Program and Diabetes and Obesity Center, Sanford-Burnham Medical Research Institute
Clary B. Clish: Broad Institute
David Vicent: Hospital Carlos III
Sudha B. Biddinger: Boston Children’s Hospital, Harvard Medical School

Nature Communications, 2015, vol. 6, issue 1, 1-10

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7498

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