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Nat Commun DOI:10.1038/ncomms7498

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

Publication TypeJournal Article
Year of Publication2015
AuthorsMiao, J, Ling, AV, Manthena, PV, Gearing, ME, Graham, MJ, Crooke, RM, Croce, KJ, Esquejo, RM, Clish, CB, Vicent, D, Biddinger, SB
Corporate AuthorsMorbid Obesity Study Group
JournalNat Commun
Date Published2015 Apr 07
KeywordsAnimals, Atherosclerosis, Blotting, Western, Cholesterol, HDL, Cholesterol, LDL, Diabetes Mellitus, Type 2, Forkhead Box Protein O1, Forkhead Transcription Factors, Gene Expression Profiling, Gene Knockdown Techniques, Hepatocytes, Humans, Hyperglycemia, Hyperlipidemias, Hypoglycemic Agents, In Vitro Techniques, Insulin, Insulin Resistance, Liver, Male, Mice, Obesity, Oxygenases, Rats, Rats, Sprague-Dawley, Real-Time Polymerase Chain Reaction, RNA, Messenger, Triglycerides

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.


Alternate JournalNat Commun
PubMed ID25849138
PubMed Central IDPMC4391288
Grant ListHL109650 / HL / NHLBI NIH HHS / United States
K99 DK100539 / DK / NIDDK NIH HHS / United States
HL48044 / HL / NHLBI NIH HHS / United States
R01 HL048044 / HL / NHLBI NIH HHS / United States
DK100539 / DK / NIDDK NIH HHS / United States
R01 HL109650 / HL / NHLBI NIH HHS / United States