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

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.

• Authors: 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, Morbid Obesity Study Group, David Vicent, Sudha B Biddinger
• Journal: Nature communications (Nat Commun) Vol. 6 Pg. 6498 (Apr 07 2015) ISSN: 2041-1723 [Electronic] England
• PMID: 25849138 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cholesterol, HDL
• Cholesterol, LDL
• Forkhead Box Protein O1
• Forkhead Transcription Factors
• Foxo1 protein, mouse
• Hypoglycemic Agents
• Insulin
• RNA, Messenger
• Triglycerides
• Oxygenases
• dimethylaniline monooxygenase (N-oxide forming)

Topics

• Animals
• Atherosclerosis (genetics, metabolism)
• Blotting, Western
• Cholesterol, HDL (metabolism)
• Cholesterol, LDL (metabolism)
• Diabetes Mellitus, Type 2 (genetics, metabolism)
• Forkhead Box Protein O1
• Forkhead Transcription Factors (genetics, metabolism)
• Gene Expression Profiling
• Gene Knockdown Techniques
• Hepatocytes (drug effects, metabolism)
• Humans
• Hyperglycemia (genetics, metabolism)
• Hyperlipidemias (genetics, metabolism)
• Hypoglycemic Agents (pharmacology)
• In Vitro Techniques
• Insulin (metabolism, pharmacology)
• Insulin Resistance
• Liver (drug effects, metabolism)
• Male
• Mice
• Obesity (genetics, metabolism)
• Oxygenases (drug effects, genetics, metabolism)
• RNA, Messenger (metabolism)
• Rats
• Rats, Sprague-Dawley
• Real-Time Polymerase Chain Reaction
• Triglycerides (metabolism)