title: 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: Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors: Ji
authors: J
authors: Miao
authors: Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors: Alisha V
authors: AV
authors: Ling
authors: Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors: Praveen V
authors: PV
authors: Manthena
authors: Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors: Mary E
authors: ME
authors: Gearing
authors: Isis Pharmaceuticals, Carlsbad, California, USA.
authors: Mark J
authors: MJ
authors: Graham
authors: Isis Pharmaceuticals, Carlsbad, California, USA.
authors: Rosanne M
authors: RM
authors: Crooke
authors: Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors: Kevin J
authors: KJ
authors: Croce
authors: Metabolic Disease Program and Diabetes and Obesity Center, Sanford-Burnham Medical Research Institute, Orlando, Florida, USA.
authors: Ryan M
authors: RM
authors: Esquejo
authors: Broad Institute, Cambridge, Massachusetts, USA.
authors: Clary B
authors: CB
authors: Clish
authors: 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.
authors: David
authors: D
authors: Vicent
authors: Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors: Sudha B
authors: SB
authors: Biddinger
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D008076:Cholesterol, HDL / Q000378:metabolism; D008078:Cholesterol, LDL / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism; D006949:Hyperlipidemias / Q000235:genetics / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D010105:Oxygenases / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D014280:Triglycerides / Q000378:metabolism
chemical_list: D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007004:Hypoglycemic Agents; D007328:Insulin; D012333:RNA, Messenger; D014280:Triglycerides; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming)