Portal de Periódicos da CAPES

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

2015; Nature Portfolio; Volume: 6; Issue: 1 Linguagem: Inglês

10.1038/ncomms7498

2041-1723

Ji Miao, Alisha V. Ling, Praveen V. Manthena, Mary E. Gearing, Mark J. Graham, Rosanne M. Crooke, Kevin Croce, Ryan M. Esquejo, Clary B. Clish, Esther Torrecilla, Gumersindo Fernández Vázquez, Miguel A. Rubio, Lucio Cabrerizo, Ana Barabash, Andrés Sánchez Pernaute, Antonio J. Torres, David Vicent, Sudha B. Biddinger,

Peroxisome Proliferator-Activated Receptors

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.