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

Author

Listed:
  • 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
    Instituto de Investigación Sanitaria del Hospital Universitario La Paz (IdiPAZ))

  • Sudha B. Biddinger

    (Boston Children’s Hospital, Harvard Medical School)

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.

Suggested Citation

  • 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 & Sudha B. Biddinger, 2015. "Flavin-containing monooxygenase 3 as a potential player in diabetes-associated atherosclerosis," Nature Communications, Nature, vol. 6(1), pages 1-10, May.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7498
    DOI: 10.1038/ncomms7498
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    Cited by:

    1. Lijuan Kong & Qijin Zhao & Xiaojing Jiang & Jinping Hu & Qian Jiang & Li Sheng & Xiaohong Peng & Shusen Wang & Yibing Chen & Yanjun Wan & Shaocong Hou & Xingfeng Liu & Chunxiao Ma & Yan Li & Li Quan &, 2024. "Trimethylamine N-oxide impairs β-cell function and glucose tolerance," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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