The TMAO-Producing Enzyme Flavin-Containing Monooxygenase 3 Regulates Obesity and the Beiging of White Adipose Tissue

Rebecca C Schugar; Diana M Shih; Manya Warrier; Robert N Helsley; Amy Burrows; Daniel Ferguson; Amanda L Brown; Anthony D Gromovsky; Markus Heine; Arunachal Chatterjee; Lin Li; Xinmin S Li; Zeneng Wang; Belinda Willard; YongHong Meng; Hanjun Kim; Nam Che; Calvin Pan; Richard G Lee; Rosanne M Crooke; Mark J Graham; Richard E Morton; Carl D Langefeld; Swapan K Das; Lawrence L Rudel; Nizar Zein; Arthur J McCullough; Srinivasan Dasarathy; W H Wilson Tang; Bernadette O Erokwu; Chris A Flask; Markku Laakso; Mete Civelek; Sathyamangla V Naga Prasad; Joerg Heeren; Aldons J Lusis; Stanley L Hazen; J Mark Brown

doi:10.1016/j.celrep.2017.05.077

The TMAO-Producing Enzyme Flavin-Containing Monooxygenase 3 Regulates Obesity and the Beiging of White Adipose Tissue

Cell Rep. 2017 Jun 20;19(12):2451-2461. doi: 10.1016/j.celrep.2017.05.077.

Authors

Rebecca C Schugar¹, Diana M Shih², Manya Warrier¹, Robert N Helsley¹, Amy Burrows¹, Daniel Ferguson¹, Amanda L Brown¹, Anthony D Gromovsky¹, Markus Heine³, Arunachal Chatterjee⁴, Lin Li¹, Xinmin S Li¹, Zeneng Wang¹, Belinda Willard¹, YongHong Meng², Hanjun Kim², Nam Che², Calvin Pan², Richard G Lee⁵, Rosanne M Crooke⁵, Mark J Graham⁵, Richard E Morton⁶, Carl D Langefeld⁷, Swapan K Das⁸, Lawrence L Rudel⁹, Nizar Zein¹⁰, Arthur J McCullough¹⁰, Srinivasan Dasarathy¹¹, W H Wilson Tang¹², Bernadette O Erokwu¹³, Chris A Flask¹³, Markku Laakso¹⁴, Mete Civelek¹⁵, Sathyamangla V Naga Prasad⁴, Joerg Heeren³, Aldons J Lusis², Stanley L Hazen¹², J Mark Brown¹⁶

Affiliations

¹ Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44195, USA.
² Departments of Medicine, Microbiology, and Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.
⁴ Department of Molecular Cardiology, Cleveland Clinic, Cleveland, OH 44195, USA.
⁵ Cardiovascular Group, Antisense Drug Discovery, Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA.
⁶ Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
⁷ Department of Biostatistical Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1040, USA.
⁸ Department of Endocrinology and Metabolism, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1040, USA.
⁹ Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1040, USA.
¹⁰ Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH 44195, USA.
¹¹ Department of Pathobiology, Cleveland Clinic, Cleveland, OH 44195, USA.
¹² Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
¹³ Departments of Radiology, Biomedical Engineering, and Pediatrics, Case Western Reserve University, Cleveland, OH 44195, USA.
¹⁴ Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, 70210 Kuopio, Finland.
¹⁵ Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22904, USA.
¹⁶ Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44195, USA. Electronic address: brownm5@ccf.org.

Abstract

Emerging evidence suggests that microbes resident in the human intestine represent a key environmental factor contributing to obesity-associated disorders. Here, we demonstrate that the gut microbiota-initiated trimethylamine N-oxide (TMAO)-generating pathway is linked to obesity and energy metabolism. In multiple clinical cohorts, systemic levels of TMAO were observed to strongly associate with type 2 diabetes. In addition, circulating TMAO levels were associated with obesity traits in the different inbred strains represented in the Hybrid Mouse Diversity Panel. Further, antisense oligonucleotide-mediated knockdown or genetic deletion of the TMAO-producing enzyme flavin-containing monooxygenase 3 (FMO3) conferred protection against obesity in mice. Complimentary mouse and human studies indicate a negative regulatory role for FMO3 in the beiging of white adipose tissue. Collectively, our studies reveal a link between the TMAO-producing enzyme FMO3 and obesity and the beiging of white adipose tissue.

Keywords: FMO3; adipose; diabetes; flavin-containing monooxygenase 3; microbiota; nutrition; obesity.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adipocytes, Beige / enzymology
Animals
Diabetes Mellitus, Type 2 / blood
Female
Gene Expression
Humans
Male
Methylamines / blood*
Mice
Mice, Inbred C57BL
Mice, Knockout
Obesity / blood
Obesity / enzymology*
Obesity / pathology
Oxygenases / physiology*
Subcutaneous Fat / enzymology*
Subcutaneous Fat / pathology
Subcutaneous Fat / physiopathology

Substances

Methylamines
Oxygenases
dimethylaniline monooxygenase (N-oxide forming)
trimethyloxamine

Abstract

Publication types

MeSH terms

Substances

Grants and funding