Cell Reports (Jun 2017)
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
Affiliations
- Rebecca C. Schugar
- Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44195, USA
- Diana M. Shih
- Departments of Medicine, Microbiology, and Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Manya Warrier
- Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44195, USA
- Robert N. Helsley
- Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44195, USA
- Amy Burrows
- Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44195, USA
- Daniel Ferguson
- Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44195, USA
- Amanda L. Brown
- Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44195, USA
- Anthony D. Gromovsky
- Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44195, USA
- Markus Heine
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
- Arunachal Chatterjee
- Department of Molecular Cardiology, Cleveland Clinic, Cleveland, OH 44195, USA
- Lin Li
- Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44195, USA
- Xinmin S. Li
- Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44195, USA
- Zeneng Wang
- Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44195, USA
- Belinda Willard
- Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44195, USA
- YongHong Meng
- Departments of Medicine, Microbiology, and Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Hanjun Kim
- Departments of Medicine, Microbiology, and Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Nam Che
- Departments of Medicine, Microbiology, and Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Calvin Pan
- Departments of Medicine, Microbiology, and Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Richard G. Lee
- Cardiovascular Group, Antisense Drug Discovery, Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA
- Rosanne M. Crooke
- Cardiovascular Group, Antisense Drug Discovery, Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA
- Mark J. Graham
- Cardiovascular Group, Antisense Drug Discovery, Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA
- Richard E. Morton
- Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA
- Carl D. Langefeld
- Department of Biostatistical Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1040, USA
- Swapan K. Das
- Department of Endocrinology and Metabolism, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1040, USA
- Lawrence L. Rudel
- Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1040, USA
- Nizar Zein
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH 44195, USA
- Arthur J. McCullough
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH 44195, USA
- Srinivasan Dasarathy
- Department of Pathobiology, Cleveland Clinic, Cleveland, OH 44195, USA
- W.H. Wilson Tang
- 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
- Bernadette O. Erokwu
- Departments of Radiology, Biomedical Engineering, and Pediatrics, Case Western Reserve University, Cleveland, OH 44195, USA
- Chris A. Flask
- Departments of Radiology, Biomedical Engineering, and Pediatrics, Case Western Reserve University, Cleveland, OH 44195, USA
- Markku Laakso
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, 70210 Kuopio, Finland
- Mete Civelek
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22904, USA
- Sathyamangla V. Naga Prasad
- Department of Molecular Cardiology, Cleveland Clinic, Cleveland, OH 44195, USA
- Joerg Heeren
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
- Aldons J. Lusis
- Departments of Medicine, Microbiology, and Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Stanley L. Hazen
- 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
- J. Mark Brown
- Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44195, USA; Corresponding author
- Journal volume & issue
-
Vol. 19,
no. 12
pp. 2451 – 2461
Abstract
Summary: 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. : Microbes resident in the human intestine represent a key transmissible environmental factor contributing to obesity and related disorders. Schugar et al. now show that expression of the TMAO-producing enzyme FMO3 is linked to obesity and energy expenditure in both mice and humans. Keywords: microbiota, nutrition, obesity, diabetes, adipose, flavin-containing monooxygenase 3, FMO3
