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Cell Rep. 2017 Jun 20;19(12):2451-2461. 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.

Author information

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

PMID:
28636934
PMCID:
PMC5672822
DOI:
10.1016/j.celrep.2017.05.077
[Indexed for MEDLINE]
Free PMC Article

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