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

Rebecca C. Schugar(Cleveland Clinic), Diana M. Shih(University of California, Los Angeles), Manya Warrier(Cleveland Clinic), Robert N. Helsley(Cleveland Clinic), Amy Burrows(Cleveland Clinic), Daniel Ferguson(Cleveland Clinic), Amanda L. Brown(Cleveland Clinic), Anthony D. Gromovsky(Cleveland Clinic), Markus Heine(Universität Hamburg), Arunachal Chatterjee(Cleveland Clinic), Lin Li(Cleveland Clinic), Xinmin S. Li(Cleveland Clinic), Zeneng Wang(Cleveland Clinic), Belinda Willard(Cleveland Clinic), Yonghong Meng(University of California, Los Angeles), Han‐Jun Kim(University of California, Los Angeles), Nam Che(University of California, Los Angeles), Calvin Pan(University of California, Los Angeles), Richard Lee(Ionis Pharmaceuticals (United States)), Rosanne M. Crooke(Ionis Pharmaceuticals (United States)), Mark J. Graham(Ionis Pharmaceuticals (United States)), Richard E. Morton(Cleveland Clinic), Carl D. Langefeld(Wake Forest University), Swapan K. Das(Wake Forest University), Lawrence L. Rudel(Wake Forest University), Nizar N. Zein(Cleveland Clinic), Arthur J. McCullough(Cleveland Clinic), Srinivasan Dasarathy(Cleveland Clinic), W.H. Wilson Tang(Cleveland Clinic), Bernadette O. Erokwu(Case Western Reserve University), Chris A. Flask(Case Western Reserve University), Markku Laakso(University of Eastern Finland), Mete Civelek(University of Virginia), Sathyamangla V. Naga Prasad(Cleveland Clinic), Jöerg Heeren(Universität Hamburg), Aldons J. Lusis(University of California, Los Angeles), Stanley L. Hazen(Cleveland Clinic), J. Mark Brown(Cleveland Clinic)
Cell Reports
June 1, 2017
10.1016/j.celrep.2017.05.077
Cited by 288Open Access
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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.

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