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; Yong Hong 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

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, Yong Hong Meng, Hanjun Kim, Nam Che, Calvin Pan, Richard G. Lee, Rosanne M. CrookeMark 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

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196 Scopus citations

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.

Original language	English
Pages (from-to)	2451-2461
Number of pages	11
Journal	Cell Reports
Volume	19
Issue number	12
DOIs	https://doi.org/10.1016/j.celrep.2017.05.077
State	Published - Jun 20 2017

Keywords

FMO3
adipose
diabetes
flavin-containing monooxygenase 3
microbiota
nutrition
obesity

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10.1016/j.celrep.2017.05.077

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Schugar, R. C., Shih, D. M., Warrier, M., Helsley, R. N., Burrows, A., Ferguson, D., Brown, A. L., Gromovsky, A. D., Heine, M., Chatterjee, A., Li, L., Li, X. S., Wang, Z., Willard, B., Meng, Y. H., Kim, H., Che, N., Pan, C., Lee, R. G., ... Brown, J. M. (2017). The TMAO-Producing Enzyme Flavin-Containing Monooxygenase 3 Regulates Obesity and the Beiging of White Adipose Tissue. Cell Reports, 19(12), 2451-2461. https://doi.org/10.1016/j.celrep.2017.05.077

@article{d009a6663dcb4f54b62a75da97a0ca55,

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

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",

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

note = "Publisher Copyright: {\textcopyright} 2017 The Authors",

year = "2017",

month = jun,

day = "20",

doi = "10.1016/j.celrep.2017.05.077",

language = "English",

volume = "19",

pages = "2451--2461",

journal = "Cell Reports",

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Schugar, RC, Shih, DM, Warrier, M, Helsley, RN, Burrows, A, Ferguson, D, Brown, AL, Gromovsky, AD, Heine, M, Chatterjee, A, Li, L, Li, XS, Wang, Z, Willard, B, Meng, YH, Kim, H, Che, N, Pan, C, Lee, RG, Crooke, RM, Graham, MJ, Morton, RE, Langefeld, CD, Das, SK, Rudel, LL, Zein, N, McCullough, AJ, Dasarathy, S, Tang, WHW, Erokwu, BO, Flask, CA, Laakso, M, Civelek, M, Naga Prasad, SV, Heeren, J, Lusis, AJ, Hazen, SL & Brown, JM 2017, 'The TMAO-Producing Enzyme Flavin-Containing Monooxygenase 3 Regulates Obesity and the Beiging of White Adipose Tissue', Cell Reports, vol. 19, no. 12, pp. 2451-2461. https://doi.org/10.1016/j.celrep.2017.05.077

TY - JOUR

T1 - The TMAO-Producing Enzyme Flavin-Containing Monooxygenase 3 Regulates Obesity and the Beiging of White Adipose Tissue

AU - Schugar, Rebecca C.

AU - Shih, Diana M.

AU - Warrier, Manya

AU - Helsley, Robert N.

AU - Burrows, Amy

AU - Ferguson, Daniel

AU - Brown, Amanda L.

AU - Gromovsky, Anthony D.

AU - Heine, Markus

AU - Chatterjee, Arunachal

AU - Li, Lin

AU - Li, Xinmin S.

AU - Wang, Zeneng

AU - Willard, Belinda

AU - Meng, Yong Hong

AU - Kim, Hanjun

AU - Che, Nam

AU - Pan, Calvin

AU - Lee, Richard G.

AU - Crooke, Rosanne M.

AU - Graham, Mark J.

AU - Morton, Richard E.

AU - Langefeld, Carl D.

AU - Das, Swapan K.

AU - Rudel, Lawrence L.

AU - Zein, Nizar

AU - McCullough, Arthur J.

AU - Dasarathy, Srinivasan

AU - Tang, W. H.Wilson

AU - Erokwu, Bernadette O.

AU - Flask, Chris A.

AU - Laakso, Markku

AU - Civelek, Mete

AU - Naga Prasad, Sathyamangla V.

AU - Heeren, Joerg

AU - Lusis, Aldons J.

AU - Hazen, Stanley L.

AU - Brown, J. Mark

PY - 2017/6/20

Y1 - 2017/6/20

N2 - 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.

AB - 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.

KW - FMO3

KW - adipose

KW - diabetes

KW - flavin-containing monooxygenase 3

KW - microbiota

KW - nutrition

KW - obesity

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U2 - 10.1016/j.celrep.2017.05.077

DO - 10.1016/j.celrep.2017.05.077

M3 - Article

C2 - 28636934

AN - SCOPUS:85020846804

SN - 2639-1856

VL - 19

SP - 2451

EP - 2461

JO - Cell Reports

JF - Cell Reports

IS - 12

ER -

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

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