Schugar Rebecca C, Shih Diana M, Warrier Manya, Helsley Robert N, Burrows Amy, Ferguson Daniel, Brown Amanda L, Gromovsky Anthony D, Heine Markus, Chatterjee Arunachal, Li Lin, Li Xinmin S, Wang Zeneng, Willard Belinda, Meng YongHong, Kim Hanjun, Che Nam, Pan Calvin, Lee Richard G, Crooke Rosanne M, Graham Mark J, Morton Richard E, Langefeld Carl D, Das Swapan K, Rudel Lawrence L, Zein Nizar, McCullough Arthur J, Dasarathy Srinivasan, Tang W H Wilson, Erokwu Bernadette O, Flask Chris A, Laakso Markku, Civelek Mete, Naga Prasad Sathyamangla V, Heeren Joerg, Lusis Aldons J, Hazen Stanley L, Brown J Mark
Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44195, USA.
Departments of Medicine, Microbiology, and Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Cell Rep. 2017 Jun 20;19(12):2451-2461. doi: 10.1016/j.celrep.2017.05.077.
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.
新出现的证据表明，人类肠道中的微生物是导致肥胖相关疾病的关键环境因素。在此，我们证明肠道微生物群启动的三甲胺 N-氧化物（TMAO）生成途径与肥胖和能量代谢有关。在多个临床队列中，观察到 TMAO 的全身水平与 2 型糖尿病密切相关。此外，在杂交小鼠多样性面板所代表的不同近交系中，循环 TMAO 水平与肥胖特征相关。此外，反义寡核苷酸介导的 TMAO 产生酶含黄素单加氧酶 3（FMO3）的敲低或基因缺失可保护小鼠免受肥胖。互补的小鼠和人类研究表明 FMO3 在白色脂肪组织米色化中起负调节作用。总体而言，我们的研究揭示了 TMAO 产生酶 FMO3 与肥胖以及白色脂肪组织米色化之间的联系。
