IRX3 Promotes the Browning of White Adipocytes and Its Rare Variants are Associated with Human Obesity Risk.
IRX3 Promotes the Browning of White Adipocytes and Its Rare Variants are Associated with Human Obesity Risk.
复制标题
IRX3 促进白色脂肪细胞褐变，其罕见变异体与人类肥胖风险相关。
DOI：
10.1016/j.ebiom.2017.09.010
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发表时间：
2017-10
期刊：
影响因子：
11.1
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Zou Y;Lu P;Shi J;Liu W;Yang M;Zhao S;Chen N;Chen M;Sun Y;Gao A;Chen Q;Zhang Z;Ma Q;Ning T;Ying X;Jin J;Deng X;Shen B;Zhang Y;Yuan B;Kauderer S;Liu S;Hong J;Liu R;Ning G;Wang W;Gu W;Wang J
IRX3 was recently reported as the effector of the FTO variants. We aimed to test IRX3's roles in the browning program and to evaluate the association between the genetic variants in IRX3 and human obesity. IRX3 expression was examined in beige adipocytes in human and mouse models, and further validated in induced beige adipocytes. The browning capacity of primary preadipocytes was assessed with IRX3 knockdown. Luciferase reporter analysis and ChIP assay were applied to investigate IRX3's effects on UCP1 transcriptional activity. Moreover, genetic analysis of IRX3 was performed in 861 young obese subjects and 916 controls. IRX3 expression was induced in the browning process and was positively correlated with the browning markers. IRX3 knockdown remarkably inhibited UCP1 expression in induced mouse and human beige adipocytes, and also repressed the uncoupled oxygen consumption rate. Further, IRX3 directly bound to UCP1 promoter and increased its transcriptional activity. Moreover, 17 rare heterozygous missense/frameshift IRX3 variants were identified, with a significant enrichment in obese subjects (P = 0.038, OR = 2.27; 95% CI, 1.02–5.05). IRX3 deficiency repressed the browning program of white adipocytes partially by regulating UCP1 transcriptional activity. Rare variants of IRX3 were associated with human obesity. IRX3 expression was positively correlated with the browning markers in both mice and humans. IRX3 deficiency repressed the browning program in human and mouse cell models by regulating UCP1 transcriptional activity. Rare variants of IRX3 were associated with human obesity. While FTO is the first risk gene for obesity identified via genome-wide association studies, its exact mechanism remains unknown until two recent studies reported that IRX3, as FTO's target, probably inhibited the browning of white fat. However, whether IRX3 gene per se predisposes to obesity in humans and how IRX3 regulates the browning process remains unclear. Herein we combined cellular and genetic evidence to support that IRX3 promotes but not inhibit the browning process in both human and mouse cell models. Mechanistically, IRX3 increased the transcriptional activity of UCP1 through directly binding to its promoter. Thus, our findings provided an intact picture of IRX3's function in browning program and human obesity.
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影响因子：
30.8
作者：
Flannick, Jason;Thorleifsson, Gudmar;Beer, Nicola L.;Jacobs, Suzanne B. R.;Grarup, Niels;Burtt, Noel P.;Mahajan, Anubha;Fuchsberger, Christian;Atzmon, Gil;Benediktsson, Rafn;Blangero, John;Bowden, Don W.;Brandslund, Ivan;Brosnan, Julia;Burslem, Frank;Chambers, John;Cho, Yoon Shin;Christensen, Cramer;Douglas, Desiree A.;Duggirala, Ravindranath;Dymek, Zachary;Farjoun, Yossi;Fennell, Timothy;Fontanillas, Pierre;Forsen, Tom;Gabriel, Stacey;Glaser, Benjamin;Gudbjartsson, Daniel F.;Hanis, Craig;Hansen, Torben;Hreidarsson, Astradur B.;Hveem, Kristian;Ingelsson, Erik;Isomaa, Bo;Johansson, Stefan;Jorgensen, Torben;Jorgensen, Marit Eika;Kathiresan, Sekar;Kong, Augustine;Kooner, Jaspal;Kravic, Jasmina;Laakso, Markku;Lee, Jong-Young;Lind, Lars;Lindgren, Cecilia M.;Linneberg, Allan;Masson, Gisli;Meitinger, Thomas;Mohlke, Karen L.;Molven, Anders;Morris, Andrew P.;Potluri, Shobha;Rauramaa, Rainer;Ribel-Madsen, Rasmus;Richard, Ann-Marie;Rolph, Tim;Salomaa, Veikko;Segre, Ayellet V.;Skaerstrand, Hanna;Steinthorsdottir, Valgerdur;Stringham, Heather M.;Sulem, Patrick;Tai, E. Shyong;Teo, Yik Ying;Teslovich, Tanya;Thorsteinsdottir, Unnur;Trimmer, Jeff K.;Tuomi, Tiinamaija;Tuomilehto, Jaakko;Vaziri-Sani, Fariba;Voight, Benjamin F.;Wilson, James G.;Boehnke, Michael;McCarthy, Mark I.;Njolstad, Pal R.;Pedersen, Oluf;Groop, Leif;Cox, David R.;Stefansson, Kari;Altshuler, David
通讯作者：
Altshuler, David
影响因子：
30.8
作者：
Krude, H;Biebermann, H;Grüters, A
通讯作者：
Grüters, A
影响因子：
30.8
作者：
Bonnefond, Amelie;Clement, Nathalie;Fawcett, Katherine;Yengo, Loic;Vaillant, Emmanuel;Guillaume, Jean-Luc;Dechaume, Aurelie;Payne, Felicity;Roussel, Ronan;Czernichow, Sebastien;Hercberg, Serge;Hadjadj, Samy;Balkau, Beverley;Marre, Michel;Lantieri, Olivier;Langenberg, Claudia;Bouatia-Naji, Nabila;Charpentier, Guillaume;Vaxillaire, Martine;Rocheleau, Ghislain;Wareham, Nicholas J.;Sladek, Robert;McCarthy, Mark I.;Dina, Christian;Barroso, Ines;Jockers, Ralf;Froguel, Philippe
通讯作者：
Froguel, Philippe
影响因子：
56.9
作者：
Frayling, Timothy M.;Timpson, Nicholas J.;McCarthy, Mark I.
通讯作者：
McCarthy, Mark I.
影响因子：
82.9
作者：
Lidell, Martin E.;Betz, Matthias J.;Enerback, Sven
通讯作者：
Enerback, Sven