Adipocyte-specific tribbles pseudokinase 1 regulates plasma adiponectin and plasma lipids in mice.
Adipocyte-specific tribbles pseudokinase 1 regulates plasma adiponectin and plasma lipids in mice.
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DOI：
10.1016/j.molmet.2021.101412
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发表时间：
2022-03
影响因子：
8.1
通讯作者：
Bauer RC
中科院分区：
文献类型：
--
作者：
Ha EE;Quartuccia GI;Ling R;Xue C;Karikari RA;Hernandez-Ono A;Hu KY;Matias CV;Imam R;Cui J;Pellegata NS;Herzig S;Georgiadi A;Soni RK;Bauer RC
多个全基因组关联研究（GWAS）已经确定了TRIB 1附近8 q24位点的SNP，这些SNP与血脂和其他心脏代谢健康标志物显著相关，先前的研究已经揭示了肝脏和骨髓Trib 1在血脂调节和动脉粥样硬化中的作用。相同的8 q24 SNP还与人类血浆脂联素水平相关，这表明TRIB 1与脂肪细胞生物学有关。在此，我们假设脂肪组织中的TRIB 1调节血浆脂联素、脂质和代谢健康。我们研究了脂肪细胞特异性Trib 1基因敲除小鼠（Trib1_ASKO）在普通饲料和高脂饮食（HFD）下的代谢表型。通过脂肪组织外植体的分泌组学和脂肪细胞和肝脏的RNA-seq，我们进一步研究TRIB 1在脂肪组织中的作用机制。Trib1_ASKO小鼠具有改善的代谢表型，血浆脂联素水平升高，葡萄糖耐量改善，血脂降低。Trib1_ASKO脂肪细胞具有增加的脂联素产生和分泌，其独立于已知的TRIB 1调节蛋白酶体降解的功能。来自Trib1_ASKO小鼠的脂肪细胞和肝脏的RNA-seq分析表明，脂肪细胞功能的改变是观察到的血浆脂质变化的基础。脂肪组织外植体分泌物组学进一步揭示Trib1_ASKO脂肪组织具有降低的ANGPTL 4产生，并且我们证明伴随的脂蛋白脂肪酶（LPL）活性的增加可能是甘油三酯表型的基础。这项研究表明，脂肪细胞Trib 1调节代谢健康的多个方面，证实了先前在人类中观察到的遗传关联，并揭示了TRIB 1调节血脂和代谢健康的进一步机制。缺乏脂肪细胞Trib 1的小鼠血浆脂联素增加，血浆胆固醇和甘油三酯降低。缺乏脂肪细胞Trib 1的小鼠可免受高脂饮食诱导的胰岛素抵抗。TRIB 1在脂肪中调节脂联素分泌，不依赖于蛋白酶体。TRIB 1缺乏的脂肪减少了ANGPTL 4分泌，增加了LPL活性。靶向脂肪细胞TRIB 1可能在代谢综合征中具有治疗益处。
Multiple genome-wide association studies (GWAS) have identified SNPs in the 8q24 locus near TRIB1 that are significantly associated with plasma lipids and other markers of cardiometabolic health, and prior studies have revealed the roles of hepatic and myeloid Trib1 in plasma lipid regulation and atherosclerosis. The same 8q24 SNPs are additionally associated with plasma adiponectin levels in humans, implicating TRIB1 in adipocyte biology. Here, we hypothesize that TRIB1 in adipose tissue regulates plasma adiponectin, lipids, and metabolic health. We investigate the metabolic phenotype of adipocyte-specific Trib1 knockout mice (Trib1_ASKO) fed on chow and high-fat diet (HFD). Through secretomics of adipose tissue explants and RNA-seq of adipocytes and livers from these mice, we further investigate the mechanism of TRIB1 in adipose tissue. Trib1_ASKO mice have an improved metabolic phenotype with increased plasma adiponectin levels, improved glucose tolerance, and decreased plasma lipids. Trib1_ASKO adipocytes have increased adiponectin production and secretion independent of the known TRIB1 function of regulating proteasomal degradation. RNA-seq analysis of adipocytes and livers from Trib1_ASKO mice indicates that alterations in adipocyte function underlie the observed plasma lipid changes. Adipose tissue explant secretomics further reveals that Trib1_ASKO adipose tissue has decreased ANGPTL4 production, and we demonstrate an accompanying increase in the lipoprotein lipase (LPL) activity that likely underlies the triglyceride phenotype. This study shows that adipocyte Trib1 regulates multiple aspects of metabolic health, confirming previously observed genetic associations in humans and shedding light on the further mechanisms by which TRIB1 regulates plasma lipids and metabolic health. Mice deficient in adipocyte Trib1 have increased plasma adiponectin and decreased plasma cholesterol and triglycerides. Mice deficient in adipocyte Trib1 are protected from high-fat diet-induced insulin resistance. TRIB1 in adipose regulates adiponectin secretion independent of the proteasome. TRIB1-deficient adipose has reduced ANGPTL4 secretion and increased LPL activity. Targeting of adipocyte TRIB1 could be therapeutically beneficial in metabolic syndrome.
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影响因子：
4.8
作者：
Combs, TP;Pajvani, UB;Scherer, PE
通讯作者：
Scherer, PE
影响因子：
30.8
作者：
Deloukas, Panos;Kanoni, Stavroula;Willenborg, Christina;Farrall, Martin;Assimes, Themistocles L.;Thompson, John R.;Ingelsson, Erik;Saleheen, Danish;Erdmann, Jeanette;Goldstein, Benjamin A.;Stirrups, Kathleen;Koenig, Inke R.;Cazier, Jean-Baptiste;Johansson, Asa;Hall, Alistair S.;Lee, Jong-Young;Willer, Cristen J.;Chambers, John C.;Esko, Tonu;Folkersen, Lasse;Goel, Anuj;Grundberg, Elin;Havulinna, Aki S.;Ho, Weang K.;Hopewell, Jemma C.;Eriksson, Niclas;Kleber, Marcus E.;Kristiansson, Kati;Lundmark, Per;Lyytikainen, Leo-Pekka;Rafelt, Suzanne;Shungin, Dmitry;Strawbridge, Rona J.;Thorleifsson, Gudmar;Tikkanen, Emmi;Van Zuydam, Natalie;Voight, Benjamin F.;Waite, Lindsay L.;Zhang, Weihua;Ziegler, Andreas;Absher, Devin;Altshuler, David;Balmforth, Anthony J.;Barroso, Ines;Braund, Peter S.;Burgdorf, Christof;Claudi-Boehm, Simone;Cox, David;Dimitriou, Maria;Do, Ron;Doney, Alex S. F.;El Mokhtari, NourEddine;Eriksson, Per;Fischer, Krista;Fontanillas, Pierre;Franco-Cereceda, Anders;Gigante, Bruna;Groop, Leif;Gustafsson, Stefan;Hager, Joerg;Hallmans, Goran;Han, Bok-Ghee;Hunt, Sarah E.;Kang, Hyun M.;Illig, Thomas;Kessler, Thorsten;Knowles, Joshua W.;Kolovou, Genovefa;Kuusisto, Johanna;Langenberg, Claudia;Langford, Cordelia;Leander, Karin;Lokki, Marja-Liisa;Lundmark, Anders;McCarthy, Mark I.;Meisinger, Christa;Melander, Olle;Mihailov, Evelin;Maouche, Seraya;Morris, Andrew D.;Mueller-Nurasyid, Martina;Nikus, Kjell;Peden, John F.;Rayner, N. William;Rasheed, Asif;Rosinger, Silke;Rubin, Diana;Rumpf, Moritz P.;Schaefer, Arne;Sivananthan, Mohan;Song, Ci;Stewart, Alexandre F. R.;Tan, Sian-Tsung;Thorgeirsson, Gudmundur;van der Schoot, C. Ellen;Wagner, Peter J.;Wells, George A.;Wild, Philipp S.;Yang, Tsun-Po;Amouyel, Philippe;Arveiler, Dominique;Basart, Hanneke;Boehnke, Michael;Boerwinkle, Eric;Brambilla, Paolo;Cambien, Francois;Cupples, Adrienne L.;de Faire, Ulf;Dehghan, Abbas;Diemert, Patrick;Epstein, Stephen E.;Evans, Alun;Ferrario, Marco M.;Ferrieres, Jean;Gauguier, Dominique;Go, Alan S.;Goodall, Alison H.;Gudnason, Villi;Hazen, Stanley L.;Holm, Hilma;Iribarren, Carlos;Jang, Yangsoo;Kahonen, Mika;Kee, Frank;Kim, Hyo-Soo;Klopp, Norman;Koenig, Wolfgang;Kratzer, Wolfgang;Kuulasmaa, Kari;Laakso, Markku;Laaksonen, Reijo;Lee, Ji-Young;Lind, Lars;Ouwehand, Willem H.;Parish, Sarah;Park, Jeong E.;Pedersen, Nancy L.;Peters, Annette;Quertermous, Thomas;Rader, Daniel J.;Salomaa, Veikko;Schadt, Eric;Shah, Svati H.;Sinisalo, Juha;Stark, Klaus;Stefansson, Kari;Tregouet, David-Alexandre;Virtamo, Jarmo;Wallentin, Lars;Wareham, Nicholas;Zimmermann, Martina E.;Nieminen, Markku S.;Hengstenberg, Christian;Sandhu, Manjinder S.;Pastinen, Tomi;Syvanen, Ann-Christine;Hovingh, G. Kees;Dedoussis, George;Franks, Paul W.;Lehtimaki, Terho;Metspalu, Andres;Zalloua, Pierre A.;Siegbahn, Agneta;Schreiber, Stefan;Ripatti, Samuli;Blankenberg, Stefan S.;Perola, Markus;Clarke, Robert;Boehm, Bernhard O.;O'Donnell, Christopher;Reilly, Muredach P.;Maerz, Winfried;Collins, Rory;Kathiresan, Sekar;Hamsten, Anders;Kooner, Jaspal S.;Thorsteinsdottir, Unnur;Danesh, John;Palmer, Colin N. A.;Roberts, Robert;Watkins, Hugh;Schunkert, Heribert;Samani, Nilesh J.
通讯作者：
Samani, Nilesh J.
影响因子：
82.9
作者：
Berg, AH;Combs, TP;Scherer, PE
通讯作者：
Scherer, PE
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
6.5
作者：
Goldberg, Ira J.;Eckel, Robert H.;Abumrad, Nada A.
通讯作者：
Abumrad, Nada A.