NAMPT-Mediated NAD(+) Biosynthesis in Adipocytes Regulates Adipose Tissue Function and Multi-organ Insulin Sensitivity in Mice.
NAMPT-Mediated NAD(+) Biosynthesis in Adipocytes Regulates Adipose Tissue Function and Multi-organ Insulin Sensitivity in Mice.
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DOI：
10.1016/j.celrep.2016.07.027
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发表时间：
2016-08-16
期刊：
影响因子：
8.8
通讯作者：
Yoshino J
中科院分区：
文献类型：
--
作者：
Stromsdorfer KL;Yamaguchi S;Yoon MJ;Moseley AC;Franczyk MP;Kelly SC;Qi N;Imai S;Yoshino J
肥胖与脂肪组织功能障碍和多器官胰岛素抵抗有关。然而，这种肥胖相关的全身代谢并发症的机制尚不清楚。在这里，我们的特点是小鼠脂肪细胞特异性缺失烟酰胺磷酸核糖转移酶（NAMPT），一种限速NAD+生物合成酶，已知减少肥胖和老年啮齿动物和人的脂肪组织。我们发现，脂肪细胞特异性Nampt基因敲除小鼠在脂肪组织、肝脏和骨骼肌中存在严重的胰岛素抵抗，脂肪组织功能障碍，表现为血浆游离脂肪酸浓度升高和主要胰岛素增敏脂肪因子脂联素血浆浓度降低。Nampt的缺失增加了CDK 5和PPARγ（丝氨酸-273）的磷酸化，并降低了脂肪组织中肥胖相关磷酸化PPARγ靶点的基因表达。值得注意的是，这些有害的改变通过给予罗格列酮或关键的NAD+中间体烟酰胺单核苷酸（NMN）而正常化。总的来说，我们的研究结果为肥胖相关的全身代谢紊乱，特别是多器官胰岛素抵抗提供了重要的机制和治疗见解。
Obesity is associated with adipose tissue dysfunction and multi-organ insulin resistance. However, the mechanisms of such obesity-associated systemic metabolic complications are not clear. Here, we characterized mice with adipocyte-specific deletion of nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting NAD+ biosynthetic enzyme known to decrease in adipose tissue of obese and aged rodents and people. We found that adipocyte-specific Nampt knockout mice had severe insulin resistance in adipose tissue, liver, and skeletal muscle, and adipose tissue dysfunction, manifested by increased plasma free fatty acids concentrations and decreased plasma concentrations of a major insulin-sensitizing adipokine, adiponectin. Loss of Nampt increased phosphorylation of CDK5 and PPARγ (serine-273) and decreased gene expression of obesity-linked phosphorylated PPARγ targets in adipose tissue. Remarkably, these deleterious alterations were normalized by administering rosiglitazone or a key NAD+ intermediate, nicotinamide mononucleotide (NMN). Collectively, our results provide important mechanistic and therapeutic insights into obesity-associated systemic metabolic derangements, particularly multi-organ insulin resistance.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.8
作者：
Banks, Alexander S.;McAllister, Fiona E.;Camporez, Joao Paulo G.;Zushin, Peter-James H.;Jurczak, Michael J.;Laznik-Bogoslavski, Dina;Shulman, Gerald I.;Gygi, Steven P.;Spiegelman, Bruce M.
通讯作者：
Spiegelman, Bruce M.
影响因子：
8.1
作者：
Mayoral R;Osborn O;McNelis J;Johnson AM;Oh DY;Izquierdo CL;Chung H;Li P;Traves PG;Bandyopadhyay G;Pessentheiner AR;Ofrecio JM;Cook JR;Qiang L;Accili D;Olefsky JM
通讯作者：
Olefsky JM
影响因子：
29
作者：
Chalkiadaki A;Guarente L
通讯作者：
Guarente L
DOI：
10.1126/science.1171641
发表时间：
2009-05-01
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Ramsey KM;Yoshino J;Brace CS;Abrassart D;Kobayashi Y;Marcheva B;Hong HK;Chong JL;Buhr ED;Lee C;Takahashi JS;Imai S;Bass J
通讯作者：
Bass J