Adipocyte SIRT1 knockout promotes PPARγ activity, adipogenesis and insulin sensitivity in chronic-HFD and obesity.
Adipocyte SIRT1 knockout promotes PPARγ activity, adipogenesis and insulin sensitivity in chronic-HFD and obesity.
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DOI：
10.1016/j.molmet.2015.02.007
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发表时间：
2015-05
影响因子：
8.1
通讯作者：
Olefsky JM
中科院分区：
文献类型：
--
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
脂肪组织是脂质沉积的主要部位，在致肥胖饮食期间营养过剩的情况下保护生物体。组蛋白去乙酰化酶Sirtuin 1（SIRT 1）通过靶向转录因子过氧化物酶体增殖物激活受体γ（PPARγ）抑制脂肪细胞分化。为了评估SIRT 1在脂肪细胞中的特异性作用，我们产生了由aP 2启动子驱动到C57 BL/6背景上的Sirt 1脂肪细胞特异性敲除小鼠（ATKO）。Sirt 1flx/flxaP 2Cre+（ATKO）和Sirt 1flx/flxaP 2Cre-（WT）小鼠喂食高脂饮食5周（短期）或15周（长期）。代谢研究与脂肪组织中的基因表达分析和磷酸化/乙酰化模式相结合。在标准食物中，与对照喂养的小鼠相比，ATKO小鼠在脂肪组织中表现出低度慢性炎症，沿着葡萄糖耐受不良和胰岛素抗性。在短期HFD中，ATKO小鼠变得更加葡萄糖不耐受、高胰岛素血症、胰岛素抵抗并显示出增加的炎症。在慢性HFD期间，WT小鼠发展出比ATKO小鼠更高的代谢功能障碍，并且因此，敲除小鼠相对于对照小鼠更葡萄糖耐受、胰岛素敏感并且发炎更少。SIRT 1通过抑制PPARγ乙酰化减弱脂肪形成，在ATKO小鼠中，脂肪细胞PPARγ过度乙酰化。这种高乙酰化与Ser 273-PPARγ磷酸化的减少有关。去磷酸化的PPARγ具有组成性活性，并导致与胰岛素敏感性增加相关的基因的更高表达。总之，这些数据确定了脂肪组织中SIRT 1的下调在由PPARγ激活介导的长期炎症缓解中起着以前未知的作用。因此，在肥胖症的背景下，通过靶向SIRT 1激活PPARγ的新疗法的开发可能为T2 DM的治疗提供新的方法。SIRT 1在肥胖和慢性HFD中的双重作用A：PPARγ活性调节。虽然p300乙酰转移酶通过增加脂肪生成来增强PPARγ的转录激活特性，但SIRT 1脱乙酰酶和CDK 5激酶通过抑制PPARγ来促进脂解。肥胖和促炎信号通过一种机制导致pY 15-CDK 5增加，该机制涉及在细胞质中将p35蛋白裂解为p25，然后p25易位至细胞核，在细胞核中与CDK 5结合并激活它。B：SIRT 1和PPARγ参与脂肪细胞中不同靶基因的抑制/表达。丙：ATKO SIRT 1小鼠在长期HFD/肥胖中表现出胰岛素敏感表型，显示增生的eWAT而不是通常与炎症、肥胖和胰岛素抵抗相关的正常肥大脂肪组织。在ATKO eWAT中，这种作用通过增加PPAR活性、释放IL-10和FGF 21而得到加强，从而减少炎症并改善代谢状态。SIRT 1，sirtuin 1。过氧化物酶体增殖物激活受体γ。CDK 5，细胞周期蛋白依赖性激酶5。p300、Ep 300 E1 A结合蛋白。p35/p25，Cdk 5 r1细胞周期蛋白依赖性激酶5，调节亚基1（p35）。NcoR，核受体辅阻遏物1。SMRT，核受体辅阻遏物2。FGF 21，成纤维细胞生长因子21。FOXO 1，叉头箱O 1。C/EBPα、CCAAT/增强子结合蛋白α。TZD，噻唑烷二酮。AC，乙酰基残留。P，磷酸盐。AD，脂肪细胞Mφ-巨噬细胞。
Adipose tissue is the primary site for lipid deposition that protects the organisms in cases of nutrient excess during obesogenic diets. The histone deacetylase Sirtuin 1 (SIRT1) inhibits adipocyte differentiation by targeting the transcription factor peroxisome proliferator activated-receptor gamma (PPARγ). To assess the specific role of SIRT1 in adipocytes, we generated Sirt1 adipocyte-specific knockout mice (ATKO) driven by aP2 promoter onto C57BL/6 background. Sirt1flx/flxaP2Cre+ (ATKO) and Sirt1flx/flxaP2Cre- (WT) mice were fed high-fat diet for 5 weeks (short-term) or 15 weeks (chronic-term). Metabolic studies were combined with gene expression analysis and phosphorylation/acetylation patterns in adipose tissue. On standard chow, ATKO mice exhibit low-grade chronic inflammation in adipose tissue, along with glucose intolerance and insulin resistance compared with control fed mice. On short-term HFD, ATKO mice become more glucose intolerant, hyperinsulinemic, insulin resistant and display increased inflammation. During chronic HFD, WT mice developed a metabolic dysfunction, higher than ATKO mice, and thereby, knockout mice are more glucose tolerant, insulin sensitive and less inflamed relative to control mice. SIRT1 attenuates adipogenesis through PPARγ repressive acetylation and, in the ATKO mice adipocyte PPARγ was hyperacetylated. This high acetylation was associated with a decrease in Ser273-PPARγ phosphorylation. Dephosphorylated PPARγ is constitutively active and results in higher expression of genes associated with increased insulin sensitivity. Together, these data establish that SIRT1 downregulation in adipose tissue plays a previously unknown role in long-term inflammation resolution mediated by PPARγ activation. Therefore, in the context of obesity, the development of new therapeutics that activate PPARγ by targeting SIRT1 may provide novel approaches to the treatment of T2DM. Dual role of SIRT1 in obesity and chronic HFD. A: PPARγ activity regulation. While p300 acetyltransferase enhances the transcriptional activation properties of PPARγ by increasing lipogenesis, SIRT1 deacetylase and CDK5 kinase promotes lipolysis by inhibiting PPARγ. Obesity and pro-inflammatory signals lead to increase pY15-CDK5 via a mechanism involving the cleavage of the p35 protein to p25 in the cytoplasm, then p25 translocate to the nucleus, where it binds to CDK5 and activates it. B: Involvement of SIRT1 and PPARγ in repression/expression of different target genes in adipocytes. C: ATKO SIRT1 mice exhibit an insulin sensitive phenotype over long-term HFD/obesity, showing a hyperplasic eWAT rather than the normal hypertrophic adipose tissue often related with inflammation, obesity and insulin resistance. This effect is is strengthened in ATKO eWAT by increasing PPAR activity, releasing of IL-10 and FGF21, leading to a reduction in inflammation and improved metabolic status. SIRT1, sirtuin 1. PPARγ, peroxisome proliferator activated receptor gamma. CDK5, cyclin-dependent kinase 5. p300, Ep300 E1A binding protein. p35/p25, Cdk5r1 cyclin-dependent kinase 5, regulatory subunit 1 (p35). NcoR, nuclear receptor co-repressor 1. SMRT, nuclear receptor co-repressor 2. FGF21, fibroblast growth factor 21. FOXO1, forkhead box O1. C/EBPα, CCAAT/enhancer binding protein alpha. TZD, thiazolidinedione. AC, Acetyl residue. P, Phosphate. AD, adipocyte. Mφ-Macrophage.
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DOI：
10.1126/science.1231097
发表时间：
2013-03-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hubbard BP;Gomes AP;Dai H;Li J;Case AW;Considine T;Riera TV;Lee JE;E SY;Lamming DW;Pentelute BL;Schuman ER;Stevens LA;Ling AJ;Armour SM;Michan S;Zhao H;Jiang Y;Sweitzer SM;Blum CA;Disch JS;Ng PY;Howitz KT;Rolo AP;Hamuro Y;Moss J;Perni RB;Ellis JL;Vlasuk GP;Sinclair DA
通讯作者：
Sinclair DA
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
4.1
作者：
Froejdoe, Sara;Durand, Christine;Pirola, Luciano
通讯作者：
Pirola, Luciano
影响因子：
29
作者：
Chalkiadaki A;Guarente L
通讯作者：
Guarente L
影响因子：
7.7
作者：
Gillum MP;Kotas ME;Erion DM;Kursawe R;Chatterjee P;Nead KT;Muise ES;Hsiao JJ;Frederick DW;Yonemitsu S;Banks AS;Qiang L;Bhanot S;Olefsky JM;Sears DD;Caprio S;Shulman GI
通讯作者：
Shulman GI