Systemic insulin sensitivity is regulated by GPS2 inhibition of AKT ubiquitination and activation in adipose tissue.
Systemic insulin sensitivity is regulated by GPS2 inhibition of AKT ubiquitination and activation in adipose tissue.
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DOI：
10.1016/j.molmet.2016.10.007
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发表时间：
2017-01
影响因子：
8.1
通讯作者：
Perissi V
中科院分区：
文献类型：
--
作者：
Cederquist CT;Lentucci C;Martinez-Calejman C;Hayashi V;Orofino J;Guertin D;Fried SK;Lee MJ;Cardamone MD;Perissi V
胰岛素信号在能量稳态的调节中起着独特的作用，胰岛素作用的受损与脂代谢改变、肥胖和2型糖尿病有关。这项研究的主要目的是通过研究非蛋白水解性泛素化在胰岛素介导的AKT激活中的作用，进一步深入了解胰岛素信号通路的调控机制。通过泛素化调节AKT的分子机制首先在体外解剖了3T3-L1前脂肪细胞，然后在体内使用脂肪特异性缺失UBC13活性的内源性抑制物GPS2的小鼠(GPS2-AKO小鼠)进行了验证。我们的结果表明，K63泛素化是胰岛素信号通路中AKT激活的关键组成部分，GPS2通过抑制UBC13酶活性来阻止AKT泛素化，从而对这一步骤进行反向调节。通过GPS2下调或基因缺失消除这个负检查点，导致胰岛素信号在体外和体内的持续激活。结果，脂肪积累和利用之间的平衡转向脂肪组织中的储存，在正常的实验室饮食下，GPS2-AKO小鼠变得肥胖。而GPS2-AKO小鼠脂肪组织未见炎症反应，循环脂联素水平升高，全身胰岛素敏感性总体改善。我们的发现描述了基于AKT的非蛋白水解性泛素化的胰岛素信号通路的一层新的调节层，并将GPS2定义为以前未被识别的胰岛素信号级联的组成部分。根据这一作用，我们已经证明，在禁食状态下，脂肪细胞中存在GPS2通过限制胰岛素信号的激活来调节全身代谢，而如果没有GPS2，脂肪组织储存脂肪的效率更高，肥胖症与炎症和胰岛素抵抗无关。UBC13介导的AKT泛素化是激活胰岛素信号通路所必需的。GPS2通过抑制AKT泛素化和激活来调节胰岛素信号转导。脂肪组织特异性的GPS2基因缺失会导致肥胖增加，改变脂肪细胞中的脂流量。GPS2-AKO小鼠的循环脂联素水平较高，尽管肥胖，但对胰岛素敏感。
Insulin signaling plays a unique role in the regulation of energy homeostasis and the impairment of insulin action is associated with altered lipid metabolism, obesity, and Type 2 Diabetes. The main aim of this study was to provide further insight into the regulatory mechanisms governing the insulin signaling pathway by investigating the role of non-proteolytic ubiquitination in insulin-mediated activation of AKT. The molecular mechanism of AKT regulation through ubiquitination is first dissected in vitro in 3T3-L1 preadipocytes and then validated in vivo using mice with adipo-specific deletion of GPS2, an endogenous inhibitor of Ubc13 activity (GPS2-AKO mice). Our results indicate that K63 ubiquitination is a critical component of AKT activation in the insulin signaling pathway and that counter-regulation of this step is provided by GPS2 preventing AKT ubiquitination through inhibition of Ubc13 enzymatic activity. Removal of this negative checkpoint, through GPS2 downregulation or genetic deletion, results in sustained activation of insulin signaling both in vitro and in vivo. As a result, the balance between lipid accumulation and utilization is shifted toward storage in the adipose tissue and GPS2-AKO mice become obese under normal laboratory chow diet. However, the adipose tissue of GPS2-AKO mice is not inflamed, the levels of circulating adiponectin are elevated, and systemic insulin sensitivity is overall improved. Our findings characterize a novel layer of regulation of the insulin signaling pathway based on non-proteolytic ubiquitination of AKT and define GPS2 as a previously unrecognized component of the insulin signaling cascade. In accordance with this role, we have shown that GPS2 presence in adipocytes modulates systemic metabolism by restricting the activation of insulin signaling during the fasted state, whereas in absence of GPS2, the adipose tissue is more efficient at lipid storage, and obesity becomes uncoupled from inflammation and insulin resistance. Ubc13-mediated ubiquitination of AKT is required for activation of the insulin signaling pathway. GPS2 regulates insulin signaling by inhibiting AKT ubiquitination and activation. Adipo-specific deletion of GPS2 results in increased adiposity and altered lipid flux in the adipocytes. GPS2-AKO mice have higher levels of circulating adiponectin and are insulin sensitive despite being obese.
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影响因子：
16
作者：
Cardamone, M. Dafne;Krones, Anna;Tanasa, Bogdan;Taylor, Havilah;Ricci, Laura;Ohgi, Kenneth A.;Glass, Christopher K.;Rosenfeld, Michael G.;Perissi, Valentina
通讯作者：
Perissi, Valentina
影响因子：
4.8
作者：
Guo, Chun;Li, Yali;Zhang, Jinsong
通讯作者：
Zhang, Jinsong
DOI：
10.1038/nri3071
发表时间：
2011-10-10
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1126/science.1210878
发表时间：
2011-10-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hussain K;Challis B;Rocha N;Payne F;Minic M;Thompson A;Daly A;Scott C;Harris J;Smillie BJ;Savage DB;Ramaswami U;De Lonlay P;O'Rahilly S;Barroso I;Semple RK
通讯作者：
Semple RK
影响因子：
29
作者：
Eguchi J;Wang X;Yu S;Kershaw EE;Chiu PC;Dushay J;Estall JL;Klein U;Maratos-Flier E;Rosen ED
通讯作者：
Rosen ED