E4orf1 induction in adipose tissue promotes insulin-independent signaling in the adipocyte.
E4orf1 induction in adipose tissue promotes insulin-independent signaling in the adipocyte.
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DOI：
10.1016/j.molmet.2015.07.004
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发表时间：
2015-10
影响因子：
8.1
通讯作者：
Scherer PE
中科院分区：
文献类型：
--
作者：
Kusminski CM;Gallardo-Montejano VI;Wang ZV;Hegde V;Bickel PE;Dhurandhar NV;Scherer PE
2型糖尿病仍然是一种世界性的流行病，由于慢性胰岛素抵抗，其主要的病理生理变化。胰岛素调节着许多与碳水化合物和脂肪代谢相关的生化途径。我们已经创造了一种新的小鼠模型，它允许我们以可诱导的方式结构性地激活胰岛素信号转导通路的远端分支，特别是在脂肪细胞中。使用腺病毒36E4orf1蛋白，我们在局部慢性刺激Ras-ERK-MAPK信号通路。在整个身体层面上，这会导致在高脂肪饮食挑战下体重增加减少。尽管葡萄糖耐量曲线重叠，但在这些条件下对胰岛素作用的需求减少了。小鼠的循环脂联素水平进一步降低，最终导致脂质清除受损，白色脂肪组织发炎和纤维化。然而，他们可以免受饮食引起的肝脏脂肪变性的影响。当我们观察到脂肪细胞中p-Akt水平的结构性升高时，即使在低胰岛素水平的条件下，这也准确地指出了转基因脂肪细胞中增强的Ras-ERK-MAPK信号是绕过近端胰岛素信号事件的潜在替代途径。我们的结论是，E4orf1在脂肪细胞中的表达导致远端胰岛素信号转导节点的基线激活增强，但在胰岛素存在的情况下削弱了胰岛素受体的刺激，这对脂联素的分泌调节具有重要意义。由此产生的全身性表型是复杂的，但强调了操纵脂肪细胞内胰岛素信号网络的选择性分支的强大本质。脂肪细胞中胰岛素途径远端分支的可诱导激活。糖耐量试验中的胰岛素节制特性。Ras-ERK-MAPK信号通路的慢性激活。在新陈代谢挑战中减轻体重。以牺牲脂肪代谢为代价来保存碳水化合物代谢。
Type 2 diabetes remains a worldwide epidemic with major pathophysiological changes as a result of chronic insulin resistance. Insulin regulates numerous biochemical pathways related to carbohydrate and lipid metabolism. We have generated a novel mouse model that allows us to constitutively activate, in an inducible fashion, the distal branch of the insulin signaling transduction pathway specifically in adipocytes. Using the adenoviral 36 E4orf1 protein, we chronically stimulate locally the Ras-ERK-MAPK signaling pathway. At the whole body level, this leads to reduced body-weight gain under a high fat diet challenge. Despite overlapping glucose tolerance curves, there is a reduced requirement for insulin action under these conditions. The mice further exhibit reduced circulating adiponectin levels that ultimately lead to impaired lipid clearance, and inflamed and fibrotic white adipose tissues. Nevertheless, they are protected from diet-induced hepatic steatosis. As we observe constitutively elevated p-Akt levels in the adipocytes, even under conditions of low insulin levels, this pinpoints enhanced Ras-ERK-MAPK signaling in transgenic adipocytes as a potential alternative route to bypass proximal insulin signaling events. We conclude that E4orf1 expression in the adipocyte leads to enhanced baseline activation of the distal insulin signaling node, yet impaired insulin receptor stimulation in the presence of insulin, with important implications for the regulation of adiponectin secretion. The resulting systemic phenotype is complex, yet highlights the powerful nature of manipulating selective branches of the insulin signaling network within the adipocyte. Inducible activation of the distal branch of the insulin pathway in adipocytes. Insulin-sparing characteristics during glucose tolerance testing. Chronic activation of the distal Ras-ERK-MAPK signaling pathway. Reduced body-weight during metabolic challenge. Preserved carbohydrate metabolism at the expense of lipid metabolism.