Nieto-Vazquez Iria, Fernández-Veledo Sonia, Krämer David K, Vila-Bedmar Rocio, Garcia-Guerra Lucia, Lorenzo Margarita
Departamento de Bioquimica y Biologia Molecular II, Facultad de Farmacia, Universidad Complutense, Madrid, Spain.
Arch Physiol Biochem. 2008 Jul;114(3):183-94. doi: 10.1080/13813450802181047.
Adipose tissue secretes proteins which may influence insulin sensitivity. Among them, tumour necrosis factor (TNF)-alpha has been proposed as a link between obesity and insulin resistance because TNF-alpha is overexpressed in adipose tissue from obese animals and humans, and obese mice lacking either TNF-alpha or its receptor show protection against developing insulin resistance. The activation of proinflammatory pathways after exposure to TNF-alpha induces a state of insulin resistance in terms of glucose uptake in myocytes and adipocytes that impair insulin signalling at the level of the insulin receptor substrate (IRS) proteins. The mechanism found in brown adipocytes involves Ser phosphorylation of IRS-2 mediated by TNF-alpha activation of MAPKs. The Ser307 residue in IRS-1 has been identified as a site for the inhibitory effects of TNF-alpha in myotubes, with p38 mitogen-activated protein kinase (MAPK) and inhibitor kB kinase being involved in the phosphorylation of this residue. Moreover, up-regulation of protein-tyrosine phosphatase (PTP)1B expression was recently found in cells and animals treated with TNF-alpha. PTP1B acts as a physiological negative regulator of insulin signalling by dephosphorylating the phosphotyrosine residues of the insulin receptor and IRS-1, and PTP1B expression is increased in peripheral tissues from obese and diabetic humans and rodents. Accordingly, down-regulation of PTP1B activity by treatment with pharmacological agonists of nuclear receptors restores insulin sensitivity in the presence of TNF-alpha. Furthermore, mice and cells deficient in PTP1B are protected against insulin resistance induced by this cytokine. In conclusion, the absence or inhibition of PTP1B in insulin-target tissues could confer protection against insulin resistance induced by cytokines.
脂肪组织分泌的蛋白质可能会影响胰岛素敏感性。其中，肿瘤坏死因子（TNF）-α被认为是肥胖与胰岛素抵抗之间的联系纽带，因为TNF-α在肥胖动物和人类的脂肪组织中过度表达，而缺乏TNF-α或其受体的肥胖小鼠对胰岛素抵抗的发展具有保护作用。暴露于TNF-α后促炎途径的激活会在肌细胞和脂肪细胞的葡萄糖摄取方面诱导胰岛素抵抗状态，这会损害胰岛素受体底物（IRS）蛋白水平的胰岛素信号传导。在棕色脂肪细胞中发现的机制涉及TNF-α激活丝裂原活化蛋白激酶（MAPK）介导的IRS-2的丝氨酸磷酸化。IRS-1中的Ser307残基已被确定为TNF-α在肌管中产生抑制作用的位点，p38丝裂原活化蛋白激酶（MAPK）和IκB激酶参与该残基的磷酸化。此外，最近在用TNF-α处理的细胞和动物中发现蛋白酪氨酸磷酸酶（PTP）1B表达上调。PTP1B通过使胰岛素受体和IRS-1的磷酸酪氨酸残基去磷酸化而作为胰岛素信号传导的生理负调节因子，并且在肥胖和糖尿病的人类及啮齿动物的外周组织中PTP1B表达增加。因此，用核受体的药理激动剂处理下调PTP1B活性可在存在TNF-α的情况下恢复胰岛素敏感性。此外，缺乏PTP1B的小鼠和细胞对这种细胞因子诱导的胰岛素抵抗具有保护作用。总之，胰岛素靶组织中PTP1B的缺失或抑制可对细胞因子诱导的胰岛素抵抗提供保护。
