肿瘤坏死因子α诱导的骨骼肌胰岛素抵抗涉及AMP激酶信号传导的抑制。

Tumor necrosis factor alpha-induced skeletal muscle insulin resistance involves suppression of AMP-kinase signaling.

作者信息

Steinberg Gregory R, Michell Belinda J, van Denderen Bryce J W, Watt Matthew J, Carey Andrew L, Fam Barbara C, Andrikopoulos Sofianos, Proietto Joseph, Görgün Cem Z, Carling David, Hotamisligil Gökhan S, Febbraio Mark A, Kay Thomas W, Kemp Bruce E

机构信息

St Vincent's Institute and Department of Medicine, University of Melbourne, Fitzroy, Vic, 3065, Australia.

出版信息

Cell Metab. 2006 Dec;4(6):465-74. doi: 10.1016/j.cmet.2006.11.005.

DOI:10.1016/j.cmet.2006.11.005

PMID:17141630

Abstract

Elevated levels of tumor necrosis factor (TNFalpha) are implicated in the development of insulin resistance, but the mechanisms mediating these chronic effects are not completely understood. We demonstrate that TNFalpha signaling through TNF receptor (TNFR) 1 suppresses AMPK activity via transcriptional upregulation of protein phosphatase 2C (PP2C). This in turn reduces ACC phosphorylation, suppressing fatty-acid oxidation, increasing intramuscular diacylglycerol accumulation, and causing insulin resistance in skeletal muscle, effects observed both in vitro and in vivo. Importantly even at pathologically elevated levels of TNFalpha observed in obesity, the suppressive effects of TNFalpha on AMPK signaling are reversed in mice null for both TNFR1 and 2 or following treatment with a TNFalpha neutralizing antibody. Our data demonstrate that AMPK is an important TNFalpha signaling target and is a contributing factor to the suppression of fatty-acid oxidation and the development of lipid-induced insulin resistance in obesity.

摘要

肿瘤坏死因子（TNFα）水平升高与胰岛素抵抗的发生有关，但其介导这些慢性效应的机制尚未完全明确。我们发现，TNFα通过肿瘤坏死因子受体（TNFR）1发出的信号，通过转录上调蛋白磷酸酶2C（PP2C）来抑制AMPK活性。这反过来又减少了ACC磷酸化，抑制脂肪酸氧化，增加肌肉内二酰甘油积累，并导致骨骼肌胰岛素抵抗，这种效应在体外和体内均能观察到。重要的是，即使在肥胖中观察到的TNFα病理升高水平下，在TNFR1和TNFR2均缺失的小鼠中，或在用TNFα中和抗体治疗后，TNFα对AMPK信号的抑制作用会被逆转。我们的数据表明，AMPK是TNFα信号的一个重要靶点，并且是肥胖中脂肪酸氧化受抑制和脂质诱导的胰岛素抵抗发生的一个促成因素。