p53-Induced Adipose Tissue Inflammation Is Critically Involved in the Development of Insulin Resistance in Heart Failure
p53-Induced Adipose Tissue Inflammation Is Critically Involved in the Development of Insulin Resistance in Heart Failure
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DOI：
10.1016/j.cmet.2011.12.006
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发表时间：
2012-01-04
期刊：
影响因子：
29
通讯作者：
Minamino, Tohru
中科院分区：
文献类型：
--
作者：
Shimizu, Ippei;Yoshida, Yohko;Minamino, Tohru
一些临床研究表明，胰岛素抵抗在心力衰竭患者中普遍存在，但其潜在机制尚未完全阐明。在这里，我们报告了与心力衰竭相关的胰岛素抵抗机制，涉及脂肪组织中p53的上调。我们发现，压力超负荷显着上调p53的表达在脂肪组织沿着脂肪组织炎症的增加。慢性压力超负荷加速脂肪分解。在压力超负荷的存在下，通过去交感神经抑制脂解显著下调脂肪p53表达和炎症，从而改善胰岛素抵抗。同样，破坏脂肪组织中的p53活化可减轻炎症并改善胰岛素抵抗，但也可改善慢性压力超负荷诱导的心功能障碍。这些结果表明，慢性压力超负荷通过促进经由交感神经系统的脂解上调脂肪组织p53，导致脂肪组织的炎症反应和胰岛素抵抗。
Several clinical studies have shown that insulin resistance is prevalent among patients with heart failure, but the underlying mechanisms have not been fully elucidated. Here, we report a mechanism of insulin resistance associated with heart failure that involves upregulation of p53 in adipose tissue. We found that pressure overload markedly upregulated p53 expression in adipose tissue along with an increase of adipose tissue inflammation. Chronic pressure overload accelerated lipolysis in adipose tissue. In the presence of pressure overload, inhibition of lipolysis by sympathetic denervation significantly downregulated adipose p53 expression and inflammation, thereby improving insulin resistance. Likewise, disruption of p53 activation in adipose tissue attenuated inflammation and improved insulin resistance but also ameliorated cardiac dysfunction induced by chronic pressure overload. These results indicate that chronic pressure overload upregulates adipose tissue p53 by promoting lipolysis via the sympathetic nervous system, leading to an inflammatory response of adipose tissue and insulin resistance.