A crucial role for adipose tissue p53 in the regulation of insulin resistance
A crucial role for adipose tissue p53 in the regulation of insulin resistance
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DOI：
10.1038/nm.2014
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发表时间：
2009-09-01
期刊：
影响因子：
82.9
通讯作者：
Komuro, Issei
中科院分区：
文献类型：
--
作者：
Minamino, Tohru;Orimo, Masayuki;Komuro, Issei
各种刺激，如端粒功能障碍和氧化应激，可以诱导不可逆的细胞生长停滞，这被称为“细胞衰老”（1，2）。这种反应由肿瘤抑制蛋白如p53和pRb控制。也有证据表明，衰老细胞促进与衰老或年龄相关疾病（3-6）的变化。在这里，我们表明，p53在脂肪组织中的表达是至关重要的参与胰岛素抵抗的发展，这是年龄相关的心血管和代谢紊乱的基础。我们发现，过量的热量摄入导致2型糖尿病样疾病小鼠脂肪组织中氧化应激的积累，并促进衰老样变化，如衰老相关β-半乳糖苷酶活性增加，p53表达增加和促炎细胞因子产生增加。抑制脂肪组织中的p53活性显著改善了这些衰老样变化，降低了促炎细胞因子的表达，改善了2型糖尿病样疾病小鼠的胰岛素抵抗。相反，脂肪组织中p53的上调引起炎症反应，导致胰岛素抵抗。糖尿病患者的脂肪组织也显示出衰老样特征。我们的研究结果显示了以前未被重视的作用，脂肪组织p53的表达在调节胰岛素抵抗，并建议在脂肪组织中的细胞衰老信号可能是一个新的目标，用于治疗糖尿病。
Various stimuli, such as telomere dysfunction and oxidative stress, can induce irreversible cell growth arrest, which is termed 'cellular senescence'(1,2). This response is controlled by tumor suppressor proteins such as p53 and pRb. There is also evidence that senescent cells promote changes related to aging or age-related diseases(3-6). Here we show that p53 expression in adipose tissue is crucially involved in the development of insulin resistance, which underlies age-related cardiovascular and metabolic disorders. We found that excessive calorie intake led to the accumulation of oxidative stress in the adipose tissue of mice with type 2 diabetes-like disease and promoted senescence-like changes, such as increased activity of senescence-associated beta-galactosidase, increased expression of p53 and increased production of proinflammatory cytokines. Inhibition of p53 activity in adipose tissue markedly ameliorated these senescence-like changes, decreased the expression of proinflammatory cytokines and improved insulin resistance in mice with type 2 diabetes-like disease. Conversely, upregulation of p53 in adipose tissue caused an inflammatory response that led to insulin resistance. Adipose tissue from individuals with diabetes also showed senescence-like features. Our results show a previously unappreciated role of adipose tissue p53 expression in the regulation of insulin resistance and suggest that cellular aging signals in adipose tissue could be a new target for the treatment of diabetes.