Autophagy Activity Is Up-Regulated in Adipose Tissue of Obese Individuals and Modulates Proinflammatory Cytokine Expression
Autophagy Activity Is Up-Regulated in Adipose Tissue of Obese Individuals and Modulates Proinflammatory Cytokine Expression
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DOI：
10.1210/en.2012-1625
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发表时间：
2012-12-01
期刊：
影响因子：
4.8
通讯作者：
Stienstra, R.
中科院分区：
文献类型：
--
作者：
Jansen, H. J.;van Essen, P.;Stienstra, R.
自噬是一种进化保守的过程，旨在回收细胞中受损的细胞器和蛋白质聚集体，也调节外周血单核细胞中促炎细胞因子的产生。由于脂肪组织炎症伴随促炎细胞因子水平升高是肥胖发展的特征，我们假设自噬的调节改变脂肪组织炎症基因的表达和分泌。我们使用人和小鼠脂肪组织的离体和体内研究来验证我们的假设。自噬标志物LC 3的水平在肥胖与瘦人受试者的皮下脂肪组织中升高，并且与全身性胰岛素抵抗和脂肪组织炎症的形态学特征正相关。类似地，与瘦小鼠相比，肥胖和胰岛素抵抗动物的脂肪组织中的自噬活性水平增加。在人类和小鼠脂肪组织外植体中，3-甲基丙氨酸抑制自噬导致IL-1 β、IL-6和IL-8 mRNA表达和蛋白分泌显著增加。值得注意的是，通过抑制自噬而增强IL-1 β、IL-6和角质形成细胞衍生的化学引诱物（KC）在肥胖的存在下更稳健。通过使用靶向ATG 7的小干扰RNA阻断人Al-Golabi-Behmel综合征脂肪细胞中的自噬获得了类似的结果。我们的研究结果表明，自噬活性在肥胖个体的脂肪组织中上调，并且自噬的抑制增强了脂肪细胞和脂肪组织外植体中的促炎基因表达。自噬可能起到抑制炎症基因表达的作用，从而限制肥胖期间脂肪组织中的过度炎症。（内分泌学153：5866-5874，2012）
Autophagy, an evolutionary conserved process aimed at recycling damaged organelles and protein aggregates in the cell, also modulates proinflammatory cytokine production in peripheral blood mononuclear cells. Because adipose tissue inflammation accompanied by elevated levels of proinflammatory cytokines is characteristic for the development of obesity, we hypothesized that modulation of autophagy alters adipose tissue inflammatory gene expression and secretion. We tested our hypothesis using ex vivo and in vivo studies of human and mouse adipose tissue. Levels of the autophagy marker LC3 were elevated in sc adipose tissue of obese vs. lean human subjects and positively correlated to both systemic insulin resistance and morphological characteristics of adipose tissue inflammation. Similarly, autophagic activity levels were increased in adipose tissue of obese and insulin resistant animals as compared with lean mice. Inhibition of autophagy by 3-methylalanine in human and mouse adipose tissue explants led to a significant increase in IL-1 beta, IL-6, and IL-8 mRNA expression and protein secretion. Noticeably, the enhancement in IL-1 beta, IL-6, and keratinocyte-derived chemoattractant (KC) by inhibition of autophagy was more robust in the presence of obesity. Similar results were obtained by blocking autophagy using small interfering RNA targeted to ATG7 in human Simpson-Golabi-Behmel syndrome adipocytes. Our results demonstrate that autophagy activity is up-regulated in the adipose tissue of obese individuals and inhibition of autophagy enhances proinflammatory gene expression both in adipocytes and adipose tissue explants. Autophagy may function to dampen inflammatory gene expression and thereby limit excessive inflammation in adipose tissue during obesity. (Endocrinology 153: 5866-5874, 2012)