Division of Life and Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea.
Antioxid Redox Signal. 2012 Feb 1;16(3):229-43. doi: 10.1089/ars.2010.3766. Epub 2011 Oct 17.
Increased oxidative stress and mitochondrial dysfunction in obese adipocytes contribute to adipokine dysregulation, inflammation, and insulin resistance.
Through an advanced proteomic analysis, we found that peroxiredoxin 3 (Prx3), a thioredoxin-dependent mitochondrial peroxidase, is highly expressed in 3T3-L1 adipocytes compared to preadipocytes. Interestingly, in obese db/db mice and human subjects, adipose Prx3 levels were significantly decreased, indicating its association with obesity. We therefore employed Prx3 knockout (KO) mice and transfected 3T3-L1 cells to examine the role of endogenous Prx3 in adipocyte metabolism. Prx3 KO mice had increased fat mass compared to wild-type due to adipocyte hypertrophy. Increased adipogenic transcription factors and lipogenic gene expression during differentiation of adipose tissue-derived stem cells from Prx3-deficient mice confirmed that these adipocytes are likely to accumulate fat. Mitochondrial protein carbonylation in Prx3 KO adipose tissue and mitochondrial superoxide level in Prx3 knockdown 3T3-L1 cells were increased showing aberrant regulation of oxidative stress. Proteomic analysis and gene expression analysis of Prx3 KO mice adipocytes also showed defect in mitochondria biogenesis along with enzymes involved in glucose/lipid metabolism and oxidative phosphorylation. In addition, expression level of adiponectin was downregulated and plasminogen activator inhibitor-1 was upregulated in Prx3 KO adipocytes. Impaired glucose tolerance and insulin resistance further implied metabolic dysregulation in Prx3 KO mice.
These data suggest that endogenous Prx3 may play an essential role in maintaining normal characteristics of adipocytes and that defect in Prx3 alters mitochondrial redox state and function, and adipokine expression in adipocytes leading to metabolic alteration.
肥胖脂肪细胞中氧化应激和线粒体功能障碍的增加导致细胞因子失调、炎症和胰岛素抵抗。
通过先进的蛋白质组学分析，我们发现过氧化物酶 3（Prx3），一种依赖硫氧还蛋白的线粒体过氧化物酶，在 3T3-L1 脂肪细胞中的表达水平明显高于前脂肪细胞。有趣的是，在肥胖的 db/db 小鼠和人类受试者中，脂肪组织 Prx3 水平显著降低，表明其与肥胖有关。因此，我们使用 Prx3 敲除（KO）小鼠和转染的 3T3-L1 细胞来研究内源性 Prx3 在脂肪细胞代谢中的作用。与野生型相比，Prx3 KO 小鼠的脂肪量增加，这是由于脂肪细胞肥大。脂肪组织衍生的干细胞分化过程中脂肪生成转录因子和脂肪生成基因表达增加，证实这些脂肪细胞可能会积累脂肪。Prx3 KO 脂肪组织中线粒体蛋白羰基化和 Prx3 敲低 3T3-L1 细胞中线粒体超氧物水平增加，表明氧化应激的调节异常。Prx3 KO 小鼠脂肪细胞的蛋白质组学分析和基因表达分析还显示，线粒体生物发生以及参与糖/脂质代谢和氧化磷酸化的酶存在缺陷。此外，Prx3 KO 脂肪细胞中的脂联素表达下调，纤溶酶原激活物抑制剂-1 上调。葡萄糖耐量受损和胰岛素抵抗进一步表明 Prx3 KO 小鼠存在代谢紊乱。
这些数据表明，内源性 Prx3 可能在维持脂肪细胞正常特征方面发挥重要作用，而 Prx3 的缺陷会改变脂肪细胞中线粒体的氧化还原状态和功能，以及细胞因子的表达，从而导致代谢改变。
