Jin Dan, Sun Jun, Huang Jing, He Yiduo, Yu An, Yu Xiaoling, Yang Zaiqing
Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, PR China.
Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, PR China.
Cytokine. 2014 Oct;69(2):196-205. doi: 10.1016/j.cyto.2014.06.005. Epub 2014 Jul 1.
Tumor necrosis factor-α (TNF-α) is a multifunctional cytokine that acts as a mediator of obesity-linked insulin resistance (IR). It is commonly accepted that macrophage-derived TNF-α acts in a paracrine manner on adjacent adipocytes, induces lipolysis, which contributes to obesity-linked hyperglycemia. Several studies suggested that G0/G1 switch gene 2 (g0s2) was up-regulated during adipogenesis, and its protein could be degraded in response to TNF-α stimulation. The aim of the present work was to investigate the transcriptional regulation of g0s2 by TNF-α stimulation. In this study, 3T3-L1 pre-adipocytes were differentiated, and treated with TNF-α for 24h. The effects of TNF-α on lipolysis and lipase expression were then examined. Our results revealed that TNF-α exerted dose- and time-dependent lipolytic effects, which could be partially reversed by overexpression of g0s2 and peroxisome proliferator-activated receptor-γ (ppar-γ). In addition, TNF-α treatment significantly reduced the expression of adiponectin, ppar-γ, hormone-sensitive Lipase (hsl), adipose triglyceride lipase (atgl) as well as ATGL co-factors. Interestingly, TNF-α significantly decreased adiponectin and PPAR-γ protein levels, while treatment with the proteasomal inhibitor MG-132 maintained PPAR-γ levels. Degradation of PPAR-γ almost completely abolished the binding of PPAR-γ to the g0s2 promoter in adipocytes treated with TNF-α. We propose that proteasomal degradation of PPAR-γ and the reduction of g0s2 content are permissive for prolonged TNF-α induced lipolysis.
肿瘤坏死因子-α（TNF-α）是一种多功能细胞因子，作为肥胖相关胰岛素抵抗（IR）的介质。普遍认为，巨噬细胞衍生的TNF-α以旁分泌方式作用于相邻的脂肪细胞，诱导脂肪分解，这导致肥胖相关的高血糖症。多项研究表明，G0/G1开关基因2（g0s2）在脂肪生成过程中上调，其蛋白质可响应TNF-α刺激而降解。本研究的目的是探讨TNF-α刺激对g0s2的转录调控。在本研究中，将3T3-L1前脂肪细胞进行分化，并用TNF-α处理24小时。然后检测TNF-α对脂肪分解和脂肪酶表达的影响。我们的结果显示，TNF-α发挥剂量和时间依赖性的脂肪分解作用，过表达g0s2和过氧化物酶体增殖物激活受体-γ（ppar-γ）可部分逆转这种作用。此外，TNF-α处理显著降低了脂联素、ppar-γ、激素敏感性脂肪酶（hsl）、脂肪甘油三酯脂肪酶（atgl）以及ATGL辅因子的表达。有趣的是，TNF-α显著降低了脂联素和PPAR-γ蛋白水平，而蛋白酶体抑制剂MG-132处理可维持PPAR-γ水平。在用TNF-α处理的脂肪细胞中，PPAR-γ的降解几乎完全消除了PPAR-γ与g0s2启动子的结合。我们认为，PPAR-γ的蛋白酶体降解和g0s2含量的降低有利于TNF-α诱导的长期脂肪分解。
