Tumor necrosis factor-α stimulates lipolysis in differentiated human Adipocytes through activation of extracellular signal-related kinase and elevation of intracellular cAMP
Tumor necrosis factor-α stimulates lipolysis in differentiated human Adipocytes through activation of extracellular signal-related kinase and elevation of intracellular cAMP
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DOI：
10.2337/diabetes.51.10.2929
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发表时间：
2002-10-01
期刊：
影响因子：
7.7
通讯作者：
Greenberg, AS
中科院分区：
文献类型：
--
作者：
Zhang, HH;Halbleib, M;Greenberg, AS
肿瘤坏死因子- α (tnf - α)刺激人体脂肪细胞的脂肪分解。然而，调节这一过程的机制在很大程度上是未知的。我们证明，tnf - α通过激活丝裂原激活的蛋白激酶（MEK）、细胞外信号相关激酶（ERK）和细胞内cAMP的升高，增加了分化的人脂肪细胞的脂肪分解。tnf - α激活ERK，增加脂肪分解；两种特异性MEK抑制剂PD98059和U0126抑制了这些作用。tnf - α处理导致perilipin的电泳从65 kDa转移到67 kDa，这与激活camp依赖性蛋白激酶A （PKA）导致的perilipin过度磷酸化一致。与tnf - α和MEK抑制剂共孵育导致perilipin以单个65-kDa带迁移。与TNF-alpha通过激活PKA诱导periilipin过度磷酸化的假设一致，TNF-alpha使细胞内cAMP增加了约1.7倍，而PD98059则消除了这种增加。此外，H89是一种特异性的。PKA抑制剂阻断了tnf - α诱导的脂肪分解和perilippin的电泳转移，提示PKA在tnf - α诱导的脂肪分解中起作用。最后，tnf - α使环核苷酸磷酸二酯酶313 （PDE3B）的表达降低了近50%，揭示了tnf - α增加细胞内cAMP的机制。与PD98059共处理可恢复PDE3B的表达。这些研究表明，在人类脂肪细胞中，tnf - α通过激活MEK-ERK和随后增加细胞内cAMP来刺激脂肪分解。
Tumor necrosis factor-alpha (TNF-alpha) stimulates lipolysis in human adipocytes. However, the mechanisms regulating this process are largely unknown. We demonstrate that TNF-alpha increases lipolysis in differentiated human adipocytes by activation of mitogen-activated protein kinase kinase (MEK), extracellular signal-related kinase (ERK), and elevation of intracellular cAMP. TNF-alpha activated ERK and increased lipolysis; these effects were inhibited by two specific MEK inhibitors, PD98059 and U0126. TNF-alpha treatment caused an electrophoretic shift of perilipin from 65 to 67 kDa, consistent with perilipin hyperphosphorylation by activated cAMP-dependent protein kinase A (PKA). Coincubation with TNF-alpha and MEK inhibitors caused perilipin to migrate as a single 65-kDa band. Consistent with the hypothesis that TNF-alpha induces perilipin hyperphosphorylation by activating PKA, TNF-alpha increased intracellular cAMP similar to1.7-fold, and the increase was abrogated by PD98059. Furthermore, H89, a specific. PKA inhibitor, blocked TNF-alpha-induced lipolysis and the electrophoretic shift of perilipin, suggesting a role for PKA in TNF-alpha-induced lipolysis. finally, TNF-alpha decreased the expression of cyclic-nucleotide phosphodiesterase 313 (PDE3B) by similar to50%, delineating a mechanism by which TNF-alpha could increase intracellular cAMP. Cotreatment with PD98059 restored PDE3B expression. These studies suggest that in human adipocytes, TNF-alpha stimulates lipolysis through activation of MEK-ERK and subsequent increase in intracellular cAMP.