Thiazolidinediones block fatty acid release by inducing glyceroneogenesis in fat cells
Thiazolidinediones block fatty acid release by inducing glyceroneogenesis in fat cells
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DOI：
10.1074/jbc.m206999200
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发表时间：
2003-05-23
影响因子：
4.8
通讯作者：
Antoine, B
中科院分区：
文献类型：
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作者：
Tordjman, J;Chauvet, G;Antoine, B
噻唑烷二酮类药物用于治疗2型糖尿病，因为它们能降低血糖、胰岛素、甘油三酯和脂肪酸水平。噻唑烷二酮类药物是过氧化物酶体增殖物激活受体的激动剂，这是一种在脂肪组织中高度表达的核受体。我们在培养的Wistar大鼠脂肪细胞和脂肪组织中发现了作为噻唑烷二酮靶点的甘油生成。噻唑烷二酮激活甘油生成主要发生在内脏脂肪中，内脏脂肪储存与肥胖发展为2型糖尿病有特殊关系。甘油生成的增加是诱导其关键酶磷酸烯醇丙酮酸羧激酶的结果，其基因表达在脂肪细胞中是过氧化物酶体增殖物激活受体γ依赖性的。这种代谢途径的主要作用是允许脂肪酸通过脂肪细胞中的无效循环进行再酯化，从而降低脂肪酸释放到血浆中。这种脂肪酸再酯化过程在脂质稳态控制中的重要性，通过涉及甘油激酶的第二噻唑烷二酮诱导途径的存在而得到强调。我们发现甘油生成至少占整个噻唑烷二酮效应的75%。由于血浆脂肪酸升高会促进胰岛素抵抗，这些结果表明噻唑烷二酮类药物的甘油生成依赖的脂肪酸降低作用可能是这些药物抗糖尿病作用的一个重要方面。
Thiazolidinediones are used to treat type 2 diabetes mellitus because they decrease plasma glucose, insulin, triglyceride, and fatty acid levels. Thiazolidinediones are agonists for peroxisome proliferator-activated receptor gamma, a nuclear receptor that is highly expressed in fat tissue. We identify glyceroneogenesis as a target of thiazolidinediones in cultured adipocytes and fat tissues of Wistar rats. The activation of glyceroneogenesis by thiazolidinediones occurs mainly in visceral fat, the same fat depot that is specifically implicated in the progression of obesity to type 2 diabetes. The increase in glyceroneogenesis is a result of the induction of its key enzyme, phosphoenolpyruvate carboxykinase, whose gene expression is peroxisome proliferator-activated receptor gamma-dependent in adipocytes. The main role of this metabolic pathway is to allow the re-esterification of fatty acids via a futile cycle in adipocytes, thus lowering fatty acid release into the plasma. The importance of such a fatty acid re-esterification process in the control of lipid homeostasis is highlighted by the existence of a second thiazolidinedione-induced pathway involving glycerol kinase. We show that glyceroneogenesis accounts for at least 75% of the whole thiazolidinedione effect. Because elevated plasma fatty acids promote insulin resistance, these results suggest that the glyceroneogenesis-dependent fatty acid-lowering effect of thiazolidinediones could be an essential aspect of the antidiabetic action of these drugs.