Overexpression of glucose-6-phosphate dehydrogenase is associated with lipid dysregulation and insulin resistance in obesity
Overexpression of glucose-6-phosphate dehydrogenase is associated with lipid dysregulation and insulin resistance in obesity
复制标题
DOI：
10.1128/mcb.25.12.5146-5157.2005
复制
发表时间：
2005-06-01
影响因子：
5.3
通讯作者：
Kim, JB
中科院分区：
文献类型：
--
作者：
Park, J;Rho, HK;Kim, JB
葡萄糖-6-磷酸脱氢酶（G6 PD）产生细胞NADPH，这是生物合成脂肪酸和胆固醇所必需的。虽然G6 PD是脂肪生成所必需的，但脂肪细胞中的G6 PD是否参与能量稳态（如脂质和葡萄糖代谢）仍知之甚少。我们在此报告G6 PD在脂肪形成中起作用，并且其增加与肥胖症中脂质代谢和胰岛素抵抗的失调密切相关。我们观察到，在肥胖模型的白色脂肪组织中，包括dbldb、ob/ob和饮食诱导的肥胖小鼠，G6 PD的酶活性和表达水平显著升高。在3 T3-L1细胞中，G6 PD过表达刺激了大多数脂肪细胞标志物基因的表达，并提高了细胞游离脂肪酸、甘油三酯和FFA的释放水平。一致地，通过小干扰RNA敲低G6 PD减弱脂肪细胞分化，具有较少的脂滴积累。令人惊讶的是，某些脂肪细胞因子，如肿瘤坏死因子α和β-内酰胺酶的表达增加，而脂联素在G6 PD过表达的脂肪细胞中减少。根据这些结果，G6 PD的过度表达损害胰岛素信号传导并抑制脂肪细胞中的胰岛素非依赖性葡萄糖摄取。总之，这些数据强烈表明，在肥胖和/或糖尿病受试者中G6 PD的异常增加将改变脂质代谢和脂肪细胞因子表达，从而导致脂肪细胞中脂质稳态和胰岛素抵抗的失败。
Glucose-6-phosphate dehydrogenase (G6PD) produces cellular NADPH, which is required for the biosynthesis of fatty acids and cholesterol. Although G6PD is required for lipogenesis, it is poorly understood whether G6PD in adipocytes is involved in energy homeostasis, such as lipid and glucose metabolism. We report here that G6PD plays a role in adipogenesis and that its increase is tightly associated with the dysregulation of lipid metabolism and insulin resistance in obesity. We observed that the enzymatic activity and expression levels of G6PD were significantly elevated in white adipose tissues of obese models, including dbldb, ob/ob, and diet-induced obesity mice. In 3T3-L1 cells, G6PD overexpression stimulated the expression of most adipocyte marker genes and elevated the levels of cellular free fatty acids, triglyceride, and FFA release. Consistently, G6PD knockdown via small interfering RNA attenuated adipocyte differentiation with less lipid droplet accumulation. Surprisingly, the expression of certain adipocytokines such as tumor necrosis factor alpha and resistin was increased, whereas that of adiponectin was decreased in G6PD overexpressed adipocytes. In accordance with these results, overexpression of G6PD impaired insulin signaling and suppressed insulindependent glucose uptake in adipocytes. Taken together, these data strongly suggest that aberrant increase of G6PD in obese and/or diabetic subjects would alter lipid metabolism and adipocytokine expression, thereby resulting in failure of lipid homeostasis and insulin resistance in adipocytes.