Expression of Mfn2, the Charcot-Marie-Tooth neuropathy type 2A gene, in human skeletal muscle -: Effects of type 2 diabetes, obesity, weight loss, and the regulatory role of tumor necrosis factor α, and interleukin-6
Expression of Mfn2, the Charcot-Marie-Tooth neuropathy type 2A gene, in human skeletal muscle -: Effects of type 2 diabetes, obesity, weight loss, and the regulatory role of tumor necrosis factor α, and interleukin-6
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DOI：
10.2337/diabetes.54.9.2685
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发表时间：
2005-09-01
期刊：
影响因子：
7.7
通讯作者：
Zorzano, A
中科院分区：
文献类型：
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作者：
Bach, D;Naon, D;Zorzano, A
在Charcot-Marie-Tooth 2A型中突变的主要基因是丝裂原蛋白-2(Mfn2)。Mfn2编码一种线粒体蛋白，参与线粒体网络的维持，并调节线粒体代谢和细胞内信号转导。在体内调节人类Mfn2基因表达的可能性在很大程度上是未知的。基于胰岛素抵抗条件下线粒体功能障碍的存在，我们研究了肥胖或非肥胖2型糖尿病受试者骨骼肌中Mfn2的表达是否异常，肌肉Mfn2的表达是否受体重减轻的调节，以及肿瘤坏死因子(TNF)α或白介素6的潜在调节作用。我们发现男性和女性肥胖受试者骨骼肌中Mfn2的mRNA浓度都降低了。在消瘦或肥胖的2型糖尿病患者中，肌肉Mfn2的表达也减少。在非糖尿病组和2型糖尿病组中，Mfn2的表达与BMI呈显著负相关。在非糖尿病和2型糖尿病患者中，Mfn2的表达与胰岛素敏感性也呈正相关。为了确定体重减轻对Mfn2mRNA表达的影响，6名病态肥胖受试者接受了胆胰管转移术的体重减轻。肌肉Mfn2基因的平均表达在体重下降后增加了3倍，并再次检测到肌肉Mfn2的表达与胰岛素敏感性正相关。体外实验显示，肿瘤坏死因子α或白介素6对培养细胞的Mfn2表达有抑制作用。我们认为，体重减轻上调肥胖人群骨骼肌Mfn2的表达，2型糖尿病下调骨骼肌Mfn2的表达，Mfn2的表达与胰岛素敏感性成正比，与体重指数成反比，肿瘤坏死因子α和白介素6下调Mfn2的表达，可能参与肥胖或2型糖尿病患者Mfn2表达的失调，体内Mfn2基因水平的调节是肌肉代谢调控的额外水平，可能为肥胖或2型糖尿病患者线粒体功能的改变提供分子机制。
The primary gene mutated in Charcot-Marie-Tooth type 2A is mitofusin-2 (Mfn2). Mfn2 encodes a mitochondrial protein that participates in the maintenance of the mitochondrial network and that regulates mitochondrial metabolism and intracellular signaling. The potential for regulation of human Mfn2 gene expression in vivo is largely unknown. Based on the presence of mitochondrial dysfunction in insulin-resistant conditions, we have examined whether Mfn2 expression is dysregulated in skeletal muscle from obese or nonobese type 2 diabetic subjects, whether muscle Mfn2 expression is regulated by body weight loss, and the potential regulatory role of tumor necrosis factor (TNF)alpha or interleukin-6. We show that mRNA concentration of Mfn2 is decreased in skeletal muscle from both male and female obese subjects. Muscle Mfn2 expression was also reduced in lean or in obese type 2 diabetic patients. There was a strong negative correlation between the Mfn2 expression and the BMI in nondiabetic and type 2 diabetic subjects. A positive correlation between the Mfn2 expression and the insulin sensitivity was also detected in nondiabetic and type 2 diabetic subjects. To determine the effect of weight loss on Mfn2 mRNA expression, six morbidly obese subjects were subjected to weight loss by bilio-pancreatic diversion. Mean expression of muscle Mfn2 mRNA increased threefold after reduction in body weight, and a positive correlation between muscle Mfn2 expression and insulin sensitivity was again detected. In vitro experiments revealed an inhibitory effect of TNF alpha or interleukin-6 on Mfn2 expression in cultured cells. We conclude that body weight loss upregulates the expression of Mfn2 mRNA in skeletal muscle of obese humans, type 2 diabetes downregulates the expression of Mfn2 mRNA in skeletal muscle, Mfn2 expression in skeletal muscle is directly proportional to insulin sensitivity and is inversely proportional to the BMI, TNF alpha and interleukin-6 downregulate Mfn2 expression and may participate in the dysregulation of Mfn2 expression in obesity or type 2 diabetes, and the in vivo modulation of Mfn2 mRNA levels is an additional level of regulation for the control of muscle metabolism and could provide a molecular mechanism for alterations in mitochondrial function in obesity or type 2 diabetes.