Overexpression of uncoupling protein 3 in skeletal muscle protects against fat-induced insulin resistance
Overexpression of uncoupling protein 3 in skeletal muscle protects against fat-induced insulin resistance
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DOI：
10.1172/jci13579
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发表时间：
2007-07-01
影响因子：
15.9
通讯作者：
Shulman, Gerald I.
中科院分区：
文献类型：
--
作者：
Choi, Cheol Soo;Fillmore, Jonathan J.;Shulman, Gerald I.
胰岛素抵抗是2型糖尿病发病机制的主要因素，并且与肥胖密切相关。据推测，细胞内脂肪酸代谢物浓度的增加会通过激活涉及骨骼肌中 PKC theta 的丝氨酸激酶级联来干扰胰岛素信号传导。解偶联蛋白 3 (UCP3) 被认为可以消除线粒体质子梯度并导致代谢效率低下。因此，我们假设骨骼肌中 UCP3 的过度表达可能通过将肌细胞内脂肪转化为热能来防止肌肉中脂肪诱导的胰岛素抵抗。喂食高脂肪饮食的野生型小鼠具有明显的胰岛素抵抗，这是由于骨骼肌中胰岛素刺激的葡萄糖摄取和肝脏胰岛素抵抗存在缺陷的结果。这些组织中的胰岛素抵抗分别与肌肉和肝脏中胰岛素刺激的胰岛素受体底物 1- (IRS-1-) 和 IRS-2 相关的 PI3K 活性降低有关。相比之下，UCP3过表达的小鼠在这些组织中完全免受脂肪诱导的胰岛素信号传导和作用缺陷的影响。此外，这些变化与二酰基甘油膜与细胞质的比率较低有关。并降低了全身脂肪匹配的 UCP3 转基因小鼠的 PKC theta 活性。这些结果表明，增加骨骼肌中的线粒体解偶联可能是 2 型糖尿病的绝佳治疗靶点。
Insulin resistance is a major factor in the pathogenesis of type 2 diabetes and is strongly associated with obesity. Increased concentrations of intracellular fatty acid metabolites have been postulated to interfere with insulin signaling by activation of a serine kinase cascade involving PKC theta in skeletal muscle. Uncoupling protein 3 (UCP3) has been postulated to dissipate the mitochondrial proton gradient and cause metabolic inefficiency. We therefore hypothesized that overexpression of UCP3 in skeletal muscle might protect against fat-induced insulin resistance in muscle by conversion of intramyocellular fat into thermal energy. Wild-type mice fed a high-fat diet were markedly insulin resistant, a result of defects in insulin-stimulated glucose uptake in skeletal muscle and hepatic insulin resistance. Insulin resistance in these tissues was associated with reduced insulin-stimulated insulin receptor substrate 1- (IRS-1-) and IRS-2-associated PI3K activity in muscle and liver, respectively. In contrast, UCP3-overexpressing mice were completely protected against fat-induced defects in insulin signaling and action in these tissues. Furthermore, these changes were associated with a lower membrane-to-cytosolic ratio of diacylglycerol. and reduced PKC theta activity in whole-body fat-matched UCP3 transgenic mice. These results suggest that increasing mitochondrial uncoupling in skeletal muscle may be an excellent therapeutic target for type 2 diabetes mellitus.