Altered skeletal muscle lipase expression and activity contribute to insulin resistance in humans.
Altered skeletal muscle lipase expression and activity contribute to insulin resistance in humans.
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作者：
Badin PM;Louche K;Mairal A;Liebisch G;Schmitz G;Rustan AC;Smith SR;Langin D;Moro C
胰岛素抵抗与骨骼肌脂质含量升高相关，包括三酰甘油（TAG）和二酰甘油（DAG）。DAG是继脂肪甘油三酯脂肪酶（ATGL）水解TAG之后的脂解副产物，随后被脂肪酶敏感性脂肪酶（HSL）水解。我们假设ATGL相对于HSL（表达或活性）的不平衡可能导致DAG积累和胰岛素抵抗。我们首先测量脂肪酶的表达在股外侧肌活检的年轻瘦（n = 9），年轻肥胖（n = 9），肥胖匹配的2型糖尿病（n = 8）的主题。我们接下来在体外研究了人原代肌管中改变的脂肪酶表达/活性对脂质含量和胰岛素信号传导的影响。在我们的人群中，肌肉ATGL蛋白与全身胰岛素敏感性呈负相关（r =-0.55，P = 0.005），而肌肉HSL蛋白在肥胖受试者中减少。我们接下来显示腺病毒介导的ATGL在人原代肌管中的过表达诱导DAG和神经酰胺积累。ATGL过表达减少胰岛素刺激的糖原合成（-30%，P < 0.05），破坏胰岛素受体底物-1的Ser 1101处的胰岛素信号传导和Ser 473处的下游Akt活化。通过非选择性蛋白激酶C抑制或伴随的HSL过表达来恢复适当的脂解平衡，这些缺陷被完全挽救。我们发现，选择性HSL抑制诱导DAG积累和胰岛素抵抗。总之，数据表明骨骼肌中ATGL和HSL表达的改变可促进DAG积累并破坏胰岛素信号传导和作用。靶向骨骼肌脂肪酶可能是改善肥胖和2型糖尿病胰岛素敏感性的一个有趣的策略。
Insulin resistance is associated with elevated content of skeletal muscle lipids, including triacylglycerols (TAGs) and diacylglycerols (DAGs). DAGs are by-products of lipolysis consecutive to TAG hydrolysis by adipose triglyceride lipase (ATGL) and are subsequently hydrolyzed by hormone-sensitive lipase (HSL). We hypothesized that an imbalance of ATGL relative to HSL (expression or activity) may contribute to DAG accumulation and insulin resistance. We first measured lipase expression in vastus lateralis biopsies of young lean (n = 9), young obese (n = 9), and obese-matched type 2 diabetic (n = 8) subjects. We next investigated in vitro in human primary myotubes the impact of altered lipase expression/activity on lipid content and insulin signaling. Muscle ATGL protein was negatively associated with whole-body insulin sensitivity in our population (r = −0.55, P = 0.005), whereas muscle HSL protein was reduced in obese subjects. We next showed that adenovirus-mediated ATGL overexpression in human primary myotubes induced DAG and ceramide accumulation. ATGL overexpression reduced insulin-stimulated glycogen synthesis (−30%, P < 0.05) and disrupted insulin signaling at Ser1101 of the insulin receptor substrate-1 and downstream Akt activation at Ser473. These defects were fully rescued by nonselective protein kinase C inhibition or concomitant HSL overexpression to restore a proper lipolytic balance. We show that selective HSL inhibition induces DAG accumulation and insulin resistance. Altogether, the data indicate that altered ATGL and HSL expression in skeletal muscle could promote DAG accumulation and disrupt insulin signaling and action. Targeting skeletal muscle lipases may constitute an interesting strategy to improve insulin sensitivity in obesity and type 2 diabetes.
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影响因子：
8.2
作者：
Krssak, M;Petersen, KF;Roden, M
通讯作者：
Roden, M
影响因子：
7.7
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Bell, Ming;Wang, Hong;Chen, Hui;McLenithan, John C.;Gong, Da-Wei;Yang, Rong-Zee;Yu, Daozhan;Fried, Susan K.;Quon, Michael J.;Londos, Constantine;Sztalryd, Carole
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影响因子：
56.9
作者：
Haemmerle, G;Lass, A;Zechner, R
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9.8
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Itani, SI;Pories, WJ;Dohm, GL
通讯作者：
Dohm, GL
影响因子：
4.8
作者：
Haemmerle, G;Zimmermann, R;Zechner, R
通讯作者：
Zechner, R