Adipose Triglyceride Lipase Deficiency Causes Tissue-specific Changes in Insulin Signaling
Adipose Triglyceride Lipase Deficiency Causes Tissue-specific Changes in Insulin Signaling
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DOI：
10.1074/jbc.m109.047787
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发表时间：
2009-10-30
影响因子：
4.8
通讯作者：
Kershaw, Erin E.
中科院分区：
文献类型：
--
作者：
Kienesberger, Petra C.;Lee, Daeho;Kershaw, Erin E.
三酰甘油在胰岛素靶组织中的蓄积与胰岛素抵抗相关。特别地，具有脂肪甘油三酯脂肪酶（ATGL）（三酰甘油水解中的限速酶）的全局靶向缺失的小鼠显示出改善的葡萄糖耐量和胰岛素敏感性，尽管三酰甘油在多个组织中积累。为了确定这种表型的分子机制，ATGL缺陷型（ATGL（-/-））和野生型小鼠注射盐水或胰岛素（10单位/kg，腹膜内），然后在胰岛素靶组织（肝脏、脂肪组织和肌肉）中确定关键胰岛素信号传导蛋白的磷酸化和活性。还在离体脂肪细胞和骨骼肌中评价了胰岛素信号传导和/或葡萄糖转运。在ATGL（-/-）小鼠中，胰岛素刺激的磷脂酰肌醇3-激酶和Akt活性以及IRS 1（Tyr（P）-612）和Akt（Ser（P）-473）关键残基的磷酸化在体内骨骼肌中增加。胰岛素刺激的磷脂酰肌醇3-激酶活性和总胰岛素受体和胰岛素受体底物1，但不是其他参数，也增加了在体内的白色脂肪组织。相反，在棕色脂肪组织和肝脏中，胰岛素信号传导的体内测量值降低。有趣的是，在体内骨骼肌和白色脂肪组织中鉴定的胰岛素信号传导增强组分及其对葡萄糖转运的预期下游效应在体外不存在。ATGL缺乏改变了肌细胞内脂质以及已知影响胰岛素敏感性的血清因子。因此，骨骼肌，而不是其他组织，主要有助于增强胰岛素敏感性的ATGL（-/-）小鼠在体内，尽管三酰甘油积累，和局部和全身因素有助于组织特异性影响的整体ATGL缺乏胰岛素的作用。
Triacylglycerol accumulation in insulin target tissues is associated with insulin resistance. Paradoxically, mice with global targeted deletion of adipose triglyceride lipase (ATGL), the rate-limiting enzyme in triacylglycerol hydrolysis, display improved glucose tolerance and insulin sensitivity despite triacylglycerol accumulation in multiple tissues. To determine the molecular mechanisms for this phenotype, ATGL-deficient (ATGL(-/-)) and wild-type mice were injected with saline or insulin (10 units/kg, intraperitoneally), and then phosphorylation and activities of key insulin-signaling proteins were determined in insulin target tissues (liver, adipose tissue, and muscle). Insulin signaling and/or glucose transport was also evaluated in isolated adipocytes and skeletal muscle ex vivo. In ATGL(-/-) mice, insulin-stimulated phosphatidylinositol 3-kinase and Akt activities as well as phosphorylation of critical residues of IRS1 (Tyr(P)-612) and Akt (Ser(P)-473) were increased in skeletal muscle in vivo. Insulin-stimulated phosphatidylinositol 3-kinase activity and total insulin receptor and insulin receptor substrate 1, but not other parameters, were also increased in white adipose tissue in vivo. In contrast, in vivo measures of insulin signaling were decreased in brown adipose tissue and liver. Interestingly, the enhanced components of insulin signaling identified in skeletal muscle and white adipose tissue in vivo and their expected downstream effects on glucose transport were not present ex vivo. ATGL deficiency altered intramyocellular lipids as well as serum factors known to influence insulin sensitivity. Thus, skeletal muscle, rather than other tissues, primarily contributes to enhanced insulin sensitivity in ATGL(-/-) mice in vivo despite triacylglycerol accumulation, and both local and systemic factors contribute to tissue-specific effects of global ATGL deficiency on insulin action.