Caveolin-3 knockout mice show increased adiposity and whole body insulin resistance, with ligand-induced insulin receptor instability in skeletal muscle
Caveolin-3 knockout mice show increased adiposity and whole body insulin resistance, with ligand-induced insulin receptor instability in skeletal muscle
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DOI：
10.1152/ajpcell.00489.2004
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发表时间：
2005-06-01
影响因子：
5.5
通讯作者：
Lisanti, MP
中科院分区：
文献类型：
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作者：
Capozza, F;Combs, TP;Lisanti, MP
Caveolin-3（Cav-3）主要在骨骼肌纤维中表达，在那里它驱动肌细胞质膜上的小窝形成。体外研究表明Cav-3可能在胰岛素信号传导和能量代谢中发挥积极作用。我们直接解决在体内代谢的后果，基因消融的Cav-3在小鼠中，因为它涉及到胰岛素的作用，葡萄糖代谢，和脂质稳态。在2月龄时，Cav-3缺失小鼠显著大于野生型小鼠，并显示显著的餐后高胰岛素血症、全身胰岛素抵抗和全身葡萄糖耐受不良。使用高胰岛素-正葡萄糖钳夹的研究显示，Cav-3缺失小鼠在胰岛素刺激的全身葡萄糖摄取和全身糖原合成方面分别表现出20%和40%的降低。全身胰岛素抵抗主要归因于Cav-3基因敲除小鼠骨骼肌中胰岛素刺激的葡萄糖摄取和葡萄糖代谢通量降低20%和40%。此外，胰岛素介导的肝葡萄糖生成抑制在Cav-3敲除小鼠中显著降低，表明肝胰岛素抵抗。在不表达Cav-3的白色脂肪组织中，胰岛素刺激的葡萄糖摄取在Cav-3缺失小鼠中降低了约70%，表明该组织处于胰岛素抵抗状态。在禁食期间，Cav-3缺失小鼠在其骨骼肌中具有正常的胰岛素受体蛋白水平。然而，在15分钟的急性胰岛素刺激后，与相同处理的野生型小鼠相比，Cav-3缺失小鼠显示出胰岛素受体蛋白水平的显著降低。这些结果表明，Cav-3通常用于增加质膜上胰岛素受体的稳定性，防止其快速降解，即，通过阻断或减缓配体诱导的受体下调。因此，我们的研究结果表明Cav-3在体内调节全身葡萄糖稳态的重要性及其在胰岛素抵抗发展中的可能作用。这些发现可能对小窝病的早期诊断和治疗具有临床意义。
Caveolin-3 (Cav-3) is expressed predominantly in skeletal muscle fibers, where it drives caveolae formation at the muscle cell's plasma membrane. In vitro studies have suggested that Cav-3 may play a positive role in insulin signaling and energy metabolism. We directly address the in vivo metabolic consequences of genetic ablation of Cav-3 in mice as it relates to insulin action, glucose metabolism, and lipid homeostasis. At age 2 mo, Cav-3 null mice are significantly larger than wild-type mice, and display significant postprandial hyperinsulinemia, whole body insulin resistance, and whole body glucose intolerance. Studies using hyperinsulinemiceuglycemic clamps revealed that Cav-3 null mice exhibited 20% and 40% decreases in insulin-stimulated whole body glucose uptake and whole body glycogen synthesis, respectively. Whole body insulin resistance was mostly attributed to 20% and 40% decreases in insulin-stimulated glucose uptake and glucose metabolic flux in the skeletal muscle of Cav-3 null mice. In addition, insulin-mediated suppression of hepatic glucose production was significantly reduced in Cav-3 null mice, indicating hepatic insulin resistance. Insulin-stimulated glucose uptake in white adipose tissue, which does not express Cav-3, was decreased by similar to 70% in Cav-3 null mice, suggestive of an insulin-resistant state for this tissue. During fasting, Cav-3 null mice possess normal insulin receptor protein levels in their skeletal muscle. However, after 15 min of acute insulin stimulation, Cav-3 null mice show dramatically reduced levels of the insulin receptor protein, compared with wild-type mice treated identically. These results suggest that Cav-3 normally functions to increase the stability of the insulin receptor at the plasma membrane, preventing its rapid degradation, i.e., by blocking or slowing ligand-induced receptor downregulation. Thus our results demonstrate the importance of Cav-3 in regulating whole body glucose homeostasis in vivo and its possible role in the development of insulin resistance. These findings may have clinical implications for the early diagnosis and treatment of caveolinopathies.