Cellular and molecular mechanisms of adipose tissue plasticity in muscle insulin receptor knockout mice
Cellular and molecular mechanisms of adipose tissue plasticity in muscle insulin receptor knockout mice
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DOI：
10.1210/en.2003-0882
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发表时间：
2004-04-01
期刊：
影响因子：
4.8
通讯作者：
Mauvais-Jarvis, F
中科院分区：
文献类型：
--
作者：
Cariou, B;Postic, C;Mauvais-Jarvis, F
白色脂肪组织（WAT）通过分泌游离脂肪酸（FFA）和脂肪细胞因子在胰岛素抵抗的发展中发挥着关键作用。尽管脂肪和血浆 FFA 显着增加，但肌肉特异性胰岛素受体敲除 (MIRKO) 小鼠在生理条件下不会出现胰岛素抵抗或糖尿病。相反，MIRKO 的 WAT 在正常血糖钳夹期间对胰岛素作用敏感，并且 WAT 葡萄糖利用率显着增加。为了深入了解 MIRKO 肥胖症的潜在抗糖尿病作用，我们研究了正常血糖、高胰岛素钳夹过程中 WAT 中的胰岛素作用，并表征了 WAT 的形态和生物学特征。在钳夹过程中，MIRKO 的 WAT 中参与葡萄糖转运的胰岛素信号分子的表达或激活没有变化，通过磷酸肌醇 3-激酶/Akt 和 CAP/Cbl 途径。 WAT 质量增加 53%，是由于脂肪细胞数量增加 48%（P < 0.05），而细胞大小没有改变，同时脂肪形成转录因子 CCAAT 增强子结合蛋白-α (C/EBP-α) 的 mRNA 水平增加了 300%（P < 0.05）。血清脂联素增加了 39.5%（P < 0.01），而血清瘦素、抵抗素和 TNF-α 没有变化。总之，MIRKO 小鼠表现出肌肉胰岛素抵抗、内脏肥胖和血脂异常，但没有出现高胰岛素血症或糖尿病。小胰岛素敏感脂肪细胞的分化加速，胰岛素增敏剂脂联素的分泌增加，并维持瘦素敏感性。 MIRKO 小鼠证实了 WAT 可塑性在维持全身胰岛素敏感性中的重要性，并代表了寻找积极改变脂肪组织生物学的新分泌分子的有趣模型。
White adipose tissue (WAT) plays a critical role in the development of insulin resistance via secretion of free fatty acids (FFA) and adipocytokines. Muscle-specific insulin receptor knockout (MIRKO) mice do not develop insulin resistance or diabetes under physiological conditions despite a marked increase in adiposity and plasma FFA. On the contrary, WAT of MIRKO is sensitized to insulin action during a euglycemic clamp, and WAT glucose utilization is dramatically increased. To get insight into the potential antidiabetic role of MIRKO adiposity, we have studied insulin action in WAT during a euglycemic, hyperinsulinemic clamp, and we have characterized the morphology and biology of WAT. During the clamp, there is no alteration in the expression or activation in the insulin signaling molecules involved in glucose transport through the phosphoinositide 3-kinase/Akt and CAP/Cbl pathways in WAT from MIRKO. The 53% increase in WAT mass results from a 48% increase in adipocyte number (P < 0.05) without alteration in cell size and contemporary to a 300% increase in mRNA levels of the adipogenic transcription factor CCAAT enhancer binding protein-alpha (C/EBP-alpha) (P < 0.05). There is a 39.5% increase in serum adiponectin (P < 0.01) without modification in serum leptin, resistin, and TNF-alpha. In conclusion, the MIRKO mouse displays muscle insulin resistance, visceral obesity, and dyslipidemia but does not develop hyperinsulinemia or diabetes. There is an accelerated differentiation of small insulin sensitive adipocytes, an increased secretion of the insulin sensitizer adiponectin, and maintenance of leptin sensitivity. The MIRKO mouse confirms the importance of WAT plasticity in the maintenance of whole body insulin sensitivity and represents an interesting model to search for new secreted molecules that positively alter adipose tissue biology.