Inducible Deletion of Protein Kinase Map4k4 in Obese Mice Improves Insulin Sensitivity in Liver and Adipose Tissues
Inducible Deletion of Protein Kinase Map4k4 in Obese Mice Improves Insulin Sensitivity in Liver and Adipose Tissues
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DOI：
10.1128/mcb.00150-15
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发表时间：
2015-07-01
影响因子：
5.3
通讯作者：
Czech, Michael P.
中科院分区：
文献类型：
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作者：
Danai, Laura V.;Flach, Rachel J. Roth;Czech, Michael P.
体外研究表明，丝裂原激活蛋白激酶激酶激酶 4 (Map4k4) 会减弱胰岛素信号传导，但缺乏体内证实，因为 Map4k4 敲除在胚胎发生过程中是致命的。因此，我们生成了具有 floxed Map4k4 等位基因和在泛素 C 启动子控制下的他莫昔芬诱导型 Cre/ERT2 重组酶的小鼠，以在这些动物成熟后诱导全身 Map4k4 缺失。对这些小鼠施用他莫昔芬会诱导所有检查组织中的 Map4k4 缺失，导致空腹血糖浓度降低，并增强脂肪组织和肝脏中 AKT 的胰岛素信号传导，但骨骼肌中则不然。然而，令人惊讶的是，脂联素阳性脂肪细胞或白蛋白阳性肝细胞中条件性 Map4k4 缺失产生的小鼠没有表现出可检测到的代谢表型。相反，在 Myf5 阳性组织（包括所有测试的骨骼肌）中删除 Map4k4 的小鼠，可以免受肥胖引起的葡萄糖不耐受和胰岛素抵抗。值得注意的是，这些小鼠的脂肪组织中的胰岛素敏感性也有所增加，但骨骼肌中的胰岛素敏感性却没有增加，这与在诱导性全身基因敲除小鼠中观察到的代谢表型类似。总而言之，这些结果表明（i）Map4k4 控制 Myf5 阳性细胞中抑制全身胰岛素敏感性的通路，（ii）Map4k4 是改善 2 型糖尿病的葡萄糖耐量和胰岛素敏感性的潜在治疗靶点。
Studies in vitro suggest that mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) attenuates insulin signaling, but confirmation in vivo is lacking since Map4k4 knockout is lethal during embryogenesis. We thus generated mice with floxed Map4k4 alleles and a tamoxifen-inducible Cre/ERT2 recombinase under the control of the ubiquitin C promoter to induce whole-body Map4k4 deletion after these animals reached maturity. Tamoxifen administration to these mice induced Map4k4 deletion in all tissues examined, causing decreased fasting blood glucose concentrations and enhanced insulin signaling to AKT in adipose tissue and liver but not in skeletal muscle. Surprisingly, however, mice generated with a conditional Map4k4 deletion in adiponectin-positive adipocytes or in albumin-positive hepatocytes displayed no detectable metabolic phenotypes. Instead, mice with Map4k4 deleted in Myf5-positive tissues, including all skeletal muscles tested, were protected from obesity-induced glucose intolerance and insulin resistance. Remarkably, these mice also showed increased insulin sensitivity in adipose tissue but not skeletal muscle, similar to the metabolic phenotypes observed in inducible whole-body knockout mice. Taken together, these results indicate that (i) Map4k4 controls a pathway in Myf5-positive cells that suppresses whole-body insulin sensitivity and (ii) Map4k4 is a potential therapeutic target for improving glucose tolerance and insulin sensitivity in type 2 diabetes.