Deficiency of phosphoinositide 3-kinase enhancer protects mice from diet-induced obesity and insulin resistance.
Deficiency of phosphoinositide 3-kinase enhancer protects mice from diet-induced obesity and insulin resistance.
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作者：
Chan CB;Liu X;Jung DY;Jun JY;Luo HR;Kim JK;Ye K
磷酸肌醇3-激酶增强子A（PIKE-A）是一种原癌基因，通过增强Akt活性促进肿瘤生长和转化。然而，PIKE-A在外周组织中的生理功能尚不清楚。在这里，我们描述了PIKE缺失在小鼠中的作用，并探讨了PIKE-A在肥胖发展中的作用。产生全身PIKE敲除小鼠并进行高脂肪饮食喂养20周。测定葡萄糖耐量、组织特异性胰岛素敏感性、脂肪细胞分化和脂质氧化状态。并探讨了PIKE在胰岛素信号通路中的分子机制。我们发现PIKE-A通过调节AMP激活蛋白激酶（AMPK）磷酸化来调节肥胖的发展。PIKE-A对于胰岛素抑制AMPK磷酸化是重要的。肥胖小鼠脂肪组织中PIKE-A的表达显著增加，而PIKE-A的缺失抑制脂肪细胞分化。PIKE基因敲除小鼠表现出脂肪萎缩的突出表型，并且对高脂饮食诱导的肥胖、肝脂肪变性和糖尿病具有抗性。PIKE敲除小鼠也具有增强的脂质氧化，其伴随着肌肉和脂肪组织中增强的AMPK磷酸化。此外，胰岛素敏感性在PIKE-A缺乏的肌肉和脂肪中得到改善，从而保护动物免受饮食诱导的糖尿病。我们的研究结果表明PIKE-A通过负调节AMPK活性参与肥胖和相关糖尿病的发展。
Phosphoinositide 3-kinase enhancer A (PIKE-A) is a proto-oncogene that promotes tumor growth and transformation by enhancing Akt activity. However, the physiological functions of PIKE-A in peripheral tissues are unknown. Here, we describe the effect of PIKE deletion in mice and explore the role of PIKE-A in obesity development. Whole-body PIKE knockout mice were generated and subjected to high-fat–diet feeding for 20 weeks. The glucose tolerance, tissue-specific insulin sensitivity, adipocyte differentiation, and lipid oxidation status were determined. The molecular mechanism of PIKE in the insulin signaling pathway was also studied. We show that PIKE-A regulates obesity development by modulating AMP-activated protein kinase (AMPK) phosphorylation. PIKE-A is important for insulin to suppress AMPK phosphorylation. The expression of PIKE-A is markedly increased in adipose tissue of obese mice, whereas depletion of PIKE-A inhibits adipocyte differentiation. PIKE knockout mice exhibit a prominent phenotype of lipoatrophy and are resistant to high-fat diet–induced obesity, liver steatosis, and diabetes. PIKE knockout mice also have augmented lipid oxidation, which is accompanied by enhanced AMPK phosphorylation in both muscle and adipose tissue. Moreover, insulin sensitivity is improved in PIKE-A–deficient muscle and fat, thus protecting the animals from diet-induced diabetes. Our results suggest that PIKE-A is implicated in obesity and associated diabetes development by negatively regulating AMPK activity.
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DOI：
10.1073/pnas.2536828100
发表时间：
2003-12-23
影响因子：
11.1
作者：
He, WM;Barak, Y;Evans, RM
通讯作者：
Evans, RM
影响因子：
16
作者：
Michael, MD;Kulkarni, RN;Kahn, CR
通讯作者：
Kahn, CR
DOI：
10.1073/pnas.0712306105
发表时间：
2008-05-27
影响因子：
11.1
作者：
Liu, Ren;Tian, Bo;Mao, Zixu
通讯作者：
Mao, Zixu
影响因子：
4.9
作者：
Kelly, T.;Yang, W.;He, J.
通讯作者：
He, J.
影响因子：
56.9
作者：
Cho, H;Mu, J;Birnbaum, MJ
通讯作者：
Birnbaum, MJ