Inactivation of class II PI3K-C2α induces leptin resistance, age-dependent insulin resistance and obesity in male mice.
Inactivation of class II PI3K-C2α induces leptin resistance, age-dependent insulin resistance and obesity in male mice.
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DOI：
10.1007/s00125-016-3963-y
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发表时间：
2016-07
期刊：
影响因子：
8.2
通讯作者：
Vanhaesebroeck B
中科院分区：
文献类型：
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作者：
Alliouachene S;Bilanges B;Chaussade C;Pearce W;Foukas LC;Scudamore CL;Moniz LS;Vanhaesebroeck B
虽然I类磷脂酰肌醇3-激酶(PI3K)是已知的正向代谢调节因子，但II类PI3K亚型(PI3K-C2α、-C2β和-C2γ)参与代谢调节的研究才刚刚起步。组织失活的PI3K-C2β增加了胰岛素信号和敏感性，而PI3K-C2γ的失活会对代谢产生负面影响。相比之下，PI3K-C2α在生物代谢中的作用尚不清楚。在这项研究中，我们研究了PI3K-C2α的激酶失活是否会影响小鼠的葡萄糖代谢。我们已经建立并鉴定了一个在编码PI3K-C2α(Pik3c2a)的基因的激活域发生结构性失活敲入(KI)突变的小鼠株系。虽然激酶死亡的PI3K-C2α的纯合子是胚胎致死的，但杂合子的PI3K-C2αKi小鼠是存活和可生育的，没有显著的组织病理学结果。然而，雄性杂合子小鼠表现出早期的瘦素抵抗，下丘脑的瘦素信号存在缺陷，与轻度、年龄相关性肥胖、胰岛素抵抗和葡萄糖耐量异常有关。在PI3K-C2αKi小鼠的胰岛素靶组织中，胰岛素信号不受影响，而以前的报道显示，PI3K-C2α的下调会抑制胰岛素信号。有趣的是，在任何年龄的雌性PI3K-C2αKi小鼠中都没有检测到代谢表型。我们的数据揭示了PI3K-C2α在调节下丘脑瘦素活动和全身葡萄糖稳态中的性别依赖性作用。所有试剂均可根据要求提供。这篇文章的在线版本(doi：10.1007/s00125-0163963-y)包含经同行审查但未经编辑的补充材料，授权用户可以使用。
While the class I phosphoinositide 3-kinases (PI3Ks) are well-documented positive regulators of metabolism, the involvement of class II PI3K isoforms (PI3K-C2α, -C2β and -C2γ) in metabolic regulation is just emerging. Organismal inactivation of PI3K-C2β increases insulin signalling and sensitivity, whereas PI3K-C2γ inactivation has a negative metabolic impact. In contrast, the role of PI3K-C2α in organismal metabolism remains unexplored. In this study, we investigated whether kinase inactivation of PI3K-C2α affects glucose metabolism in mice. We have generated and characterised a mouse line with a constitutive inactivating knock-in (KI) mutation in the kinase domain of the gene encoding PI3K-C2α (Pik3c2a). While homozygosity for kinase-dead PI3K-C2α was embryonic lethal, heterozygous PI3K-C2α KI mice were viable and fertile, with no significant histopathological findings. However, male heterozygous mice showed early onset leptin resistance, with a defect in leptin signalling in the hypothalamus, correlating with a mild, age-dependent obesity, insulin resistance and glucose intolerance. Insulin signalling was unaffected in insulin target tissues of PI3K-C2α KI mice, in contrast to previous reports in which downregulation of PI3K-C2α in cell lines was shown to dampen insulin signalling. Interestingly, no metabolic phenotypes were detected in female PI3K-C2α KI mice at any age. Our data uncover a sex-dependent role for PI3K-C2α in the modulation of hypothalamic leptin action and systemic glucose homeostasis. All reagents are available upon request. The online version of this article (doi:10.1007/s00125-016-3963-y) contains peer-reviewed but unedited supplementary material, which is available to authorised users.