Inositol Hexakisphosphate Kinase 3 Regulates Metabolism and Lifespan in Mice
Inositol Hexakisphosphate Kinase 3 Regulates Metabolism and Lifespan in Mice
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DOI：
10.1038/srep32072
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发表时间：
2016-08-31
影响因子：
4.6
通讯作者：
Tozawa, Ryuichi
中科院分区：
文献类型：
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作者：
Moritoh, Yusuke;Oka, Masahiro;Tozawa, Ryuichi
肌醇六磷酸激酶3（IP 6 K3）产生肌醇焦磷酸，其调节多种细胞功能。然而，人们对其自身的生理作用知之甚少。在这里，我们展示了IP 6 K3在代谢调节中的作用。我们在肌管和肌肉组织中检测到高水平的小鼠和人IP 6 K3 mRNA。在人肌管中，IP 6 K3通过地塞米松治疗上调，已知地塞米松抑制葡萄糖代谢。此外，Ip 6 k3表达升高糖尿病，禁食，废用条件下，小鼠骨骼肌。Ip 6 k3（-/-）小鼠表现出较低的血糖、减少的循环胰岛素、减少的脂肪量、较低的体重、增加的血浆乳酸、增强的葡萄糖耐量、在胰岛素耐量试验期间较低的葡萄糖以及在正常饮食条件下减少的肌肉Pdk 4表达。值得注意的是，Ip 6 k3缺失延长了动物的寿命，同时减少了心脏中S6核糖体蛋白的磷酸化。相反，Ip 6 k3（-/-）小鼠显示骨骼肌质量不变，对高脂饮食的影响没有抵抗力。目前的观察表明IP 6 K3在细胞调节中的新作用，影响代谢控制和寿命。
Inositol hexakisphosphate kinase 3 (IP6K3) generates inositol pyrophosphates, which regulate diverse cellular functions. However, little is known about its own physiological role. Here, we show the roles of IP6K3 in metabolic regulation. We detected high levels of both mouse and human IP6K3 mRNA in myotubes and muscle tissues. In human myotubes, IP6K3 was upregulated by dexamethasone treatment, which is known to inhibit glucose metabolism. Furthermore, Ip6k3 expression was elevated under diabetic, fasting, and disuse conditions in mouse skeletal muscles. Ip6k3(-/-) mice demonstrated lower blood glucose, reduced circulating insulin, deceased fat mass, lower body weight, increased plasma lactate, enhanced glucose tolerance, lower glucose during an insulin tolerance test, and reduced muscle Pdk4 expression under normal diet conditions. Notably, Ip6k3 deletion extended animal lifespan with concomitant reduced phosphorylation of S6 ribosomal protein in the heart. In contrast, Ip6k3(-/-) mice showed unchanged skeletal muscle mass and no resistance to the effects of high fat diet. The current observations suggest novel roles of IP6K3 in cellular regulation, which impact metabolic control and lifespan.