PI3K-resistant GSK3 controls adiponectin formation and protects from metabolic syndrome
PI3K-resistant GSK3 controls adiponectin formation and protects from metabolic syndrome
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DOI：
10.1073/pnas.1601355113
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发表时间：
2016-05-17
影响因子：
11.1
通讯作者：
Foeller, Michael
中科院分区：
文献类型：
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作者：
Chen, Hong;Fajol, Abul;Foeller, Michael
代谢综合征以胰岛素抵抗、肥胖和血脂异常为特征。这是热量摄入和能量消耗不平衡的结果。脂联素可以预防代谢综合征。胰岛素诱导的信号传导包括PI3激酶和蛋白激酶B (PKB)/Akt的激活。PKB/Akt反过来使糖原合成酶激酶（GSK） 3失活，GSK 3是代谢的主要调节因子。在这里，我们研究了pi3k依赖性GSK3失活对饮食诱导代谢综合征中脂联素形成的意义。表达pi3k不敏感GSK3的小鼠(GSK3 (KI))和野生型小鼠(GSK3 (WT))被喂食高脂肪饲料。与gsk3（WT）小鼠相比，gsk3（KI）小鼠可显著降低体重增加、降低全身和肝脏脂肪积累、改善葡萄糖耐量、增强肝脏胰岛素依赖性PKB/Akt磷酸化、降低血清胰岛素、胆固醇和甘油三酯水平，以及提高能量消耗，从而防止代谢综合征的发生。gsk3（KI）小鼠血清脂联素浓度和控制脂肪组织中脂联素表达的转录因子C/EBP α活性显著高于gsk3（WT）小鼠。GSK3抑制剂锂可显著降低GSK3 （KI）小鼠血清脂联素浓度，消除基因型间C/EBP α活性差异。综上所述，我们的数据表明，pi3k不敏感的GSK3的表达刺激脂联素的产生，并保护免受饮食诱导的代谢综合征。
Metabolic syndrome is characterized by insulin resistance, obesity, and dyslipidemia. It is the consequence of an imbalance between caloric intake and energy consumption. Adiponectin protects against metabolic syndrome. Insulin-induced signaling includes activation of PI3 kinase and protein kinase B (PKB)/Akt. PKB/Akt in turn inactivates glycogen synthase kinase (GSK) 3, a major regulator of metabolism. Here, we studied the significance of PI3K-dependent GSK3 inactivation for adiponectin formation in diet-induced metabolic syndrome. Mice expressing PI3K-insensitive GSK3 (gsk3(KI)) and wild-type mice (gsk3(WT)) were fed a high-fat diet. Compared with gsk3(WT) mice, gsk3(KI) mice were protected against the development of metabolic syndrome as evident from a markedly lower weight gain, lower total body and liver fat accumulation, better glucose tolerance, stronger hepatic insulin-dependent PKB/Akt phosphorylation, lower serum insulin, cholesterol, and triglyceride levels, as well as higher energy expenditure. Serum adiponectin concentration and the activity of transcription factor C/EBP alpha controlling the expression of adiponectin in adipose tissue was significantly higher in gsk3(KI) mice than in gsk3(WT) mice. Treatment with GSK3 inhibitor lithium significantly decreased the serum adiponectin concentration of gsk3(KI) mice and abrogated the difference in C/EBP alpha activity between the genotypes. Taken together, our data demonstrate that the expression of PI3K-insensitive GSK3 stimulates the production of adiponectin and protects from diet-induced metabolic syndrome.