CaMKIV limits metabolic damage through induction of hepatic autophagy by CREB in obese mice
CaMKIV limits metabolic damage through induction of hepatic autophagy by CREB in obese mice
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CaMKIV 通过 CREB 诱导肥胖小鼠肝自噬来限制代谢损伤
DOI：
10.1530/joe-19-0251
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发表时间：
2019
影响因子：
4
通讯作者：
Yan Geng
中科院分区：
文献类型：
--
作者：
Jiali Liu;Yue Li;Xiaoyan Zhou;Xi Zhang;Hao Meng;Sanyuan Liu;Lei Zhang;Juntao He;Qian He;Yan Geng
高脂饮食不仅可诱导肝脏胰岛素抵抗，还可引起自噬失衡和代谢紊乱，增加慢性炎症反应，诱导线粒体功能障碍。钙/钙调素依赖性蛋白激酶IV（CaMKIV）是近年来发现的一种重要的糖代谢和骨骼肌胰岛素作用的调节因子。它的激活参与了肝脏和脂肪胰岛素作用的改善。但其潜在机制尚未完全了解。在本研究中，我们的目的是解决直接影响的CaMKIV在体内和评估潜在的相互作用受损的胰岛素敏感性和自噬性疾病在肝胰岛素抵抗。我们的结果表明，与注射溶剂相比，接受CaMKIV的肥胖小鼠显示血糖和血清胰岛素降低，胰岛素敏感性改善，糖耐量增加。同时，注射CaMKIV也能有效缓解高脂饮食诱导的肝脏自噬活性缺陷、胰岛素信号传导受损、炎症反应增强和肝组织线粒体功能障碍。与这些结果相一致，添加CaMKIV到BNL cl.2肝细胞的培养基中显着恢复棕榈酸诱导的肝胰岛素抵抗和自噬失衡。这些影响被环磷酸腺苷反应元件结合蛋白（CREB）的阻断所抵消，表明CREB在CaMKIV作用中的致病作用。我们的研究结果表明，CaMKIV通过磷酸化CREB信号通路恢复肝脏自噬失衡，改善受损的胰岛素敏感性，这可能为肥胖和糖尿病的治疗提供新的机会。
High-fat diet (HFD) not only induces insulin resistance in liver, but also causes autophagic imbalance and metabolic disorders, increases chronic inflammatory response and induces mitochondrial dysfunction. Calcium/calmodulin-dependent protein kinase IV (CaMKIV) has recently emerged as an important regulator of glucose metabolism and skeletal muscle insulin action. Its activation has been involved in the improvement of hepatic and adipose insulin action. But the underlying mechanism is not fully understood. In the present study, we aimed to address the direct effects of CaMKIV in vivo and to evaluate the potential interaction of impaired insulin sensitivity and autophagic disorders in hepatic insulin resistance. Our results indicated obese mice receiving CaMKIV showed decreased blood glucose and serum insulin and improved insulin sensitivity as well as increased glucose tolerance compared with vehicle injection. Meanwhile, defective hepatic autophagy activity, impaired insulin signaling, increased inflammatory response and mitochondrial dysfunction in liver tissues which are induced by high-fat diet were also effectively alleviated by injection of CaMKIV. Consistent with these results, the addition of CaMKIV to the culture medium of BNL cl.2 hepatocytes markedly restored palmitate-induced hepatic insulin resistance and autophagic imbalance. These effects were nullified by blockade of cyclic AMP response element-binding protein (CREB), indicating the causative role of CREB in action of CaMKIV. Our findings suggested that CaMKIV restores hepatic autophagic imbalance and improves impaired insulin sensitivity via phosphorylated CREB signaling pathway, which may offer novel opportunities for treatment of obesity and diabetes.