Abstract
BackgroundRecently, CaMKIV has been identified as a potential regulator of skeletal muscle glucose metabolism, it can also affect insulin gene expression in pancreas. However, its effects on adipose insulin resistance have yet to be explored. Autophagy has been shown as a potential therapeutic target for ER (endoplasmic reticulum) stress and insulin resistance. The purpose of this study is to investigate the effects of CaMKIV on ER stress, autophagic function and insulin signaling in tunicamycin-treated adipocytes.MethodsIn this study, mature 3 T3-L1 adipocytes were treated with tunicamycin to induce ER stress. Tunicamycin-treated 3 T3-L1 adipocytes were treated with recombinant CaMKIV in the presence or absence of targeted-siRNA mediated down-regulation of CREB and mTOR. The ER stress markers, autophagy activation, mTOR/CREB signaling and insulin sensitivity were analyzed by western blotting or electron microscopy.ResultsTreatment with CaMKIV significantly reversed tunicamycin-induced expression of p-PERK, cleaved-ATF6, Atg7 and LC3II. It also reduced p62 expression. In addition, levels of p-Akt and p-IRS-1 were increased. Moreover, CaMKIV inhibited activated ER stress and insulin resistance in Atg7 siRNA transfected adipocytes. However, the protective effects of CaMKIV on ER stress, insulin signaling, and autophagy function were nullified by suppression of mTOR or CREB in tunicamycin-treated adipocytes.ConclusionThis study proves recombinant CaMKIV inhibits tunicamycin-induced ER stress and insulin resistance by regulating autophagy. The protective effect of CaMKIV in adipocytes is affected at least partly through mTOR/CREB signaling. Our finding may offer novel opportunities for treating obesity and type 2 diabetes.
Highlights
Calcium/calmodulin-dependent protein kinase IV (CaMKIV) has been identified as a potential regulator of skeletal muscle glucose metabolism, it can affect insulin gene expression in pancreas
Our results provided a reciprocal functional interaction among CaMKIV, Endoplasmic reticulum (ER) stress, autophagy and insulin signaling in Tun-treated adipocytes, indicating that CaMKIV regulated autophagy may function as an adaptive role in response to ER stress-induced insulin resistance
T3-L1 adipocytes To determine the effects of pharmacological ER stress on autophagic function, the mature 3 T3-L1 adipocytes were treated with various dose of Tun (0-5 μg/ml) for 4 h, the ER stress and autophagy markers were examined
Summary
CaMKIV has been identified as a potential regulator of skeletal muscle glucose metabolism, it can affect insulin gene expression in pancreas. Autophagy has been shown as a potential therapeutic target for ER (endoplasmic reticulum) stress and insulin resistance. The purpose of this study is to investigate the effects of CaMKIV on ER stress, autophagic function and insulin signaling in tunicamycin-treated adipocytes. Adipocytes and adipose tissue dysfunctions are believed to promote insulin resistance and lead to obesity [3, 4]. The expression of Atg in adipose tissue has a protective effect on insulin sensitivity in high-fat diet induced obesity, indicating autophagy activation contributes to the regulation of fat mass [7]. Autophagic dysfunction has been suggested a potential link to obesity and ER stress. Several strategies have been proposed to target ER stress as a therapeutic approach for pharmacological intervention in obesity and type 2 diabetes. Downregulation of autophagy could be beneficial for adipocytes under ER stress and insulin resistance
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