Adiponectin improves insulin sensitivity via activation of autophagic flux
Adiponectin improves insulin sensitivity via activation of autophagic flux
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DOI：
10.1530/jme-17-0096
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发表时间：
2017-11-01
影响因子：
3.5
通讯作者：
Sweeney, Gary
中科院分区：
文献类型：
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作者：
Ahlstrom, Penny;Rai, Esther;Sweeney, Gary
骨骼肌胰岛素抵抗在糖尿病的发病机制中起重要作用，内质网应激是其潜在的细胞机制之一。脂联素通过直接代谢作用和改善胰岛素敏感性来介导抗糖尿病作用，我们最近证实了脂联素在刺激自噬中的重要作用。然而，关于骨骼肌中自噬和内质网应激之间的串扰，特别是脂联素是如何调控它们的，人们知之甚少。在这里，我们利用高胰岛素/葡萄糖(HiHG)诱导的胰岛素抵抗模型，通过测量L6骨骼肌细胞Akt磷酸化(T308和S473)和葡萄糖摄取来确定。通过免疫印迹和串联荧光RFP/GFP-LC3免疫荧光(IF)检测，HiHG降低了自噬通量。HiHG还通过硫黄素T/KDEL IF、pIRE1、pPERK、peIF2α和ATF6 Western blotting以及GRP78-mCherry报告基因的诱导来诱导内质网应激。脂联素或雷帕霉素诱导的自噬减弱了高血糖诱导的内质网应激并改善了胰岛素敏感性。在ATG5显性负突变过表达所产生的自噬缺陷细胞中，脂联素没有改善胰岛素敏感性，从而验证了增强自噬的功能意义。总之，脂联素诱导的骨骼肌细胞自噬减轻了HIGH诱导的内质网应激和胰岛素抵抗。
Skeletal muscle insulin resistance is known to play an important role in the pathogenesis of diabetes, and one potential causative cellular mechanism is endoplasmic reticulum (ER) stress. Adiponectin mediates anti-diabetic effects via direct metabolic actions and by improving insulin sensitivity, and we recently demonstrated an important role in stimulation of autophagy by adiponectin. However, there is limited knowledge on crosstalk between autophagy and ER stress in skeletal muscle and in particular how they are regulated by adiponectin. Here, we utilized the model of high insulin/glucose (HIHG)-induced insulin resistance, determined by measuring Akt phosphorylation (T308 and S473) and glucose uptake in L6 skeletal muscle cells. HIHG reduced autophagic flux measured by LC3 and p62 Western blotting and tandem fluorescent RFP/GFP-LC3 immunofluorescence (IF). HIHG also induced ER stress assessed by thioflavin T/KDEL IF, pIRE1, pPERK, peIF2 alpha and ATF6 Western blotting and induction of a GRP78-mCherry reporter. Induction of autophagy by adiponectin or rapamycin attenuated HIHG-induced ER stress and improved insulin sensitivity. The functional significance of enhanced autophagy was validated by demonstrating a lack of improved insulin sensitivity in response to adiponectin in autophagy-deficient cells generated by overexpression of dominant negative mutant of Atg5. In summary, adiponectin-induced autophagy in skeletal muscle cells alleviated HIHG-induced ER stress and insulin resistance.