Choi Jungmi, Kobayashi Hatasu, Okuda Hiroko, Harada Kouji H, Takeda Midori, Fujimoto Hiroyuki, Yamane Shunsuke, Tanaka Daisuke, Youssefian Shohab, Inagaki Nobuya, Koizumi Akio
Department of Health and Environmental Science, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai, Japan.
PLoS One. 2018 Jan 5;13(1):e0190863. doi: 10.1371/journal.pone.0190863. eCollection 2018.
Adiponectin, a metabolically-active cytokine secreted from adipose tissue, is reported to have anti-apoptotic effects on β-cells as well as anti-hyperglycemic effects through adiponectin receptor signaling. However, the anti-apoptotic effects of adiponectin on β-cells have not been confirmed in established diabetic models, and the anti-hyperglycemic effects and their associated signal cascades remain controversial. To investigate the effects of adiponectin on β-cell protection and its down-stream signaling events, we have generated β-cell-specific rat insulin promoter (RIP)-AdipoR1 transgenic mice (AdipoR1 mice), in which the adiponectin receptor, AdipoR1, is overexpressed in β-cells in a manner synchronous with insulin demand. AdipoR1 mice were then mated with Akita mice, a diabetes model in which β-cell apoptosis results from endoplasmic reticulum (ER) stress. AdipoR1 protein expression and localization in islets from AdipoR1 mice as well as in an AdipoR1-transfected mouse insulinoma cell line were confirmed, as was the activation of both AMPK and Akt in AdipoR1 mice by adiponectin. Nevertheless, there were no significant differences in Ad lib feed and fasting blood glucose levels, or in glucose tolerance tests, between Akita mice [Ins2Akita (C96Y) +/- mouse model] and AdipoR1/Akita and from 4 weeks to 10 weeks of age. Similarly, pancreatic insulin contents of AdipoR1/Akita mice were not significantly different from those in Akita mice from 15 to 20 weeks of age, but they were significantly lower than in wild-type mice. Immunostaining for insulin and subsequent electron microscopy showed that β-cell destruction in AdipoR1/Akita mice was not markedly improved in comparison with that in Akita mice. Serum adiponectin concentrations were confirmed to be extremely high (> 30 μg / ml) compared with the Kd value (0.06 μg / ml) in all mouse groups at 15 to 20 weeks of age. Therefore, although the physiological levels of adiponectin are sufficient to activate AMPK and Akt when AdipoR1 is overexpressed in β-cells, yet adiponectin cannot protect β-cells in Akita mice from ER stress-induced destruction.
脂联素是一种由脂肪组织分泌的具有代谢活性的细胞因子，据报道它通过脂联素受体信号传导对β细胞具有抗凋亡作用以及降血糖作用。然而，在已建立的糖尿病模型中，脂联素对β细胞的抗凋亡作用尚未得到证实，其降血糖作用及其相关信号级联仍存在争议。为了研究脂联素对β细胞保护作用及其下游信号事件的影响，我们构建了β细胞特异性大鼠胰岛素启动子（RIP）-AdipoR1转基因小鼠（AdipoR1小鼠），其中脂联素受体AdipoR1在β细胞中以与胰岛素需求同步的方式过表达。然后将AdipoR1小鼠与秋田小鼠交配，秋田小鼠是一种糖尿病模型，其中β细胞凋亡是由内质网（ER）应激引起的。证实了AdipoR1小鼠胰岛以及AdipoR1转染的小鼠胰岛素瘤细胞系中AdipoR1蛋白的表达和定位，以及脂联素对AdipoR1小鼠中AMPK和Akt的激活作用。然而，在15至20周龄时，秋田小鼠[Ins2Akita（C96Y）+/-小鼠模型]与AdipoR1/秋田小鼠之间，在自由采食和空腹血糖水平以及葡萄糖耐量试验方面没有显著差异。同样，在15至20周龄时，AdipoR1/秋田小鼠的胰腺胰岛素含量与秋田小鼠相比没有显著差异，但显著低于野生型小鼠。胰岛素免疫染色及随后的电子显微镜检查显示，与秋田小鼠相比，AdipoR1/秋田小鼠的β细胞破坏没有明显改善。在15至20周龄时，所有小鼠组的血清脂联素浓度与Kd值（0.06μg/ml）相比均被证实极高（>30μg/ml）。因此，尽管当AdipoR1在β细胞中过表达时，脂联素的生理水平足以激活AMPK和Akt，但脂联素不能保护秋田小鼠的β细胞免受内质网应激诱导的破坏。
