Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea.
Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, Republic of Korea.
J Cell Physiol. 2019 Nov;234(11):20888-20899. doi: 10.1002/jcp.28694. Epub 2019 Apr 17.
It has been reported that asprosin is a novel adipokine which is augmented in mice and humans with type 2 diabetes (T2DM). Asprosin stimulates hepatic gluconeogenesis under fasting conditions. However, the roles of asprosin in inflammation, endoplasmic reticulum (ER) stress, and insulin resistance in skeletal muscle has not been studied. In the currents study, elevated levels of asprosin expression were observed in adipocytes under hyperlipidemic conditions. Treatment of C2C12 myocytes with asprosin-induced ER stress markers (phosphorylated inositol-requiring enzyme 1 and eukaryotic initiation factor 2, and CHOP expression) as well as inflammation markers (interleukin-6 expression, phosphorylated IκB, and nuclear translocated nuclear factor-κβ). Finally, asprosin treatment promoted exacerbation of insulin sensitivity as determined by levels of insulin receptor substrate 1 and Akt phosphorylation as well as glucose uptake. Moreover, treatment of asprosin augmented protein kinase C-δ (PKCδ) phosphorylation and nuclear translocation, but suppressed messenger RNA expression of sarcoplasmic reticulum Ca ATPase 2b in both C2C12 myocytes and in mouse soleus skeletal muscle. These asprosin-induced effects were markedly decreased in small interfering (si) RNA-mediated PKCδ-knockdown in C2C12 myocytes. These results suggest that asprosin results in impairment of insulin sensitivity in skeletal muscle through PKCδ-associated ER stress/inflammation pathways and may be a valuable strategy for management of insulin resistance and T2DM.
有报道称，天冬酰胺酶是一种新型脂肪因子，在 2 型糖尿病（T2DM）的小鼠和人类中增加。天冬酰胺酶在禁食条件下刺激肝糖异生。然而，天冬酰胺酶在骨骼肌中的炎症、内质网（ER）应激和胰岛素抵抗中的作用尚未研究。在目前的研究中，在高脂血症条件下观察到脂肪细胞中天冬酰胺酶表达水平升高。用天冬酰胺酶处理 C2C12 肌母细胞可诱导 ER 应激标志物（磷酸化肌醇需求酶 1 和真核起始因子 2，以及 CHOP 表达）以及炎症标志物（白细胞介素-6 表达、磷酸化 IκB 和核易位核因子-κβ）。最后，天冬酰胺酶处理促进胰岛素受体底物 1 和 Akt 磷酸化以及葡萄糖摄取水平确定的胰岛素敏感性恶化。此外，天冬酰胺酶处理可增加蛋白激酶 C-δ（PKCδ）磷酸化和核易位，但抑制 C2C12 肌母细胞和小鼠比目鱼肌骨骼肌中肌浆网 Ca ATPase 2b 的信使 RNA 表达。在 C2C12 肌母细胞中，用小干扰（si）RNA 介导的 PKCδ 敲低显著降低了天冬酰胺酶诱导的这些作用。这些结果表明，天冬酰胺酶通过与 PKCδ 相关的 ER 应激/炎症途径导致骨骼肌胰岛素敏感性受损，可能是管理胰岛素抵抗和 T2DM 的有价值策略。
