Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea; Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea.
Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY, USA.
Mol Cell Endocrinol. 2019 Apr 15;486:96-104. doi: 10.1016/j.mce.2019.03.001. Epub 2019 Mar 7.
Severe inflammation in the islets is observed in obese patients with type 2 diabetes. Inflammation in the islets is caused by obesity-induced serum free fatty acids. Asprosin is a fasting-induced adipokine, which contributes to hepatic glucose production. However, the effects of asprosin on inflammation and cellular dysfunction in pancreatic β-cells remain to be elucidated. Here, we demonstrated that treatment of mouse insulinoma MIN6 cells and human primary islets containing β-cells with palmitate increased asprosin expression and secretion. Treatment of MIN6 cells and human primary islets with palmitate increased phosphorylation of the inflammatory marker nuclear factor-kappa B (NFκB) and the release of pro-inflammatory cytokines including TNF and MCP-1 and decreased glucose-stimulated insulin secretion and cell viability. However, siRNA-mediated suppression of asprosin reversed these changes. Recombinant asprosin treatment of MIN6 cells and human primary islets augmented the inflammation response, cellular dysfunction, and apoptosis in a dose-dependent manner. Asprosin induced toll-like receptor (TLR) 4 expression and JNK phosphorylation. siRNA for TLR4 or JNK mitigated the effects of asprosin on inflammation and cellular dysfunction. These results suggest that palmitate-derived asprosin secretion from β-cells results in their inflammation and dysfunction through a TLR4/JNK-mediated pathway. This report suggests asprosin as a novel therapeutic target for the treatment of type 2 diabetes through preservation of β-cell function.
肥胖的 2 型糖尿病患者的胰岛中观察到严重的炎症。胰岛炎症是由肥胖引起的血清游离脂肪酸引起的。Asprosin 是一种禁食诱导的脂肪因子，有助于肝葡萄糖生成。然而，Asprosin 对胰腺β细胞炎症和细胞功能障碍的影响仍有待阐明。在这里，我们证明棕榈酸处理小鼠胰岛素瘤 MIN6 细胞和含β细胞的人原代胰岛会增加 Asprosin 的表达和分泌。棕榈酸处理 MIN6 细胞和人原代胰岛会增加炎症标志物核因子-κB（NFκB）的磷酸化，并释放包括 TNF 和 MCP-1 在内的促炎细胞因子，同时降低葡萄糖刺激的胰岛素分泌和细胞活力。然而，Asprosin 的 siRNA 介导抑制逆转了这些变化。重组 Asprosin 处理 MIN6 细胞和人原代胰岛会以剂量依赖性方式增强炎症反应、细胞功能障碍和细胞凋亡。Asprosin 诱导 Toll 样受体（TLR）4 表达和 JNK 磷酸化。TLR4 或 JNK 的 siRNA 减轻了 Asprosin 对炎症和细胞功能障碍的影响。这些结果表明，β细胞中棕榈酸衍生的 Asprosin 分泌会通过 TLR4/JNK 介导的途径导致其炎症和功能障碍。本报告表明 Asprosin 可作为通过保留β细胞功能治疗 2 型糖尿病的新型治疗靶点。
