Division of Endocrinology and Metabolism, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, Sichuan, China.
Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu 610041, Sichuan, China.
Mol Metab. 2019 May;23:14-23. doi: 10.1016/j.molmet.2019.02.003. Epub 2019 Feb 20.
The mixed lineage kinase domain like (MLKL) protein, receptor interacting protein (RIPK) 1, and RIPK3 are key regulators of necroptosis, a highly pro-inflammatory mode of cell death that has been implicated in various pathological processes and human diseases. However, the role of these necroptotic regulators in diabetes remains unknown. Here we sought to delineate the role of MLKL in insulin resistance and type 2 diabetes (T2D).
We first analyzed the expression of key necroptotic regulators in obese/diabetic mouse models. We then utilized MLKL knockout (MLKL) mice to evaluate the effects of MLKL on obesity-induced metabolic complications. We further determined the consequences of MLKL inhibition on hepatic insulin signaling and explored the underlying mechanism. Finally, we assessed the potential therapeutic effects of necroptotic inhibitor, necrostatin-1 (Nec-1), in ob/ob mice.
In wild-type or obese mice (ob/ob, db/db, or diet-induced obesity), MLKL was increased in certain obesity-associated tissues, particularly in the liver. Whole-body deficiency of MLKL prevented obesity-induced insulin resistance and glucose intolerance. Inhibition of MLKL or other key necroptotic regulators enhanced hepatic insulin sensitivity. MLKL modulated insulin-stimulated PI(3,4,5)P3 production in liver cells but did not affect the expression of inflammatory genes in vitro and in vivo. Nec-1 administration ameliorated insulin resistance and glucose intolerance in ob/ob mice.
These findings reveal MLKL as a regulator of insulin sensitivity and suggest necroptotic regulators might be potential therapeutic targets for insulin resistance and T2D.
混合谱系激酶结构域样（MLKL）蛋白、受体相互作用蛋白（RIPK）1 和 RIPK3 是细胞程序性坏死（necroptosis）的关键调节因子，细胞程序性坏死是一种高度促炎的细胞死亡方式，与各种病理过程和人类疾病有关。然而，这些程序性坏死调节因子在糖尿病中的作用尚不清楚。本研究旨在阐明 MLKL 在胰岛素抵抗和 2 型糖尿病（T2D）中的作用。
我们首先分析了肥胖/糖尿病小鼠模型中关键程序性坏死调节因子的表达。然后，我们利用 MLKL 敲除（MLKL）小鼠评估 MLKL 对肥胖引起的代谢并发症的影响。我们进一步确定了 MLKL 抑制对肝胰岛素信号的影响，并探讨了潜在的机制。最后，我们评估了坏死抑制剂 necrostatin-1（Nec-1）在 ob/ob 小鼠中的潜在治疗效果。
在野生型或肥胖小鼠（ob/ob、db/db 或饮食诱导的肥胖）中，MLKL 在某些与肥胖相关的组织中增加，特别是在肝脏中。全身性缺乏 MLKL 可预防肥胖引起的胰岛素抵抗和葡萄糖不耐受。抑制 MLKL 或其他关键程序性坏死调节因子可增强肝胰岛素敏感性。MLKL 调节肝细胞中胰岛素刺激的 PI(3,4,5)P3 产生，但不影响体外和体内炎症基因的表达。Nec-1 给药可改善 ob/ob 小鼠的胰岛素抵抗和葡萄糖不耐受。
这些发现表明 MLKL 是胰岛素敏感性的调节因子，并提示程序性坏死调节因子可能是胰岛素抵抗和 T2D 的潜在治疗靶点。
