The pseudokinase MLKL regulates hepatic insulin sensitivity independently of inflammation

Haixia Xu, Xiao Du, Geng Liu, Shuang Huang, Wenya Du, Sailan Zou, Dongmei Tang, Chen Fan, Yongmei Xie, Yuquan Wei, Yan Tian, Xianghui Fu

Inflammation and cell death contribute to the development of type 2 diabetes (T2D). Necroptosis, a recently characterized necrosis integrated with the extrinsic apoptosis pathway, is widely viewed as a highly proinflammatory mode of cell death. The pseudokinase MLKL is a key protein in necroptosis. However, the involvement of necroptotic markers in insulin resistance and T2D remains unclear. Xu, Du, and colleagues show that the loss of MLKL in mice prevents obesity-induced insulin resistance and glucose intolerance. These findings reveal a role of MLKL in insulin sensitivity and suggest the potential involvement of necroptotic regulators in the physiopathology of T2D.

Objective: 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).

Methods: 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.

Results: 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.

Conclusions: These findings reveal MLKL as a regulator of insulin sensitivity and suggest necroptotic regulators might be potential therapeutic targets for insulin resistance and T2D.