The pseudokinase MLKL regulates hepatic insulin sensitivity independently of inflammation.

Abstract

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.

• Authors: Haixia Xu, Xiao Du, Geng Liu, Shuang Huang, Wenya Du, Sailan Zou, Dongmei Tang, Chen Fan, Yongmei Xie, Yuquan Wei, Yan Tian, Xianghui Fu
• Journal: Molecular metabolism (Mol Metab) Vol. 23 Pg. 14-23 (05 2019) ISSN: 2212-8778 [Electronic] Germany
• PMID: 30837196 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 The Authors. Published by Elsevier GmbH.. All rights reserved.

Chemical References

• Imidazoles
• Indoles
• Phosphatidylinositol Phosphates
• necrostatin-1
• phosphatidylinositol 3,4,5-triphosphate
• MLKL protein, human
• MLKL protein, mouse
• Protein Kinases
• Receptor-Interacting Protein Serine-Threonine Kinases
• Ripk1 protein, mouse
• Ripk3 protein, mouse

Topics

• Animals
• Diabetes Mellitus, Experimental (chemically induced)
• Diabetes Mellitus, Type 2 (metabolism)
• Diet, High-Fat (adverse effects)
• Disease Models, Animal
• Female
• Gene Knockdown Techniques
• Hep G2 Cells
• Hepatitis, Animal (metabolism)
• Hepatocytes (metabolism)
• Humans
• Imidazoles (pharmacology)
• Indoles (pharmacology)
• Insulin Resistance (genetics)
• Liver (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Obesity (etiology, metabolism)
• Phosphatidylinositol Phosphates (metabolism)
• Protein Kinases (genetics, metabolism)
• Receptor-Interacting Protein Serine-Threonine Kinases (antagonists & inhibitors, genetics)
• Transfection