JNK at the crossroad of obesity, insulin resistance, and cell stress response

Abstract

Background: The cJun-N-terminal-kinase (JNK) plays a central role in the cell stress response, with outcomes ranging from cell death to cell proliferation and survival, depending on the specific context. JNK is also one of the most investigated signal transducers in obesity and insulin resistance, and studies have identified new molecular mechanisms linking obesity and insulin resistance. Emerging evidence indicates that whereas JNK1 and JNK2 isoforms promote the development of obesity and insulin resistance, JNK3 activity protects from excessive adiposity. Furthermore, current evidence indicates that JNK activity within specific cell types may, in specific stages of disease progression, promote cell tolerance to the stress associated with obesity and type-2 diabetes.

Scope of review: This review provides an overview of the current literature on the role of JNK in the progression from obesity to insulin resistance, NAFLD, type-2 diabetes, and diabetes complications.

Major conclusion: Whereas current evidence indicates that JNK1/2 inhibition may improve insulin sensitivity in obesity, the role of JNK in the progression from insulin resistance to diabetes, and its complications is largely unresolved. A better understanding of the role of JNK in the stress response to obesity and type-2 diabetes, and the development of isoform-specific inhibitors with specific tissue distribution will be necessary to exploit JNK as possible drug target for the treatment of type-2 diabetes.

Keywords: Autophagy; Diabetes; Endoplasmic eeticulum stress; Inflammation; MAPK; Oxidative stress.

Figure 1

Molecular mechanisms of JNK1 and JNK2 in obesity-driven insulin resistance. The JNK1/2 kinases were proposed to play a central role in obesity-driven insulin resistance by four mechanisms: (A) In insulin-target cells, JNK1/2 directly phosphorylate IRS1 and IRS2 at serine and threonine residues leading to reduced tyrosine-phosphorylation of IRS1/2 molecules and decreased recruitment of the PI3K-AKT signaling pathway in response to insulin. (B) JNK1/2 play a major role in obesity-driven macrophage activation, leading to increased levels of inflammatory “M1” cytokines driving insulin resistance. (C) During obesity JNK1/2 activity in pituitary thyrotropic cells sustains the expression of DIO2 leading to a T3-dependent reduction of TSH production. Reduced TSH level leads to low circulating levels of thyroid hormone, increased metabolic efficiency, and increased adiposity, which drives insulin resistance. (D) During obesity, JNK1/2 activity in the hepatocyte sustains the expression of the transcription co-repressor NCor1, which inhibits PPARα-driven gene-expression leading to reduced FGF21 production, reduced fatty acid oxidation, and ketogenesis, promoting fatty liver and insulin resistance.

Figure 2

A general model for JNK action in the cell stress response. The JNK kinases are activated in response to several cellular stressors and inflammatory mediators, and JNK activation can either promote cell death or survival depending on the specific context. An important variable in determining the outcome of JNK signaling is the length and intensity of its activation. Early-transient activation of JNK was linked to stress tolerance and survival, whereas intense and sustained JNK activation often correlates with cell death. JNK action on stress tolerance and proliferation depends on its activity on the transcription factors AP-1 and Foxo, whereas JNK promotes cell death by phosphorylating cytoplasmic proteins implicated in programmed cell death including Bid, Bim, and ITCH which controls cFlip stability. JNK was also shown to promote autophagy by phosphorylating Bcl-2, which causes the release of Beclin1. Autophagy is a process of lysosomal-mediated cellular self-digestion, which can promote stress tolerance by removing damaged organelles but, when excessive, can also lead to autophagic cell death.

Figure 3

JNK at the crossroad of obesity, insulin resistance, and the cell stress response. The role of JNK in obesity-driven insulin resistance was extensively investigated and the evidence indicates that JNK1 and JNK2 isoforms promote positive energy balance, adiposity, metabolic inflammation, and insulin resistance by the mechanisms described in Figure 1. However, JNK3 was reported to play an important homeostatic function in leptin control of food intake, and its inhibition is expected to increase food intake and aggravate adiposity and insulin resistance in obese subjects. The role of JNK in the β-cell failure occurring in type-2 diabetes and in the complications of obesity and type-2 diabetes was not investigated to the same extent as the role of JNK in insulin resistance. However, emerging evidence indicates that the action of JNK in loss of β-cell function, NAFLD progression, and diabetes complications may be more complex, with JNK activity driving disease promotion or being protective depending on the context. This dual action of JNK in the response to the metabolic stress associated to obesity and type-2 diabetes is reminiscent of the general role of JNK in cellular stress response described in Figure 2.