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

      review-article
      Author(s): ∗ ,
      Publication date (Electronic):
      Journal: Molecular Metabolism
      Publisher: Elsevier
      Keywords: Oxidative stress, Endoplasmic eeticulum stress, Autophagy, MAPK, Diabetes, Inflammation

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          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.

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          Most cited references86

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          ER stress-induced cell death mechanisms.

          Renata Sano, John C. Reed (2013)
          The endoplasmic-reticulum (ER) stress response constitutes a cellular process that is triggered by a variety of conditions that disturb folding of proteins in the ER. Eukaryotic cells have developed an evolutionarily conserved adaptive mechanism, the unfolded protein response (UPR), which aims to clear unfolded proteins and restore ER homeostasis. In cases where ER stress cannot be reversed, cellular functions deteriorate, often leading to cell death. Accumulating evidence implicates ER stress-induced cellular dysfunction and cell death as major contributors to many diseases, making modulators of ER stress pathways potentially attractive targets for therapeutics discovery. Here, we summarize recent advances in understanding the diversity of molecular mechanisms that govern ER stress signaling in health and disease. This article is part of a Special Section entitled: Cell Death Pathways. © 2013.
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            Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases.

            Hideaki Kamata, Shi-Ichi Honda, Shin Maeda … (2005)
            TNFalpha is a pleiotropic cytokine that induces either cell proliferation or cell death. Inhibition of NF-kappaB activation increases susceptibility to TNFalpha-induced death, concurrent with sustained JNK activation, an important contributor to the death response. Sustained JNK activation in NF-kappaB-deficient cells was suggested to depend on reactive oxygen species (ROS), but how ROS affect JNK activation was unclear. We now show that TNFalpha-induced ROS, whose accumulation is suppressed by mitochondrial superoxide dismutase, cause oxidation and inhibition of JNK-inactivating phosphatases by converting their catalytic cysteine to sulfenic acid. This results in sustained JNK activation, which is required for cytochrome c release and caspase 3 cleavage, as well as necrotic cell death. Treatment of cells or experimental animals with an antioxidant prevents H(2)O(2) accumulation, JNK phosphatase oxidation, sustained JNK activity, and both forms of cell death. Antioxidant treatment also prevents TNFalpha-mediated fulminant liver failure without affecting liver regeneration.
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              Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis.

              Congcong He, Michael C. Bassik, Viviana Moresi … (2012)
              Exercise has beneficial effects on human health, including protection against metabolic disorders such as diabetes. However, the cellular mechanisms underlying these effects are incompletely understood. The lysosomal degradation pathway, autophagy, is an intracellular recycling system that functions during basal conditions in organelle and protein quality control. During stress, increased levels of autophagy permit cells to adapt to changing nutritional and energy demands through protein catabolism. Moreover, in animal models, autophagy protects against diseases such as cancer, neurodegenerative disorders, infections, inflammatory diseases, ageing and insulin resistance. Here we show that acute exercise induces autophagy in skeletal and cardiac muscle of fed mice. To investigate the role of exercise-mediated autophagy in vivo, we generated mutant mice that show normal levels of basal autophagy but are deficient in stimulus (exercise- or starvation)-induced autophagy. These mice (termed BCL2 AAA mice) contain knock-in mutations in BCL2 phosphorylation sites (Thr69Ala, Ser70Ala and Ser84Ala) that prevent stimulus-induced disruption of the BCL2-beclin-1 complex and autophagy activation. BCL2 AAA mice show decreased endurance and altered glucose metabolism during acute exercise, as well as impaired chronic exercise-mediated protection against high-fat-diet-induced glucose intolerance. Thus, exercise induces autophagy, BCL2 is a crucial regulator of exercise- (and starvation)-induced autophagy in vivo, and autophagy induction may contribute to the beneficial metabolic effects of exercise.
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                Author and article information

                Contributors
                Giovanni Solinas
                Journal
                Journal ID (nlm-ta): Mol Metab
                Journal ID (iso-abbrev): Mol Metab
                Title: Molecular Metabolism
                Publisher: Elsevier
                ISSN (Electronic): 2212-8778
                Publication date PMC-release: 08 December 2016
                Publication date Collection: February 2017
                Publication date (Electronic): 08 December 2016
                Volume: 6
                Issue: 2
                Pages: 174-184
                Affiliations
                [1]The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, 41345 Gothenburg, Sweden
                Author notes
                [∗ ]Corresponding author. Giovanni.Solinas@ 123456wlab.gu.se
                Article
                Publisher ID: S2212-8778(16)30244-7
                DOI: 10.1016/j.molmet.2016.12.001
                PMC ID: 5279903
                PubMed ID: 28180059
                SO-VID: 966f8d01-fe76-4639-9065-85ca903999dd
                Copyright © © 2016 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 9 November 2016
                Date revision received : 28 November 2016
                Date accepted : 2 December 2016
                Categories
                Subject: Review

                Keywords: oxidative stress,endoplasmic eeticulum stress,autophagy,mapk,diabetes,inflammation
                Data availability:
                Keywords: oxidative stress, endoplasmic eeticulum stress, autophagy, mapk, diabetes, inflammation

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