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The role of stress kinases in metabolic disease

Nature Reviews Endocrinology volume 16, pages 697–716 (2020)Cite this article

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Abstract

Obesity is a health condition that has reached pandemic levels and is implicated in the development and progression of type 2 diabetes mellitus, cancer and heart failure. A key characteristic of obesity is the activation of stress-activated protein kinases (SAPKs), such as the p38 and JNK stress kinases, in several organs, including adipose tissue, liver, skeletal muscle, immune organs and the central nervous system. The correct timing, intensity and duration of SAPK activation contributes to cellular metabolic adaptation. By contrast, uncontrolled SAPK activation has been proposed to contribute to the complications of obesity. The stress kinase signalling pathways have therefore been identified as potential targets for the development of novel therapeutic approaches for metabolic syndrome. The past few decades have seen intense research efforts to determine how these kinases are regulated in a cell-specific manner and to define their contribution to the development of obesity and insulin resistance. Several studies have uncovered new and unexpected functions of the non-classical members of both pathways. Here, we provide an overview of the role of SAPKs in metabolic control and highlight important discoveries in the field.

Key points

  • The activation of stress-activated protein kinases (SAPKs) is associated with obesity and metabolic alterations such as insulin resistance.

  • JNK and p38 function in diverse signalling pathways that affect metabolic processes such as insulin sensitivity, thermogenesis, adipogenesis and lipolysis.

  • The activation of SAPKs in immune cells triggers inflammation in different tissues and affects systemic metabolism in obesity.

  • SAPKs have tissue-specific and substrate-specific functions and their activation is involved in obesity-related disorders such as non-alcoholic steatohepatitis, liver cancer, heart failure and complications of type 2 diabetes mellitus.

  • Targeting SAPK pathways in different tissues is a potential therapeutic approach for the prevention and treatment of metabolic syndrome and associated disorders.

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Fig. 1: Stress-activated protein kinase signalling pathways.
Fig. 2: Role of JNKs in the central nervous system.
Fig. 3: p38 and JNK kinases are crucial molecular players in adipose tissue.
Fig. 4: Stress kinases control metabolism and insulin resistance in muscle.
Fig. 5: SAPK pathways in the liver.
Fig. 6: p38 and JNK regulate the development of liver cancer.
Fig. 7: p38 controls physiological and pathophysiological heart development and growth.

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Acknowledgements

We thank S. Bartlett for English editing and C. López-Otín for his helpful discussion and valuable comments. I.N. was funded by EFSD/Lilly grants (2017 and 2019), the CNIC IPP FP7 Marie Curie Programme (PCOFUND-2012-600396), an EFSD Rising Star award (2019) and grant MINECO IJC2018-035390-I. M.L. was supported by Spanish grant MINECO-FEDER SAF2015-74112-JIN and Fundación AECC: INVES20026LEIV. G.S. received funding from the following programmes and organizations: European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement number ERC 260464; EFSD/Lilly European Diabetes Research Programme; Fundación AECC PROYE19047SABI; BBVA Foundation Leonardo Grants program for Researchers and Cultural Creators (Investigadores-BBVA-2017) IN[17]_BBM_BAS_0066; MINECO-FEDER SAF2016-79126-R and PID2019-104399RB-I00; and the Comunidad de Madrid (IMMUNOTHERCAN-CM S2010/BMD-2326 and B2017/BMD-3733). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia, Innovación y Universidades (MCNU) and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505). We thank our collaborators and the students and fellows who contributed to the studies in the Sabio group over the years. We regret that we were unable to include citations to all other relevant studies owing to space constraints.

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    Ivana Nikolic, Magdalena Leiva & Guadalupe Sabio

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Glossary

Toll-like receptors

(TLR). Crucial innate immune system receptors that recognize various pathogen-associated molecular patterns.

Cyclin-dependent kinases

(CDK). A protein kinase family that regulates the cell cycle.

Insulin receptor substrate

(IRS). A family of cytoplasmic adaptor proteins that intermediate insulin signalling pathways.

T helper 2 phenotype

A T cell population involved in the humoral immune response against pathogens such as helminths; their effector cytokines are IL-4, IL-5, IL-10 and IL-13, among others.

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Nikolic, I., Leiva, M. & Sabio, G. The role of stress kinases in metabolic disease. Nat Rev Endocrinol 16, 697–716 (2020). https://doi.org/10.1038/s41574-020-00418-5

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