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Endoplasmic reticulum stress as the basis of obesity and metabolic diseases: focus on adipose tissue, liver, and pancreas

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Abstract

Obesity challenges lipid and carbohydrate metabolism. The resulting glucolipotoxicity  causes endoplasmic reticulum (ER) dysfunction, provoking the accumulation of immature proteins, which triggers the unfolded protein reaction (UPR) as an attempt to reestablish ER homeostasis. When the three branches of UPR fail to correct the unfolded/misfolded proteins, ER stress happens. Excessive dietary saturated fatty acids or fructose exhibit the same impact on the ER stress, induced by excessive ectopic fat accumulation or rising blood glucose levels, and meta-inflammation. These metabolic abnormalities can alleviate through dietary interventions. Many pathways are disrupted in adipose tissue, liver, and pancreas during ER stress, compromising browning and thermogenesis, favoring hepatic lipogenesis, and impairing glucose-stimulated insulin secretion within pancreatic beta cells. As a result, ER stress takes part in obesity, hepatic steatosis, and diabetes pathogenesis, arising as a potential target to treat or even prevent metabolic diseases. The scientific community seeks strategies to alleviate ER stress by avoiding inflammation, apoptosis, lipogenesis suppression, and insulin sensitivity augmentation through pharmacological and non-pharmacological interventions. This comprehensive review aimed to describe the contribution of excessive dietary fat or sugar to ER stress and the impact of this adverse cellular environment on adipose tissue, liver, and pancreas function.

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Acknowledgments

This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES)—Finance Code 001 (Master scholarships for AFS, CSM, DASO, doctoral scholarship for FMS-V, and post-doctoral scholarship for FFM), and Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (Faperj – Master scholarships for BOC and CRA). The corresponding author is supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (Brazil) (CNPq, Grant N° 305867/2017-2), and FAPERJ (Grant N° E-26/202.657/2018). These agencies did not interfere with the accomplishment and submission of the manuscript.

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  1. Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Av 28 de Setembro 87 fds, Rio de Janeiro, RJ, 20551-030, Brazil

    Aline Fernandes-da-Silva, Carolline Santos Miranda, Daiana Araujo Santana-Oliveira, Brenda Oliveira-Cordeiro, Camilla Rangel-Azevedo, Flávia Maria Silva-Veiga, Fabiane Ferreira Martins & Vanessa Souza-Mello

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  1. Aline Fernandes-da-Silva
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  2. Carolline Santos Miranda
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VS-M had the idea for the article and critically revised the work, all authors performed the literature search, data analysis, and drafted the manuscript.

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Correspondence to Vanessa Souza-Mello.

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Fernandes-da-Silva, A., Miranda, C.S., Santana-Oliveira, D.A. et al. Endoplasmic reticulum stress as the basis of obesity and metabolic diseases: focus on adipose tissue, liver, and pancreas. Eur J Nutr 60, 2949–2960 (2021). https://doi.org/10.1007/s00394-021-02542-y

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