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The NAD+-dependent deacetylase SIRT2 attenuates oxidative stress and mitochondrial dysfunction and improves insulin sensitivity in hepatocytes

Lookup NU author(s): Professor Tiago OuteiroORCiD


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© The Author 2017. Published by Oxford University Press. All rights reserved. Insulin resistance is a major predictor of the development of metabolic disorders. Sirtuins (SIRTs) have emerged as potential targets that can be manipulated to counteract age-related diseases, including type 2 diabetes. SIRT2 has been recently shown to exert important metabolic effects, but whether SIRT2 regulates insulin sensitivity in hepatocytes is currently unknown. The aim of this study is to investigate this possibility and to elucidate underlying molecular mechanisms. Here, we show that SIRT2 is downregulated in insulin-resistant hepatocytes and livers, and this was accompanied by increased generation of reactive oxygen species, activation of stress-sensitive ERK1/2 kinase, and mitochondrial dysfunction. Conversely, SIRT2 overexpression in insulin-resistant hepatocytes improved insulin sensitivity, mitigated reactive oxygen species production and ameliorated mitochondrial dysfunction. Further analysis revealed a reestablishment of mitochondrial morphology, with a higher number of elongated mitochondria rather than fragmented mitochondria instigated by insulin resistance. Mechanistically, SIRT2 was able to increase fusion-related protein Mfn2 and decrease mitochondrial-associated Drp1. SIRT2 also attenuated the downregulation of TFAM, a key mtDNA-associated protein, contributing to the increase in mitochondrial mass. Importantly, we found that SIRT2 expression in PBMCs of human subjects was negatively correlated with obesity and insulin resistance. These results suggest a novel function for hepatic SIRT2 in the regulation of insulin sensitivity and raise the possibility that SIRT2 activators may offer novel opportunities for preventing or treating insulin resistance and type 2 diabetes.

Publication metadata

Author(s): Lemos V, de Oliveira RM, Naia L, Szego E, Ramos E, Pinho S, Magro F, Cavadas C, Cristina Rego A, Costa V, Outeiro TF, Gomes P

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 2017

Volume: 26

Issue: 21

Pages: 4105-4117

Print publication date: 01/11/2017

Online publication date: 26/07/2017

Acceptance date: 23/07/2017

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press


DOI: 10.1093/hmg/ddx298


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