Abstract
A high-glucose diet (HGD) is associated with the development of metabolic diseases that decrease life expectancy, including obesity and type-2 diabetes (T2D); however, the mechanism through which a HGD does so is still unclear. Autophagy, an evolutionarily conserved mechanism, has been shown to promote both cell and organismal survival. The goal of this study was to determine whether exposure of Caenorhabditis elegans to a HGD affects autophagy and thus contributes to the observed lifespan reduction under a HGD. Unexpectedly, nematodes exposed to a HGD showed increased autophagic flux via an HLH-30/TFEB-dependent mechanism because animals with loss of HLH-30/TFEB, even those with high glucose exposure, had an extended lifespan, suggesting that HLH-30/TFEB might have detrimental effects on longevity through autophagy under this stress condition. Interestingly, pharmacological treatment with okadaic acid, an inhibitor of the PP2A and PP1 protein phosphatases, blocked HLH-30 nuclear translocation, but not TAX-6/calcineurin suppression by RNAi, during glucose exposure. Together, our data support the suggested dual role of HLH-30/TFEB and autophagy, which, depending on the cellular context, may promote either organismal survival or death.
Highlights
The amount and type of food consumed is a fundamental determinant of human health
To verify whether autophagic flux was increased, we used a transgenic reporter strain that expressed the LGG-1 protein fused with a dimeric green fluorescent protein [22]; when the autophagic process is active, the dFP-LGG-1 construct is cleaved and releases the protease-resistant Monomeric FP (mFP) and indicates an increase in autophagic flux demonstrated by an increase in the mFP/dFP-LGG-1 ratio
We found that (i) a high glucose diet increased HLH-30 nuclear translocation and its activity, which was observed by the induction at the transcriptional level of the autophagy-related genes (ATGs) lgg-1, lmp-1, pgp-2, and unc-51; (ii) high glucose activates autophagic flux in an HLH-30dependent manner; and (iii) HLH-30 nuclear translocation is dependent on phosphatases unrelated to calcineurin and concomitantly enhances autophagic genes
Summary
The amount and type of food consumed is a fundamental determinant of human health. Evidence suggests an association between high sugar consumption and the risk of developing metabolic diseases, including obesity and type-2 diabetes (T2D), which eventually lead to decreased life expectancy [1].Autophagy is an evolutionarily conserved catabolic process that has been linked to both human health and metabolic diseases, such as obesity and T2D [2].Normally, autophagy is present at a basal level but can be enhanced under metabolic stresses, such as hypoxia, starvation, endoplasmic reticulum stress and lysosomal stress [3], indicating that, depending on the intensity of these stressors, autophagy may be beneficial or detrimental for organismal survival [4]. The amount and type of food consumed is a fundamental determinant of human health. Evidence suggests an association between high sugar consumption and the risk of developing metabolic diseases, including obesity and type-2 diabetes (T2D), which eventually lead to decreased life expectancy [1]. Autophagy is an evolutionarily conserved catabolic process that has been linked to both human health and metabolic diseases, such as obesity and T2D [2]. Autophagy is present at a basal level but can be enhanced under metabolic stresses, such as hypoxia, starvation, endoplasmic reticulum stress and lysosomal stress [3], indicating that, depending on the intensity of these stressors, autophagy may be beneficial or detrimental for organismal survival [4]. Autophagy is considered a double-edged sword that can promote either cell survival or death [5]
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