Metabolic Syndrome Triggered by Fructose Diet Impairs Neuronal Function and Vascular Integrity in ApoE-KO Mouse Retinas: Implications of Autophagy Deficient Activation.

María C Paz,Gustavo A Chiabrando,Pablo F Barcelona,Claudia Castro,Magali E Ridano,María C Sánchez,Paula V Subirada

doi:10.3389/fcell.2020.573987

Abstract

Metabolic syndrome is a disorder characterized by a constellation of clinical findings such as elevated blood glucose, hyperinsulinemia, dyslipidemia, hypertension, and obesity. A positive correlation has been found between metabolic syndrome or its components and retinopathy, mainly at microvascular level, in patients without a history of diabetes. Here, we extend the investigations beyond the vascular component analyzing functional changes as well as neuronal and glial response in retinas of Apolipoprotein E knockout (ApoE-KO) mice fed with 10% w/v fructose diet. Given that autophagy dysfunction is implicated in retinal diseases related to hyperglycemia and dyslipidemia, the activation of this pathway was also analyzed. Two months of fructose intake triggered metabolic derangements in ApoE-KO mice characterized by dyslipidemia, hyperglycemia and hyperinsulinemia. An increased number of TUNEL positive cells, in addition to the ganglion cell layer, was observed in the inner nuclear layer in retina. Vascular permeability, evidenced by albumin–Evans blue leakage and extravasation of albumin was also detected. Furthermore, a significant decrease of the glial fibrillary acidic protein expression was confirmed by Western blot analysis. Absence of both Müller cell gliosis and pro-angiogenic response was also demonstrated. Finally, retinas of ApoE-KO FD mice showed defective autophagy activation as judged by LC3B mRNA and p62 protein levels correlating with the increased cell death. These results demonstrated that FD induced in ApoE-KO mice biochemical alterations compatible with metabolic syndrome associated with neuronal impairment and mild vascular alterations in the retina.

Highlights

Metabolic Syndrome (MetS) is a complex disorder of metabolism considered a global epidemic that involves a high socioeconomic cost (Sherling et al, 2017)
At 6 months of diet, an additional increase was observed for triglycerides in Apolipoprotein E knockout (ApoE-KO) fructose diet (FD) (p < 0.05) compared with ApoE-KO normal diet (ND) group, whereas in wild type (WT) mice fed with FD group it returned to baseline levels (Figure 1A)
Our results showed that WT mice fed with FD as well as ApoE-KO ND mice evidenced some metabolic alterations that were correlated with a mild retinal damage

Summary

Introduction

Metabolic Syndrome (MetS) is a complex disorder of metabolism considered a global epidemic that involves a high socioeconomic cost (Sherling et al, 2017). Individuals with MetS have two to threefold risk of developing cardiovascular disease and fivefold risk of developing type 2 Diabetes Mellitus (DM) (Wild et al, 2004) In this sense, deleterious effects of MetS extend beyond the heart affecting other organs such as the retina (Thierry et al, 2015; Zarei et al, 2017), doubling the number of people with visual impairment. ApoE-KO mice spontaneously hypercholesterolemic were fed with a diet supplemented with 10% of fructose (FD), an important and pervasive sweetener in Western diets that produces impaired glucose tolerance and increases the blood triglyceride concentrations (Tappy and Rosset, 2019) In this in vivo model of MetS, we characterized the effects of metabolic derangement on retinal function over time and analyzed the vascular, neuronal and glial alterations

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