Sustained Exposure to High‐Sucrose Diet Triggers Endoplasmic Reticulum Stress in Hippocampus and Anticipates Cognitive and Motor Impairments in Adults Rats

Abstract

BackgroundMetabolic syndrome (MS)‐related conditions promotes endoplasmic reticulum stress (ERS) in order to control their deleterious effects through activation of adaptive responses known as Unfolded Protein Response (UPR). However, under chronic stress, UPR can evolve to apoptotic pathways. Previously, we have shown that MS induced by high‐sucrose diet triggers the ERS and apoptotic pathways in hippocampus and lead to motor and behavioral impairments in young rats.AimsIn the present study we sought to investigate if sustained exposure to such diet is capable to intensify those metabolic disturbances and anticipate neurological impairments in adult rats.MethodsThus, weaned Wistar rats were divided in two groups: the control group (CTR, n=7), fed with a standard chow; and obese group (HSD, n=7), fed with high‐sucrose diet (25% sucrose). Both groups were followed for 6 months and evaluated for MS development; serum redox profile; and hippocampal gene and protein expressions of UPR sensors (IRE1α, PERK and ATF6), chaperones (GRP78, GRP94, PDI, calnexin and calreticulin), neural plasticity marker (BDNF), antioxidant defense (NRF2), senescence (P53 and P21) and apoptosis (BCL2, CHOP and PARP‐1). Furthermore, cognitive, behavioral and motor functions were also assessed, through Morris water maze, open field and rotarod test, respectively. For aging control, 20 month‐old rats (OLD, n=7) fed with standard chow were included as an aging control for gene/protein expressions and neurological assessments.ResultsThe exposure to high‐sucrose diet was capable to induce MS with marked weight gain, central obesity, dysglicemia in both fasting and fed states, hypertriglyceridemia and high free fatty acids, fat storage in liver, glucose intolerance, hyperinsulinemia and peripheral as well as hepatic insulin resistance. The redox profile assessment showed higher lipid peroxidation with increased serum MDA levels and higher SOD activity in HSD as compared to CTR, but catalase was unchanged. UPR sensors gene expression was reduced in both HSD and OLD groups. All chaperones evaluated presented decreased gene expression, but only GRP78 and GRP94 also presented a decreased protein expression. BDNF expression was reduced in HSD (FC 0.3) and OLD groups, but NRF2 did not present any difference. As expected, the senescence markers were increased in OLD group, but only P21 was increased in HSD (FC 1.8). Assessment of apoptotic pathways showed decreased expression of BCL2 and increased gene and protein expression of CHOP. Assessment of PARP‐1 protein expression suggested the presence of calpain, a necrosis marker. Neurological evaluation demonstrated motor deficit, anxiogenic behavior and cognitive impairments (learning and spatial memory) in HSD.ConclusionsIn to to, our data support that sustained exposure to high‐sucrose diet promotes metabolic disturbances, which disrupt hippocampus homeostasis and lead to cognitive and motor impairments in 6‐months old rats.Support or Funding InformationFundação de Amparo à Pesquisa e ao Desenvolvimento Científico e Tecnológico do Maranhão – FAPEMA and rede INCT Redoxoma