Early exposure to high‐sucrose diet triggers hippocampal endoplasmic reticulum‐stress in young rats
Authors: de Andrade Paes Antonio Marcus , Pinto Bruno Araújo Serra , Melo Thamys Marinho , Flister Karla Frida Torres , França Lucas Martins , Tanaka Leonardo Yudi , Laurindo Francisco Rafael Martins 
Published: November 2023

Early‐life environmental insults have been shown to promote long‐term development of chronic non‐communicable diseases, including metabolic disturbances and mental illnesses. As such, premature consumption of high‐sugar foods has been associated to early onset of detrimental outcomes, whereas underlying mechanisms are still poorly understood. In the present study, we sought to investigate whether early exposure to high‐sucrose diet promotes metabolic disturbances that ultimately might anticipate neurological injuries. At postnatal day 21, weaned male rats started to be fed a standard chow (10% sucrose, CTR, n = 9) or a high‐sucrose diet (25% sucrose, HSD, n = 7) for 9 weeks prior to euthanasia at postnatal day 90. HSD did not alter weight gain and feed efficiency between groups, but increased visceral, non‐visceral and brown adipose tissue accumulation in 39, 55 and 25%, respectively, as compared to CTR. HSD rats demonstrated elevated blood glucose levels in both fasting (102.7 ± 1.38 vs. 94.67 ± 1.43 mg/dL, p = 0.0007) and fed (128.3 ± 2.2 vs. 106.7 ± 3.49 mg/dL, p = 0.0001) states, which were associated to impaired glucose tolerance. Peripheral insulin sensitivity did not change, whereas hepatic insulin resistance was supported by increased serum triglyceride levels (145.3 ± 14.24 vs. 88.89 ± 5.79 mg/dL, p = 0.0007), as well as higher TyG index values (8.88 ± 0.10 vs. 8.33 ± 0.06). Assessment of hippocampal gene expression showed endoplasmic reticulum (ER) stress pathways were activated in HSD rats, as compared to CTR. HSD rats had overexpression of unfolded protein response sensors, PERK (3.31 ± 0.64 fold change (FC); p = 0.0039) and ATF6 (2.3 ± 0.47 FC; p = 0.0229); ER chaperone, PDIA2 (4.46 ± 0.44 FC; p = 0.0001) and apoptosis‐related genes, CHOP (2.04 ± 0.27 FC, p = 0.0262) and Caspase 3 (2.66 ± 0.49 FC, p = 0.027); but decreased expression of chaperone GRP78 (0.19 ± 0.29 FC; p = 0.0367). Bcl2 mRNA levels, an anti‐apoptotic gene, showed a non‐significant downward trend. mRNA levels of IRE‐1α, Calnexin and Nrf2 did not change. In total, six of ten ER stress‐related genes tested demonstrated significant differential expression in the hippocampus of our 90‐days old HSD‐fed rats. Finally, HSD rats demonstrated impaired neuromuscular function and anxious behavior, but no spatial learning‐memory impairment, as assessed by rotarod, open field and water maze tests, respectively. In summary, this study reinforces the knowledge on the consequences of early introduction of high dietary levels of sucrose, thus fructose and glucose, on metabolic control of body functions. Moreover, it originally shows that the hippocampus homeostasis is particularly disrupted with very precocious development of ER stress, as well as neuromotor and behavioral impairments; expanding the branches of metabolic syndrome‐related disturbances.Support or Funding InformationThis work was funded by Fundação de Amparo à Pesquisa e ao Desenvolvimento Científico e Tecnológico do Maranhão – FAPEMA through the grants PAEDT‐00380/14, UNIVERSAL‐00523/14, and UNIVERSAL‐00792/14.