Maternal fructose–induced oxidative stress occurs via Tfam and Ucp5 epigenetic regulation in offspring hippocampi

Abstract

Fructose consumption is rising globally, but maternal high fructose intake might adversely affect offspring. Our previous report demonstrated that excess maternal fructose intake impairs hippocampal function in offspring, indicating that the hippocampi of offspring are highly sensitive to maternal fructose. Here, we examined the effect of maternal high fructose on mitochondrial physiology and uncoupling protein (UCP) expression. Rat dams received a 20% fructose solution during gestation and lactation. Immediately after weaning, offspring hippocampi were isolated. Maternal high fructose consumption attenuated the mitochondrial O2 consumption rate and stimulated lipid hydroperoxide production in the hippocampi of offspring. Reduced Ucp5 and mitochondrial transcription factor A (Tfam) mRNA levels were also observed after maternal exposure to fructose. We assessed the promoter regions of both genes and found that this treatment enhanced DNA methylation levels. In addition, luciferase assays showed that this DNA methylation could reduce the transcription of both genes. Chromatin immunoprecipitation analysis demonstrated that specificity protein 1 binding to the Ucp5 promoter regions was reduced by DNA methylation. In addition, Ucp5 knockdown induced the up‐regulation of reactive oxygen species levels in a rat brain glioma cell line, whereas reduced O2 consumption was observed with Tfam knockdown. Maternal high fructose intake thus induces reduced O2 oxygen consumption and increases oxidative stress in offspring, at least partly through epigenetic mechanisms involving Ucp5 and Tfam.—Yamada, H., Munetsuna, E., Yamazaki, M., Mizuno, G., Sadamoto, N., Ando, Y., Fujii, R., Shiogama, K., Ishikawa, H., Suzuki, K., Shimono, Y., Ohashi, K., Hashimoto, S. Maternal fructose‐induced oxidative stress occurs via Tfam and Ucp5 epigenetic regulation in offspring hippocampi. FASEB J. 33, 11431–11442 (2019). http://www.fasebj.org

Exogenous exposure to dihydroxyacetone mimics high fructose induced oxidative stress and mitochondrial dysfunction

“…As expected from the low dose fructose results, high fructose doses further increased intracellular ROS and oxidative stress. A 20% fructose diet increased oxidative stress levels in Fischer and Sprague–Dawley animal models for 20 weeks and during lactation/gestation periods, respectively (Dornas et al ., 2017; Yamada et al ., 2019). Hippocampal analysis of Sprague–Dawley rats demonstrated a 1.5‐fold increase in total ROS due to increased fructose consumption (Yamada et al ., 2019).…”

“…A 20% fructose diet increased oxidative stress levels in Fischer and Sprague–Dawley animal models for 20 weeks and during lactation/gestation periods, respectively (Dornas et al ., 2017; Yamada et al ., 2019). Hippocampal analysis of Sprague–Dawley rats demonstrated a 1.5‐fold increase in total ROS due to increased fructose consumption (Yamada et al ., 2019). Fischer rats treated with 20% fructose combined with 8% saline experienced hypertension, linking dysfunction to AGE formation and contractile changes in the vasculature (Dornas et al ., 2017).…”

“…Of the studies discussed here, dietary supplementation of 7–10% and 60% fructose per day elevated reactive species formation in hepatic tissue of Sprague–Dawley rats and Wistar rats, respectively (Cavarape et al ., 2001; Zhang et al ., 2015; Cioffi et al ., 2017). However, hepatic tissue from Wistar rats with 25% fructose administration exhibited no elevation in ROS levels (Garcia‐Berumen et al ., 2019; Yamada et al ., 2019). Cardiac tissue showed increased ROS for C57BL/6 mice with 10% and 60% dietary fructose and Wistar rats given 60% fructose (Zhang et al ., 2015; Szucs et al ., 2019).…”

“…Only limited analysis of kidney tissue was conducted with ROS formation observed after 20% fructose exposure in Fischer rat models (Dornas et al ., 2017). Finally, Sprague–Dawley rats given a 20% fructose diet showed elevated ROS formation in hippocampal tissue, and Spontaneously Hypertensive rats administered a 60% fructose diet presented increased ROS in rostral ventrolateral medulla (RVLM) tissue (Wu et al ., 2017; Yamada et al ., 2019). While the models and dosing vary, these studies demonstrate excess fructose generates reactive species.…”

“…Decreases in cellular glucose uptake for high‐dose fructose supplementation to animal models leads to a decreased mitochondrial respiration (Table 2). Reduced glucose integration into metabolic pathways contributed to impaired mitochondrial function, as shown with high‐dose fructose exposures to Sprague–Dawley and Wistar rats that exhibit decreased rates of respiration (Garcia‐Berumen et al ., 2019; Yamada et al ., 2019).…”