Resveratrol Supplementation Attenuates Cognitive and Molecular Alterations under Maternal High-Fat Diet Intake: Epigenetic Inheritance over Generations

Abstract

Environmental factors such as maternal high-fat diet (HFD) intake can increase the risk of age-related cognitive decline in adult offspring. Epigenetic mechanisms are a possible link between diet effect and neurodegeneration across generations. Here, we found a significant decrease in triglyceride levels in a high-fat diet with resveratrol (RSV) HFD + RSV group and the offspring. Firstly, we obtained better cognitive performance in HFD+RSV groups and their offspring. Molecularly, a significant increase in DNA methylation (5-mC) levels, as well as increased gene expression of <i>DNA methyl</i><i>tran</i><i>s</i><i>f</i><i>e</i><i>rase</i> <i>1</i> (<i>Dnmt1</i><i>)</i> and <i>Dnmt3a</i> in HFD + RSV F1 group, were found. Furthermore, a significant increase of N⁶-Methyladenosine methylation (m⁶A) levels in HFD+RSV F1, as well as changes in gene expression of its enzymes <i>Methyltransferase like 3 (Mettl3</i>) and <i>FTO alpha-ketoglutarate dependent dioxygenase (</i><i>Fto</i><i>)</i> were found. Moreover, we found a decrease in gene expression levels of pro-inflammatory markers such as <i>Interleukin</i> <i>1β</i> <i>(</i><i>Il1-β</i><i>)</i><i>,</i> <i>Interleukin 6 (</i><i>Il-6</i><i>)</i>, <i>Tumor necrosis factor-α (</i><i>Tnf</i><i>-α</i><i>)</i><i>,</i> <i>C-X-C motif</i> <i>chemokine ligand 10 (Cxcl-10)</i>, the pro-inflammatory factors monocyte chemoattractant protein 1 (Mcp-1) and <i>Tumor growth factor-β1 (</i><i>Tgf</i><i>-β1</i><i>)</i> in HFD+RSV and HFD+RSV F1 groups. Moreover, there was increased gene expression of neurotrophins such as <i>Neural growth factor (</i><i>Ngf</i>), Neurotrophin-3 (Nt3), and its receptors <i>Tropomyosin receptor kinase</i> <i>TrkA</i> and <i>TrkB</i>. Likewise, an increase in protein levels of brain-derived neurotrophic factor (BDNF) and phospho-protein kinase B (p-Akt) in HFD+RSV F1 was found. These results suggest that maternal RSV supplementation under HFD intake prevents cognitive decline in senescence-accelerated mice prone 8 (SAMP8) adult offspring, promoting a reduction in triglycerides and leptin plasma levels, changes in the pro-inflammatory profile, and restoring the epigenetic landscape as well as synaptic plasticity.