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

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 DNA methyltransferase 1 (Dnmt1) and Dnmt3a 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 Methyltransferase like 3 (Mettl3) and FTO alpha-ketoglutarate dependent dioxygenase (Fto) were found. Moreover, we found a decrease in gene expression levels of pro-inflammatory markers such as Interleukin 1β (Il1-β), Interleukin 6 (Il-6), Tumor necrosis factor-α (Tnf-α), C-X-C motif chemokine ligand 10 (Cxcl-10), the pro-inflammatory factors monocyte chemoattractant protein 1 (Mcp-1) and Tumor growth factor-β1 (Tgf-β1) in HFD+RSV and HFD+RSV F1 groups. Moreover, there was increased gene expression of neurotrophins such as Neural growth factor (Ngf), Neurotrophin-3 (Nt3), and its receptors Tropomyosin receptor kinase TrkA and TrkB. 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.