Multi-tissue Multi-omics Nutrigenomics Indicates Context-specific Effects of DHA on Rat Brain

Scope We explored the influence of DHA on cardiometabolic and cognitive phenotypes, and multiomic alterations in the brain under two metabolic conditions to understand context-specific nutritional effects. Methods and Results Rats were randomly assigned to a DHA-rich or a control chow diet while drinking water or high fructose solution, followed by profiling of metabolic and cognitive phenotypes and the transcriptome and DNA methylome of the hypothalamus and hippocampus. DHA reduced serum triglyceride and improved insulin resistance and memory exclusively in the fructose-consuming rats. In hippocampus, DHA affected genes related to synapse functions in the chow group but immune functions in the fructose group; in hypothalamus, DHA altered immune pathways in the chow group but metabolic pathways in the fructose group. Network modeling revealed context-specific regulators of DHA effects, including Klf4 and Dusp1 for chow condition and Lum, Fn1 , and Col1a1 for fructose condition in hippocampus, as well as Cyr61, JunB, Ier2 , and Pitx2 under chow condition and Hcar1, Cdh1 , and Osr1 under fructose condition in hypothalamus. Conclusion DHA exhibits differential influence on epigenetic loci, genes, pathways, and metabolic and cognitive phenotypes under different dietary contexts, supporting population stratification in DHA studies to achieve precision nutrition. ### Competing Interest Statement The authors have declared no competing interest. * PUFAs : Long chain polyunsaturated fatty acids EPA : Eicosapentaenoic acid T2D : Type 2 diabetes CHD : Coronary heart disease CVD : Cardiovascular disease RNA-Seq : RNA Sequencing FDR : False discovery rate GEO : Gene Expression Omnibus wKDA : weighted key driver analysis RRBS : Reduced Representation Bisulfite Sequencing DMLs : Differentially methylated loci