Multi-Tissue Multi-Omics Nutrigenomics Indicates Context-Specific Effects of Docosahexaenoic Acid on Rat Brain

Guanglin Zhang; Qingying Meng; Montgomery Blencowe; Rahul Agrawal; Fernando Gomez-Pinilla; Xia Yang

doi:10.1002/mnfr.202000788

Multi-Tissue Multi-Omics Nutrigenomics Indicates Context-Specific Effects of Docosahexaenoic Acid on Rat Brain

Mol Nutr Food Res. 2020 Dec;64(23):e2000788. doi: 10.1002/mnfr.202000788. Epub 2020 Oct 26.

Authors

Guanglin Zhang^{1

2}, Qingying Meng¹, Montgomery Blencowe^{1

3}, Rahul Agrawal^{1

2

4}, Fernando Gomez-Pinilla^{1

2

4}, Xia Yang^{1

3

5}

Affiliations

¹ Department of Integrative Biology and Physiology, University of California, Los Angeles, 610 Charles E. Young Drive East, Los Angeles, CA, 90095, USA.
² Department of Neurosurgery, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
³ Molecular, Cellular, and Integrative Physiology Interdepartmental Program, University of California, Los Angeles, 610 Charles E. Young Drive East, Los Angeles, CA, 90095, USA.
⁴ Brain Injury Research Center, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
⁵ Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, 610 Charles E. Young Drive East, Los Angeles, CA, 90095, USA.

Abstract

Scope: The influence of docosahexaenoic acid (DHA) on cardiometabolic and cognitive phenotypes, and multi-omic alterations in the brain under two metabolic conditions is explored to understand context-specific nutritional effects.

Methods and results: Rats are 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 reduces serum triglyceride and improves insulin resistance and memory exclusively in the fructose-consuming rats. In hippocampus, DHA affects genes related to synapse functions in the chow group but immune functions in the fructose group; in hypothalamus, DHA alters immune pathways in the chow group but metabolic pathways in the fructose group. Network modeling reveals 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.

Keywords: docosahexaenoic acid; epigenome; hippocampus; hypothalamus; transcriptome.

Grants and funding

R01 DK104363/DK/NIDDK NIH HHS/United States