Systems Nutrigenomics Reveals Brain Gene Networks Linking Metabolic and Brain Disorders
Qingying Meng,
Zhe Ying,
Emily Noble,
Yuqi Zhao,
Rahul Agrawal,
Andrew Mikhail,
Yumei Zhuang,
Ethika Tyagi,
Qing Zhang,
Jae-Hyung Lee,
Marco Morselli,
Luz Orozco,
Weilong Guo,
Tina M. Kilts,
Jun Zhu,
Bin Zhang,
Matteo Pellegrini,
Xinshu Xiao,
Marian F. Young,
Fernando Gomez-Pinilla,
Xia Yang
Affiliations
Qingying Meng
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
Zhe Ying
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
Emily Noble
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
Yuqi Zhao
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
Rahul Agrawal
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
Andrew Mikhail
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
Yumei Zhuang
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
Ethika Tyagi
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
Qing Zhang
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
Jae-Hyung Lee
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
Marco Morselli
Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA
Luz Orozco
Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA
Weilong Guo
Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA
Tina M. Kilts
Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA
Jun Zhu
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York 10029, USA
Bin Zhang
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York 10029, USA
Matteo Pellegrini
Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA
Xinshu Xiao
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
Marian F. Young
Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA
Fernando Gomez-Pinilla
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
Xia Yang
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
Nutrition plays a significant role in the increasing prevalence of metabolic and brain disorders. Here we employ systems nutrigenomics to scrutinize the genomic bases of nutrient–host interaction underlying disease predisposition or therapeutic potential. We conducted transcriptome and epigenome sequencing of hypothalamus (metabolic control) and hippocampus (cognitive processing) from a rodent model of fructose consumption, and identified significant reprogramming of DNA methylation, transcript abundance, alternative splicing, and gene networks governing cell metabolism, cell communication, inflammation, and neuronal signaling. These signals converged with genetic causal risks of metabolic, neurological, and psychiatric disorders revealed in humans. Gene network modeling uncovered the extracellular matrix genes Bgn and Fmod as main orchestrators of the effects of fructose, as validated using two knockout mouse models. We further demonstrate that an omega-3 fatty acid, DHA, reverses the genomic and network perturbations elicited by fructose, providing molecular support for nutritional interventions to counteract diet-induced metabolic and brain disorders. Our integrative approach complementing rodent and human studies supports the applicability of nutrigenomics principles to predict disease susceptibility and to guide personalized medicine.
