Systems Nutrigenomics Reveals Brain Gene Networks Linking Metabolic and Brain Disorders.
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.
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Qingying
Q
Meng
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Zhe
Z
Ying
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Emily
E
Noble
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Yuqi
Y
Zhao
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Rahul
R
Agrawal
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Andrew
A
Mikhail
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Yumei
Y
Zhuang
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Ethika
E
Tyagi
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Qing
Q
Zhang
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Maxillofacial Biomedical Engineering, School of Dentistry, Kyung Hee University, Seoul 130-701, Korea.
Jae-Hyung
JH
Lee
Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Marco
M
Morselli
Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Luz
L
Orozco
Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Center for Synthetic & Systems Biology, TNLIST, Tsinghua University, Beijing 100084, China.
Weilong
W
Guo
Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
Tina M
TM
Kilts
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York 10029, USA.
Jun
J
Zhu
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York 10029, USA.
Bin
B
Zhang
Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Matteo
M
Pellegrini
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Xinshu
X
Xiao
Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
Marian F
MF
Young
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Neurosurgery, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: fgomezpi@mednet.ucla.edu.
Fernando
F
Gomez-Pinilla
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: xyang123@ucla.edu.
Xia
X
Yang
D000818:Animals; D058578:Biglycan / Q000235:genetics / Q000378:metabolism; D003072:Cognition Disorders / Q000235:genetics*; D057890:Epigenomics / Q000379:methods; D000071235:Fibromodulin / Q000235:genetics / Q000378:metabolism; D005632:Fructose / Q000008:administration & dosage*; D020869:Gene Expression Profiling / Q000379:methods; D053263:Gene Regulatory Networks; D006624:Hippocampus / Q000737:chemistry; D006801:Humans; D007031:Hypothalamus / Q000737:chemistry; D008297:Male; D008659:Metabolic Diseases / Q000235:genetics*; D053858:Metabolic Networks and Pathways; D023421:Models, Animal; D054647:Nutrigenomics / Q000379:methods*; D057285:Precision Medicine; D051381:Rats; D049490:Systems Biology / Q000379:methods
C546885:Bgn protein, mouse; D058578:Biglycan; C000604332:Fmod protein, mouse; D000071235:Fibromodulin; D005632:Fructose
Brain disorders; Brain networks; DHA; Epigenome; Extracellular matrix; Fructose; Metabolic diseases; Omega-3 fatty acid; Systems nutrigenomics; Transcriptome