Systems Nutrigenomics Reveals Brain Gene Networks Linking Metabolic and Brain Disorders.

EBioMedicine 7 (2016) 157–166 Contents lists available at ScienceDirect EBioMedicine journal homepage: www.ebiomedicine.com Research Paper Systems Nutrigenomics Reveals Brain Gene Networks Linking Metabolic and Brain Disorders Qingying Meng a, Zhe Ying a, Emily Noble a, Yuqi Zhao a, Rahul Agrawal a, Andrew Mikhail a, Yumei Zhuang a, Ethika Tyagi a, Qing Zhang a, Jae-Hyung Lee a,f, Marco Morselli b, Luz Orozco b, Weilong Guo b,g, Tina M. Kilts c, Jun Zhu d, Bin Zhang d, Matteo Pellegrini b, Xinshu Xiao a, Marian F. Young c, Fernando Gomez-Pinilla a,e,⁎, Xia Yang a,⁎⁎ a Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA c Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA d Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York 10029, USA e Department of Neurosurgery, University of California, Los Angeles, Los Angeles, CA 90095, USA f Department of Maxillofacial Biomedical Engineering, School of Dentistry, Kyung Hee University, Seoul 130-701, Korea g Center for Synthetic & Systems Biology, TNLIST, Tsinghua University, Beijing 100084, China b a r t i c l e i n f o Article history: Received 1 February 2016 Received in revised form 5 April 2016 Accepted 7 April 2016 Available online 13 April 2016 Keywords: Systems nutrigenomics Fructose Omega-3 fatty acid DHA Epigenome Transcriptome Brain networks Metabolic diseases Brain disorders Extracellular matrix a b s t r a c t 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. © 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 1. Introduction Metabolic disorders (MetDs) such as metabolic syndrome, obesity, and type 2 diabetes (T2D) have become a pressing health apprehension worldwide due to their increasing prevalence and high mortality rate, and even more recently to their ability to escalate the pathology of neurological and psychiatric disorders (Bomfim et al., 2012, Newcomer, 2007; Farooqui et al., 2012, Lowette et al., 2015). Among the potential culprits for the rising epidemic of metabolic and brain disorders are ⁎ Correspondence to: F. Gomez-Pinilla, Department of Neurosurgery and Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA. ⁎⁎ Correspondence to: X. Yang, Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA. E-mail addresses: (F. Gomez-Pinilla), (X. Yang). dietary components introduced through industrialization (Chassaing et al., 2015, Suez et al., 2014). In particular, fructose, which has been widely used as a “safe and healthy” sweetener in soft drinks and processed foods in the past decades, is emerging as a significant contributor to MetDs in humans (Lyssiotis and Cantley, 2013, Lustig et al., 2012). Fructose-induced MeDs has been shown to reduce hippocampaldependent memory (Agrawal and Gomez-Pinilla, 2012) and to worsen the pathology of brain disorders in rodents (Agrawal et al., 2015). Conversely, the omega-3 fatty acid docosahexaenoic acid (DHA) has been shown to attenuate MetDs (Steffen et al., 2015, Virtanen et al., 2014, De caterina, 2011), and to counteract the deleterious effects of fructose on brain function and plasticity (Bremer et al., 2014, Agrawal and Gomez-Pinilla, 2012). Our understanding of the molecular mechanisms underlying the actions of fructose and DHA on MetDs and brain disorders has been limited by conventional approaches focusing on isolated molecular events. This limitation has delayed major advances http://dx.doi.org/10.1016/j.ebiom.2016.04.008 2352-3964/© 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 158 Q. Meng et al. / EBioMedicine 7 (2016) 157–166 in the utilization of nutrient-based strategies for the prevention and treatment of common complex disorders. As fundamental aspects of gene regulation, disruptions in epigenomic reprogramming, transcript abundance, alternative splicing, and gene–gene interactions are increasingly recognized as core aspects of wide-ranging pathogenesis (Chen et al., 2008, Zhang et al., 2013, Rhinn et al., 2013, Narayanan et al., 2014, Makinen et al., 2014, Yang et al., 2009). Systems nutrigenomics is emerging as a powerful approach to reveal the hidden aspects of pathogenesis under dietary modulation (Zhao et al., 2015, De Graaf et al., 2009, Panagiotou and Nielsen, 2009). Here we apply systems nutrigenomics to unveil the multidimensional molecular interactions driven by fructose and DHA that regulate pathogenesis and recovery, and to provide proof-of-principle on the potential of systems nutrigenomics to guide personalized medicine. The comparative account of nutrigenomics signals between fructose and DHA is crucial to understand how select diets impact the molecular substrates governing the balance between normal brain function and disease, and holds potential for guiding effective preventative and therapeutic strategies to mitigate common human diseases. 2. Materials and Methods We describe essential methods in the main text and detailed experimental procedures are available in the Supplemental Materials. 2.1. Overall Study Design As depicted in the analysis flow in Fig. 1, we focus our st (...truncated)