Chronic psychological stress and high-fat high-fructose diet disrupt metabolic and inflammatory gene networks in the brain, liver, and gut and promote behavioral deficits in mice

• Type of Material: Article
• Authors: Maria Elizabeth de Sousa Rodrigues, Emory University; Mandakh Bekhbat, Emory University; Madelyn C. Houser, Emory University; Jianjun Chang, Emory University; Douglas I. Walker, Emory University; Dean P Jones, Emory University; Claudia M.P. Oller do Nascimento, Federal University of Sao Paulo; Christopher J. Barnum, Emory University; Malu Tansey, Emory University
• Language: English
• Date: 2017-01-01
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 Elsevier Inc. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1016/j.bbi.2016.08.021
• Title of Journal or Parent Work: Brain, Behavior, and Immunity
• ISSN: 0889-1591
• Volume: 59
• Start Page: 158
• End Page: 172
• Grant/Funding Information: Additional support was provided by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR000454.; The content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institutes of Health.; The present study was supported in part by the Emory Multiplexed Immunoassay Core (EMIC), which is subsidized by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities.; Other funding support for this study was obtained from NIH/NIMHS 1R43MH105048-01A1 (MGT and RJT).
• Keywords: Biliverdin; INDUCED OBESITY; Metabolomics; Immunology; PSYCHOSOCIAL STRESS; ALZHEIMERS-DISEASE; LIPID-METABOLISM; MAJOR DEPRESSION; Cholesterol; Insulin; Lipocalin-2; Depression; GELATINASE-ASSOCIATED LIPOCALIN; Science & Technology; INDUCED INSULIN-RESISTANCE; Life Sciences & Biomedicine; INTESTINAL PERMEABILITY; COGNITIVE IMPAIRMENT; Neurosciences & Neurology; BILIVERDIN REDUCTASE-A; Predatory stress; Metabolic syndrome; Neurosciences
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Animal Physiology

Abstract

The mechanisms underlying the association between chronic psychological stress, development of metabolic syndrome (MetS), and behavioral impairment in obesity are poorly understood. The aim of the present study was to assess the effects of mild chronic psychological stress on metabolic, inflammatory, and behavioral profiles in a mouse model of diet-induced obesity. We hypothesized that (1) high-fat high-fructose diet (HFHF) and psychological stress would synergize to mediate the impact of inflammation on the central nervous system in the presence of behavioral dysfunction, and that (2) HFHF and stress interactions would impact insulin and lipid metabolism. C57Bl/6 male mice underwent a combination of HFHF and two weeks of chronic psychological stress. MetS-related conditions were assessed using untargeted plasma metabolomics, and structural and immune changes in the gut and liver were evaluated. Inflammation was measured in plasma, liver, gut, and brain. Our results show a complex interplay of diet and stress on gut alterations, energetic homeostasis, lipid metabolism, and plasma insulin levels. Psychological stress and HFHF diet promoted changes in intestinal tight junctions proteins and increases in insulin resistance and plasma cholesterol, and impacted the RNA expression of inflammatory factors in the hippocampus. Stress promoted an adaptive anti-inflammatory profile in the hippocampus that was abolished by diet treatment. HFHF increased hippocampal and hepatic Lcn2 mRNA expression as well as LCN2 plasma levels. Behavioral changes were associated with HFHF and stress. Collectively, these results suggest that diet and stress as pervasive factors exacerbate MetS-related conditions through an inflammatory mechanism that ultimately can impact behavior. This rodent model may prove useful for identification of possible biomarkers and therapeutic targets to treat metabolic syndrome and mood disorders.