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.
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.
Department of Physiology, School of Medicine at Emory University, United States; Department of Physiology of Nutrition, Federal University of Sao Paulo, SP, Brazil. Electronic address: mdesou2@emory.edu.
Maria Elizabeth
ME
de Sousa Rodrigues
Department of Physiology, School of Medicine at Emory University, United States. Electronic address: mandakh.bekhbat@emory.edu.
Mandakh
M
Bekhbat
Department of Physiology, School of Medicine at Emory University, United States. Electronic address: mcrawf4@emory.edu.
Madelyn C
MC
Houser
Department of Physiology, School of Medicine at Emory University, United States. Electronic address: jchan47@emory.edu.
Jianjun
J
Chang
Division of Pulmonary, Allergy and Critical Care Medicine, School of Medicine at Emory University, United States. Electronic address: Douglas.Walker@emory.edu.
Douglas I
DI
Walker
Division of Pulmonary, Allergy and Critical Care Medicine, School of Medicine at Emory University, United States. Electronic address: dpjones@emory.edu.
Dean P
DP
Jones
Department of Physiology of Nutrition, Federal University of Sao Paulo, SP, Brazil. Electronic address: claudia.oller@unifesp.br.
Claudia M P
CMP
Oller do Nascimento
Department of Physiology, School of Medicine at Emory University, United States. Electronic address: cjbarnum@me.com.
Christopher J
CJ
Barnum
Department of Physiology, School of Medicine at Emory University, United States. Electronic address: malu.tansey@emory.edu.
Malú G
MG
Tansey
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001835:Body Weight; D001923:Brain Chemistry / Q000235:genetics; D059305:Diet, High-Fat / Q000009:adverse effects*; D004734:Energy Metabolism / Q000187:drug effects; D005632:Fructose / Q000009:adverse effects*; D041981:Gastrointestinal Tract / Q000378:metabolism; D053263:Gene Regulatory Networks / Q000187:drug effects*; D007249:Inflammation / Q000235:genetics*; D050356:Lipid Metabolism / Q000187:drug effects; D000071068:Lipocalin-2 / Q000096:biosynthesis / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008297:Male; D008660:Metabolism / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D012919:Social Behavior; D013315:Stress, Psychological / Q000503:physiopathology* / Q000523:psychology*
D000071068:Lipocalin-2; C071332:Lcn2 protein, mouse; D005632:Fructose
Biliverdin; Cholesterol; Depression; Insulin; Lipocalin-2; Metabolic syndrome; Metabolomics; Predatory stress