High fried food consumption impacts anxiety and depression due to lipid metabolism disturbance and neuroinflammation

Abstract

Western dietary patterns have been unfavorably linked with mental health. However, the long-term effects of habitual fried food consumption on anxiety and depression and underlying mechanisms remain unclear. Our population-based study with 140,728 people revealed that frequent fried food consumption, especially fried potato consumption, is strongly associated with 12% and 7% higher risk of anxiety and depression, respectively. The associations were more pronounced among male and younger consumers. Consistently, long-term exposure to acrylamide, a representative food processing contaminant in fried products, exacerbates scototaxis and thigmotaxis, and further impairs exploration ability and sociality of adult zebrafish, showing anxiety- and depressive-like behaviors. Moreover, treatment with acrylamide significantly down-regulates the gene expression of tjp2a related to the permeability of blood-brain barrier. Multiomics analysis showed that chronic exposure to acrylamide induces cerebral lipid metabolism disturbance and neuroinflammation. PPAR signaling pathway mediates acrylamide-induced lipid metabolism disorder in the brain of zebrafish. Especially, chronic exposure to acrylamide dysregulates sphingolipid and phospholipid metabolism, which plays important roles in the development of anxiety and depression symptoms. In addition, acrylamide promotes lipid peroxidation and oxidation stress, which participate in cerebral neuroinflammation. Acrylamide dramatically increases the markers of lipid peroxidation, including (±)5-HETE, 11(S)-HETE, 5-oxoETE, and up-regulates the expression of proinflammatory lipid mediators such as (±)12-HETE and 14(S)-HDHA, indicating elevated cerebral inflammatory status after chronic exposure to acrylamide. Together, these results both epidemiologically and mechanistically provide strong evidence to unravel the mechanism of acrylamide-triggered anxiety and depression, and highlight the significance of reducing fried food consumption for mental health.

Keywords: acrylamide; anxiety and depression; fried foods; lipid metabolism disturbance; neuroinflammation.

Fig. 1.

Study design and basic characteristics of the study participants. (A) Study design and the associations between fried food and fried potato consumption and the risk of anxiety and depression. (B) Baseline characteristics of participants across fried food consumption in UK biobank (n=140,728). Data are expressed as mean ± SD or numbers with percentages.

Fig. 2.

Behavioral profiles of zebrafish by the long-term exposure to acrylamide (AA) in the light/dark preference test. (A) Schematic of the zebrafish study by the long-term exposure to acrylamide. (B and C) Effects of long-term exposure to acrylamide for 180 d on body mass and length of zebrafish, respectively. (D) Representative swimming trajectories of zebrafish in the control group and three acrylamide exposure groups (0 mM wide type, 0.125 mM, 0.25 mM, and 0.5 mM). The left side is the light chamber, and the right side is the dark chamber. (E) Radar chart of 12 behavioral parameters of zebrafish in different groups (0 mM wide type, 0.125 mM, 0.25 mM, and 0.5 mM). a, duration; b, distance; c, average velocity (cm/s); d, accelerated speed; e, average entry time duration (s); f, turning angle (°); g, turning angle (°)/time; h, activity; i, rapid move ratio; j, normal move ratio; k, freezing time ratio (s); l, freezing time duration (s). (F) Heatmap visualization of zebrafish trajectories in the light/dark preference test. (G) Duration time spent in the light or dark zone of total time (%). (H) Distance traveled in the light or dark zone of total distance (%). (I) Freezing duration time (s) in the light or dark zone. (J) Traversing times between the light and dark zones. (K) Hierarchical clustering of zebrafish in the light/dark preference test. All the histograms were present with mean ± SEM, while all behavioral parameter data were analyzed by the two-way ANOVA followed by multiple comparisons. The level of significance was defined as *P < 0.05, **P < 0.01, ****P < 0.0001; ^#P < 0.05, ^##P < 0.01, ^###P < 0.001, ^####P < 0.0001 (* indicates significance between different groups and # indicates significance between different regions within the same group).

Fig. 3.

Behavioral profiles of zebrafish by the long-term exposure to acrylamide in the novel object exploration test and the social preference test. (A) Representative swimming trajectories of zebrafish in the control group and three acrylamide exposure groups (0 mM wide type, 0.125 mM, 0.25 mM, and 0.5 mM). A novel object for zebrafish was placed in the left part (Zone 1) and the right part was Zone 2. (B) Heatmap visualization of zebrafish trajectories in the novel object exploration test. (C) Duration time spent in Zone 1 or Zone 2 of total time (%). (D) Distance traveled in Zone 1 or Zone 2 of total distance (%). (E) Representative swimming trajectories of zebrafish in different groups (0 mM wide type, 0.125 mM, 0.25 mM, and 0.5 mM). (F) Radar chart of 12 behavioral parameters of zebrafish in different groups (0 mM wide type, 0.125 mM, 0.25 mM, and 0.5 mM). a, duration; b, distance; c, average velocity (cm/s); d, accelerated speed; e, average entry time duration (s); f, turning angle (°); g, turning angle (°)/time; h, activity; i, rapid move ratio; j, normal move ratio; k, freezing time ratio (s); l, freezing time duration (s). (G) Heatmap visualization of zebrafish trajectories in the social preference test. (H) Duration time spent in the left or right chamber of total time (%). (I) Distance traveled in the left or right chamber of total distance (%). (J) Traversing times between the left and right chambers. (K) Numbers of crossing the middle line. (L) Hierarchical clustering of zebrafish in the social preference test. All the histograms were present with mean ± SEM, while all behavioral parameter data were analyzed by the two-way ANOVA followed by multiple comparisons or the one-way ANOVA followed by the Turkey post hoc test. The level of significance was defined as *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001; ^#P < 0.05, ^##P < 0.01, ^###P < 0.001, ^####P < 0.0001 (* indicates significance between different groups and # indicates significance between different regions within the same group).

Fig. 4.

Chronic exposure to acrylamide induces lipid perturbation and inflammatory response based on DEGs analysis. (A) The control and acrylamide-treated groups were completely distinguished by different colors in PCA plots. (B) Volcano map based on DEGs [p_adj < 0.05 and absolute Log₂ FC (fold change) ≥ 1]. (C) Enrichment analysis of GO function based on DEGs. (D) Dotplot of the enriched KEGG pathway for DEGs in the brain of zebrafish due to acrylamide exposure. (E) Interaction network of differentially expressed proteins in major pathways with significant changes due to acrylamide exposure. (F) Relationship between DEGs and KEGG pathways. (G) Visual analysis of DEGs in major pathways. A horizontal bar graph of gene expression (Left) and a heat map of gene expression (Right). (H) GSEA results showing response to lipid-related pathways with significant changes in the brain of zebrafish after exposure to acrylamide for 180 d.

Fig. 5.

Chronic exposure to acrylamide disturbed cholesterol metabolism and arachidonic acid metabolism via the PPAR signaling pathway. (A) Network of the DEGs and lipid metabolites in zebrafish with exposure to acrylamide. Squares represent lipid metabolites and circles represent genes. (B) Key pathways (PPAR signaling pathway, cholesterol metabolism, arachidonic acid metabolism, lipid peroxidation, fatty acid degradation, sphingolipid metabolism, and linoleic acid metabolism) in the integration of transcriptomics and lipidomics. The bars are shown as mean ± SD. Statistical differences were determined using an unpaired Student's t test. AA, the acrylamide-treated (0.5 mM) group; CTL, the control group.