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. 2023 Sep;26(9):864-874.
doi: 10.1080/1028415X.2022.2103613. Epub 2022 Jul 28.

Interleukin-6 and tumor necrosis factor-α attenuate dopamine release in mice fed a high-fat diet, but not medium or low-fat diets

H A Emmons  1 , C W Wallace  1   2 , S C Fordahl  1
Affiliations

Interleukin-6 and tumor necrosis factor-α attenuate dopamine release in mice fed a high-fat diet, but not medium or low-fat diets

H A Emmons et al. Nutr Neurosci. 2023 Sep.

Abstract

Chronic low-grade inflammation is associated with a state of diet-induced obesity that impacts systemic tissues and can cross the blood-brain barrier to act directly on the brain. The extent to which pro-inflammatory cytokines released in these conditions affect dopamine presynaptic neurotransmission has not been previously investigated. The purpose of this study was to examine how dopamine terminals are affected by pro-inflammatory cytokines, and to determine if dietary fat consumption potentiates cytokine effects on dopamine release and reuptake rate in the nucleus accumbens (NAc). Male and female C57BL/6J mice were fed high, medium, or low-fat diets (60%, 30%, or 10% total kcals from fat, respectively) for six weeks. Fast scan cyclic voltammetry (FSCV) was used to measure dopamine release and reuptake rate in the NAc core from ex vivo coronal brain slices. Electrically evoked dopamine release and the maximal rate of dopamine reuptake (Vmax) were significantly lower in mice fed the 30% and 60% high-fat diets compared to the 10% low-fat group (p < 0.05). IL-6 5 or 10 nM or TNFα 30 or 300 nM was added to artificial cerebrospinal fluid (aCSF) bathed over brain slices during FSCV. No effect on dopamine release or Vmax was observed with lower concentrations. However, 10 nM IL-6 and 300 nM TNFα significantly reduced dopamine release in the 60% fat group (p < 0.05). No effect of added cytokine was observed on Vmax. Overall, these data provide evidence that dietary fat increases neural responsiveness to cytokines, which may help inform comorbidities between diet-induced obesity and depression or other mood disorders.

Keywords: Diet-induced Obesity; Dopamine; High Fat Diet; IL-6; Inflammation; Neurochemistry; Saturated Fat; TNFα; Voltammetry.

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Conflict of interest statement

Disclosure of Interest

The authors report no conflict of interest.

Figures

Figure 1:
Figure 1:. Body Weight Changes and Blood Glucose Comparisons-
Anthropometric and metabolic changes in a model of diet-induced obesity. (A) Body weight gain (g) of males and females in each experimental diet group (LF, HF30, HF60) over six weeks. (B) Percent body weight change compared body weight gain between diet group and sex. (C) Fasting blood glucose (mg/dL) for males and females in LF, HF30, and HF60 groups. (D) Area under the curve (AUC) for intraperitoneal glucose tolerance test (IPGTT) showing HF30 and HF60 groups (male and female) had greater AUC than the LF control counterpart. Data are presented as group mean ± SEM. (* denotes differences between diet groups; *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001) (+ denotes differences within diet group; +p<0.05, ++p<0.01, ++++p<0.0001)
Figure 2:
Figure 2:. Effects of Sex and Diet on Dopamine Release and Reuptake Rate-
(A) Two-way ANOVA table showing diet × sex effects for single-pulse (1p) and multi-pulse (5p at 20hz) electrical stimulation of dopamine release (μM) and reuptake rate (Vmax) in the nucleus accumbens (NAc) core. Because we only observed effects of diet on these parameters, male and female data were combined for baseline analyses. Dopamine release after (B) single- (1p) and (C) multi- (5p) pulse stimulations for LF, HF30, and HF60 groups. (D) Vmax (μM/s) measuring maximal dopamine reuptake rate and comparing across experimental groups. Data represent 1–2 recordings collected from up to three slices per mouse used for ex-vivo FSCV. In the LF group n=49 total recordings were collected in n=23 slices from n=14 males, and n=26 slices from n=14 females. The HF30 group n=22 total recordings were collected in n=10 slices from n=6 males, and n=12 slices from n=6 females. In the HF60 group n=56 recordings were collected in n=26 slices from n=13 males, and n=20 slices from n=14 females. (B-D) data points with solid fill represent males; symbols with white fill represent females. Data is presented as individual means ± SEM, with *p<0.05, ***p<0.001.
Figure 3:
Figure 3:. Effects of IL-6 on Dopamine Release and Reuptake Rate-
Two concentrations of IL-6 were used to examine dopamine kinetics; 5nM IL-6 (A-D) and 10nM IL-6 (E-H). Dopamine release is reported as percent of the average μM dopamine release in the last three baseline collections prior to adding IL-6 for (A) 5nM IL-6 and (E) 10nM IL-6. IL-6 was washed over the slices for 30 minutes followed by a 30-minute washout with standard aCSF. (B) and (F) Comparison of dopamine release during the final washout collections of 5nM or 10nM IL-6, respectively. (C) and (G) Comparison of the maximal rate of dopamine reuptake (Vmax) during the last aCSF washout collection, expressed as % of baseline, for 5nM or 10nM IL-6, respectively. One FSCV recording was collected per slice for each IL-6 dose. A representative line trace from each dietary group is shown for both 5nM (D) and 10nM (H) IL-6 concentrations. This collection occurred after baseline dopamine parameters were assessed. For 5nM IL-6; LF: n=6 males and n=8 females, HF30: n=4 males and n=3 females, HF60: n=6 males and n=8 females. For 10nM IL-6; LF: n=4 males and n=4 females, HF30: n=3 males and n=4 females, HF60: n=6 males and n=5 females. Data represents group means ± SEM with *p<0.05. (B-C) and (F-G) show data points with solid fill that represent males while symbols with white fill represent females.
Figure 4:
Figure 4:. Effects of TNFα on Dopamine Release and Reuptake Rate-
Two concentrations of TNFα were used to examine dopamine kinetics; 30nM TNFα (A-D) and 300nM TNFα (E-H). Dopamine release is reported as percent of the average μM dopamine release in the last three baseline collections prior to adding TNFα for (A) 30nM TNFα and (E) 300nM TNFα. TNFα was washed over the slices for 30 minutes followed by a 30-minute washout with standard aCSF. (B) and (F): comparisons of dopamine release during the final washout collections of 30nM or 300nM TNFα, respectively. (C) and (G): comparisons for maximal rate of dopamine reuptake (Vmax) during the last aCSF washout collection, expressed as % of baseline, for 30nM or 300nM TNFα, respectively. One FSCV recording was collected per slice for each TNFα dose. A representative line trace from each dietary group is shown for both 30nM (D) and 300nM (H) TNF⍺, respectively. This collection occurred after baseline dopamine parameters were assessed. For 30nM TNFα; LF: n=5 males and n=6 females, HF30: n=4 males and n=4 females, HF60: n=6 males and n=6 females. For 300nM TNFα; LF: n=6 males and n=6 females, HF30: n=3 males and n=4 females, HF60: n=4 males and n=5 females. Data represents group means ± SEM. *p<0.05 (B-C) and (F-G) show data points with solid fill that represent males while symbols with white fill represent females.
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