Long-term high fat diet consumption reversibly alters feeding behavior via a dopamine-associated mechanism in mice

Abstract

Obesity is a costly, global epidemic that is perpetuated by an unhealthy diet. A significant factor in the initial consumption and maintenance of an unhealthy diet is the abundance of highly palatable, calorically dense foods. The aim of the present study is to better understand the effects of high fat diet (HFD) consumption on food valuation and preference, and to elucidate the neurobiological mechanisms mediating these effects. By using a novel food preference assay, we found that prolonged consumption of a HFD diminishes preference for and consumption of the more calorically dense food choice when two lab diets are presented. Additionally, we demonstrated that prolonged HFD consumption dampens ventral tegmental c-fos induction during hedonic feeding, implicating the mesolimbic dopamine signaling pathway as a target of HFD. Notably, both the changes in food preference and this reduced c-fos induction were reversed during withdrawal from HFD. Further, HFD-induced alterations in food preference were attenuated by exercise. Our findings suggest that prolonged HFD consumption leads to anhedonia and altered feeding choices, and this is associated with changes in mesolimbic dopamine signaling.

Keywords: Dopamine; Exercise; Feeding behavior; Food preference; Nucleus accumbens; Ventral tegmental area.

Fig.1.

Prolonged consumption of a high fat diet diminishes preference for and consumption of a more palatable liquid or solid food choice. (A) Schematic illustrating the 2-bottle experimental setup. (B) Preference for sucrose over water in a two-bottle choice test. Student’s two-tailed t-test; n=9/group. (C) Total fluid consumed (sucrose and water) during the two-bottle choice test. Student’s two-tailed t-test; n=9/group. (D) Schematic illustrating food preference experimental setup. (E) Preference for the more energy dense test chow during the food preference test. Student’s two-tailed t-test; n=10/group. (F) Total amount of both test chows consumed during the food preference test corrected for body weight. Student’s two-tailed t-test; n=10/group. Data are represented as mean ± SEM. **p < 0.01; ***p<0.001; ****p < 0.0001. See also Supplemental Figures 1 and 2.

Fig.2.

HFD-induced alterations in food preference are reversed by dieting. (A) Schematic illustrating the experimental setup. (B) Preference for the more energy dense test chow during the food preference test. One-way ANOVA with Bonferroni post-hoc comparison; n=10/group; F(2,27)=26.40; p<0.0001. (C) Total amount of both test chows consumed during the food preference test corrected for body weight. One-way ANOVA with Bonferroni post-hoc comparison; n=10/group; F(2,27)=78.70; p<0.0001. Data are represented as mean ± SEM. **p < 0.01; ****p < 0.0001. See also Supplemental Figure 4.

Fig.3.

HFD-induced alterations in food preference are reversed by exercise. (A) Schematic illustrating the experimental setup. (B) Preference for the more energy dense test chow during the food preference test. Two-way ANOVA with Bonferroni post-hoc comparison; n=8–14/group; F_exercise(1,35)=7.401, p=0.0101; F_diet(1,35)=11.01, p=0.0021. (C) Total amount of both test chows consumed during the food preference test corrected for body weight. Two-way ANOVA with Bonferroni post-hoc comparison; n=8–14/group; F_exercise(1,35)=1.516, p=0.2264; F_diet(1,35)=68.63, p<0.0001. Data are represented as mean ± SEM. **p < 0.01; ***p < 0.001; ****p < 0.0001. See also Supplemental Figure 5.

Fig.4.

Prolonged HFD consumption leads to a failure of the VTA to respond to a novel food reward. (A) Total number of VTA c-Fos positive cells. One-way ANOVA with Bonferroni post-hoc comparison; n=9–12/group; F(2,28)=5.302; p=0.0111. (B) Total number of VTA TH positive cells. One-way ANOVA with Bonferroni post-hoc comparison; n=9–12/group; F(2,28)=1.892; p= 0.1696. (C) Percentage of VTA TH positive cells that are also c-Fos positive. One-way ANOVA with Bonferroni post-hoc comparison; n=9–12/group; F(2,28)=14.18; p <0.0001. (D) Representative images of VTA sections stained for c-Fos and TH. Dashed boxes represent corresponding areas of the same section. Arrows indicate c-Fos immunoreactivity. Data are represented as mean ± SEM. *p<0.05; ****p < 0.0001. See also Supplemental Figure 6.