Low Dopamine D2 Receptor Increases Vulnerability to Obesity Via Reduced Physical Activity, Not Increased Appetitive Motivation

Abstract

Background: The dopamine D2 receptor (D2R) has received much attention in obesity studies. Data indicate that D2R is reduced in obesity and that the TaqA1 D2R variant may be more prevalent among obese persons. It is often suggested that reduced D2R generates a reward deficiency and altered appetitive motivation that induces compulsive eating and contributes to obesity. Although dopamine is known to regulate physical activity, it is often neglected in these studies, leaving open the question of whether reduced D2R contributes to obesity through alterations in energy expenditure and activity.

Methods: We generated a D2R knockdown (KD) mouse line and assessed both energy expenditure and appetitive motivation under conditions of diet-induced obesity.

Results: The KD mice did not gain more weight or show increased appetitive motivation compared with wild-type mice in a standard environment; however, in an enriched environment with voluntary exercise opportunities, KD mice exhibited dramatically lower activity and became more obese than wild-type mice, obtaining no protective benefit from exercise opportunities.

Conclusions: These data suggest the primary contribution of altered D2R signaling to obesity lies in altered energy expenditure rather than the induction of compulsive overeating.

Keywords: Behavioral thrift; D(2)R; Dietary induced obesity; Reward deficiency; Running wheels; Voluntary exercise.

Figure 1. Effect of running wheels on WT and KD mice in dietary induced obesity

(A) Body weights across experiment (weights taken 1x/week). (B) Percent change from initial to final weight, sexes shown separately. (C) total caloric consumption during a 14-day home cage concurrent choice with freely available high fat diet and sucrose via operant responding (b.w., body weight). (D) total daily wheel running across 14-day period. (D) Average daily running across 14-day period. ** p < .01, *** p < .001, N.S., not significant. WT: N=16/group; KD: N=8/group. (E) Average daily running across 14-day period. **p < .01, ***p < .001. WT: n = 16/group; D2KD: n = 8/group. N.S., not significant.

Figure 2. Wheel activity patterns in WT and KD mice

(A) Total number of wheel turns in one-minute bins across the entire 14-day experiment. (B) Wheel turns in one-minute bins across circadian cycles of a 24 hour period, averaged across experiment. (C) Bout analysis, showing (C1) average daily number of running bouts, (C2) average duration of bouts, (C3) average speed of running (turns/min) and (C4) the average inter-bout interval. * p < .05, ** p < .01, *** p < .001, N.S., not significant difference. N=11, WT; N=6, KD.

Figure 3. Open field activity in WT and KD mice

(A) Ambulatory distance (cm) in 5-minute blocks across a 60 minute testing session, averaged across 3 consecutive sessions. (B) Time resting (no ambulation) in 5-minute blocks. (C) Average number of ambulatory blocks per 5-minute block. (D) Average ambulatory velocity across entire session. * p < .05, N=8.

Figure 4. Indirect calorimetry

(A) average daily consumption normalized to body weight, (B) metabolic rate (kcal/hr/kg bodyweigh, b.w.), (C) horizontal activity counts and (D) vertical activity counts for active and inactive periods for KD homozygotes (red), heterozygotes (pink) and WT littermates (blue). ** p < .01, N = 7, WT; 9, hom; 8, het.

Figure 5. Home cage concurrent choice with freely available high fat diet

(A) average daily sucrose pellets earned per gram of body weight. (B) Percentage of total daily kilocalorie (kcal) intake derived from sucrose. (C) average daily active lever presses (LP) for sucrose normalized to body weight (b.w.). (D) average daily inactive lever presses (not normalized). (E) Average breakpoint for bouts of sucrose seeking. (F) Average size of bouts of sucrose consumption normalized to body weight. (G) Average daily number of bouts of sucrose seeking. (H) Average cost per pellet in lever presses. * p < .05, ** p < .01, *** p < .001, N.S., not significant. WT: N=16/group; KD: N=8/group.

Figure 6. Effect of wheels on glucose regulation in WT and KD mice

Fasting (6 hr) blood glucose levels for (A) male and (B) female mice. (C and E) Glucose challenge (dextrose, 1 g/kg total body mass, i.p.) for WT (blue) and KD (red). Offset: area under the curve (AUC). (D and F) Insulin challenge (0.5 U/kg total body mass, i.p.), WT (blue), KD (red). Offset: AUC. ** p < .01, *** p < .001, N.S., not significant difference. WT: N=16/group; KD: N=8/group.