Sleep Restriction Enhances the Daily Rhythm of Circulating Levels of Endocannabinoid 2-Arachidonoylglycerol

Abstract

Study objectives: Increasing evidence from laboratory and epidemiologic studies indicates that insufficient sleep may be a risk factor for obesity. Sleep curtailment results in stimulation of hunger and food intake that exceeds the energy cost of extended wakefulness, suggesting the involvement of reward mechanisms. The current study tested the hypothesis that sleep restriction is associated with activation of the endocannabinoid (eCB) system, a key component of hedonic pathways involved in modulating appetite and food intake.

Methods: In a randomized crossover study comparing 4 nights of normal (8.5 h) versus restricted sleep (4.5 h) in healthy young adults, we examined the 24-h profiles of circulating concentrations of the endocannabinoid 2-arachidonoylglycerol (2-AG) and its structural analog 2-oleoylglycerol (2-OG). We concomitantly assessed hunger, appetite, and food intake under controlled conditions.

Results: A robust daily variation of 2-AG concentrations with a nadir around the middle of the sleep/overnight fast, followed by a continuous increase culminating in the early afternoon, was evident under both sleep conditions but sleep restriction resulted in an amplification of this rhythm with delayed and extended maximum values. Concentrations of 2-OG followed a similar pattern, but with a lesser amplitude. When sleep deprived, participants reported increases in hunger and appetite concomitant with the afternoon elevation of 2-AG concentrations, and were less able to inhibit intake of palatable snacks.

Conclusions: Our findings suggest that activation of the eCB system may be involved in excessive food intake in a state of sleep debt and contribute to the increased risk of obesity associated with insufficient sleep.

Commentary: A commentary on this article appears in this issue on page 495.

Keywords: appetite; endocannabinoid; hedonic food intake; hunger; obesity; sleep restriction.

Figure 1

The protocol followed a randomized crossover design with two 5-night in-laboratory sessions spaced by at least 1 month. Each session included one habituation night, followed by 4 experimental nights with either 4.5 (RS1-RS4, red bars) or 8.5 (NS1-NS4, black bars) h/night in bed. Over the third experimental night beginning at 21:00, 24-h blood sampling was initiated to examine circulating endocannabinoid, cortisol, leptin, and ghrelin levels (dashed lines). Throughout the following day, identical carbohydrate-rich meals were served at 09:00, 14:00, and 19:00 (denoted by black arrows). Questionnaires to assess hunger, appetite, vigor, and affect were administered at 08:35, 10:35, 13:35, 15:35, 18:35, and 20:35 (denoted by v). In the afternoon following the fourth experimental night, participants were exposed to an ad libitum (ad lib) buffet for lunch at 15:00 and dinner at 19:30 (denoted by open arrows), with a snack period between the meal opportunities (graded line).

Figure 2

Mean 24-h profiles of 2-AG (A) and 2-OG (B), expressed as % of 24-h mean of the normal sleep condition during the restricted 4.5 h (red) or normal 8.5 h (black) sleep condition (n = 14). Vertical bars at each time point represent the standard error of the mean. The sleep period is denoted with red or black bars. Closed arrows represent the identical carbohydrate-rich meals, presented at 09:00, 14:00, and 19:00. Open arrows denote the acrophase of the normal sleep condition (black) and restricted sleep condition (red) profiles. 2-AG, 2-arachidonoylglycerol; 2-OG, 2-oleoylglycerol.

Figure 3

Mean 24-h profiles of leptin (A), total ghrelin (B), and cortisol (C) expressed as % of the 24-h during normal sleep (NS) during the restricted 4.5 h (red) or normal 8.5 h (black) sleep condition (n = 14). Vertical bars at each time point represent the standard error of the mean. The sleep period is denoted with red or black bars. Arrows represent the identical carbohydrate-rich meals, presented at 09:00, 14:00, and 19:00.

Figure 4

Ratings of hunger (A), desire to eat (B), quantity of food that could be eaten (C), feeling of fullness (D), global appetite (E), vigor (F), and mood (G) following 3 experimental nights of either 4.5 h (red) or 8.5 h (black) in bed (n = 14). Participants were asked to score visual analog scales 25 min before and 1.5 h after each meal, for a total of six ratings across the day.

Figure 5

Caloric intake for each of the ad libitum (ad lib) eating opportunities in the 8.5 h in bed (black) or in the 4.5 h in bed (red) conditions. Eating opportunities included a 15:00 and a 19:30 meal (n = 14), and an intervening period where palatable snacks were presented (n = 13). Data shown are mean (± standard error of the mean). Horizontal panels present Kcal intake for each eating opportunity (left) and compensatory decrease in snack intake after consumption of the 15:00 meal (right) for each sleep condition (back bars: normal sleep; red bars: restricted sleep). From top to bottom: total caloric intake (A,B), carbohydrate intake (C,D), fat intake (E,F), and protein intake (G,H). Please note the difference in eating patterns between the two conditions; in the normal sleep (NS) condition there is a rebound in intake during the dinner meal, however there is no large increase in dinner intake following snack consumption in the RS (restricted sleep) condition. This lack of increase in dinner meal from snack intake is due to high kcal intake during the snack opportunity in the RS group.