Sex differences in the circadian misalignment effects on energy regulation

Abstract

Shift work causes circadian misalignment and is a risk factor for obesity. While some characteristics of the human circadian system and energy metabolism differ between males and females, little is known about whether sex modulates circadian misalignment effects on energy homeostasis. Here we show-using a randomized cross-over design with two 8-d laboratory protocols in 14 young healthy adults (6 females)-that circadian misalignment has sex-specific influences on energy homeostasis independent of behavioral/environmental factors. First, circadian misalignment affected 24-h average levels of the satiety hormone leptin sex-dependently (P < 0.0001), with a ∼7% decrease in females (P < 0.05) and an ∼11% increase in males (P < 0.0001). Consistently, circadian misalignment also increased the hunger hormone ghrelin by ∼8% during wake periods in females (P < 0.05) without significant effect in males. Females reported reduced fullness, consistent with their appetite hormone changes. However, males reported a rise in cravings for energy-dense and savory foods not consistent with their homeostatic hormonal changes, suggesting involvement of hedonic appetite pathways in males. Moreover, there were significant sex-dependent effects of circadian misalignment on respiratory quotient (P < 0.01), with significantly reduced values (P < 0.01) in females when misaligned, and again no significant effects in males, without sex-dependent effects on energy expenditure. Changes in sleep, thermoregulation, behavioral activity, lipids, and catecholamine levels were also assessed. These findings demonstrate that sex modulates the effects of circadian misalignment on energy metabolism, indicating possible sex-specific mechanisms and countermeasures for obesity in male and female shift workers.

Keywords: appetite; circadian disruption; energy metabolism; sex difference; shift work.

Fig. 1.

Circadian alignment protocol (Top) and circadian misalignment protocol (Bottom) as part of the randomized, cross-over design. Twenty-four-hour metabolic profiles were assessed on days 5 and 7 in the circadian alignment protocol and across days 5/6 and 7/8 in the circadian misalignment protocol (red and purple dashed lines as test day 1 and test day 3, respectively). Light levels indicated are in the horizontal angle of gaze. Green and blue bars represent test meals (green), other meals (wide blue), and snacks (narrow blue).

Fig. 2.

Effects of circadian misalignment on leptin (A) and active ghrelin (B) levels and hunger (C) and full (D) ratings in females (Left) and males (Middle). Gray bar represents sleep opportunity; green dotted line represents a meal. Percentage changes (A and B) or absolute changes (C and D) under circadian misalignment as compared to circadian alignment across 24 h or during SP and WP are shown in the bar graphs (Right). As aforementioned, since there were no significant interaction effects of duration of exposure and other main effects, values are reported as both test days combined. Each black dot represents an individual value. P values, statistical significance for interaction effect of misalignment and sex. Adj. P values for subgroup analysis by sex, *adj. P < 0.05; ***adj. P < 0.0001.

Fig. 3.

Effects of circadian misalignment on cravings for various foods in females (Left) and males (Middle). Green dotted line represents a meal. Changes under circadian misalignment as compared to circadian alignment are shown in the bar graphs (Right). Values are reported as both test days combined. Each black dot represents an individual value. P values, statistical significance for interaction effect of misalignment and sex. Adj. P values for subgroup analysis by sex, *adj. P < 0.05; **adj. P < 0.01.

Fig. 4.

Effects of circadian misalignment on energy expenditure (A), respiratory quotient (B), glucose oxidation rate (C), and lipid oxidation rate (D) in females (Left) and males (Middle). Green bar represents a meal. Percentage changes (A and B) or absolute changes (C and D) under circadian misalignment as compared to circadian alignment are shown in the bar graphs (Right). Values are reported as both test days combined. Each black dot represents an individual value. P values, statistical significance for interaction effect of misalignment and sex. Adj. P values for subgroup analysis by sex, *adj. P < 0.05; **adj. P < 0.01, ***adj. P < 0.0001.