Insomnia patients had significantly lower nocturnal ghrelin levels measured at three times (2300 h, 0200 h and 0600 h) than age- and weight-matched healthy control subjects. Leptin levels across the night were similar in both groups. Insomnia patients, who were diagnosed based on clinical interviews using DSM-IV criteria, also had significantly poorer sleep as indicated by polysomnography including less total sleep time, less time spent in stage 2 and REM sleep, more time in stage 1 sleep and poorer sleep efficiency, as compared to healthy controls. Consistent with previous findings (Schuessler et al., 2005
), ghrelin levels negatively correlated with amount of stage 1 sleep. Ghrelin levels did not correlate with any other sleep measure.
Ghrelin plays a role in both energy intake and sleep processes. Ghrelin stimulates appetitive behaviors; levels rise before mealtime and daytime administration promotes appetite and food intake (Cummings and Shannon, 2003
). At night, recent evidence suggests that ghrelin affects sleep. Ghrelin levels rise between 0100 h and 0300 h during sleep and ghrelin stimulates the nocturnal rise in growth hormone. Intravenous administration of ghrelin before bedtime can increase non-REM sleep in men (Kluge et al., 2008
), although sleep propensity and the timing of administration are important. Ghrelin administered in the very early morning (after 400 h) did not affect sleep (Kluge et al., 2007b
). Sleep processes can exert effects on ghrelin levels. Experimental sleep deprivation in healthy adults is associated with decreased
ghrelin levels at night (Dzaja et al., 2004
) but increased
levels during the following day especially in the following afternoon (Spiegel et al., 2004
) and evening (Schussler et al., 2006
). Similarly, in a community-dwelling sample of men and women from the Wisconsin Sleep Cohort Study, increased morning levels of ghrelin were associated with less sleep time (Taheri et al., 2004
). Findings from the current study are consistent with experimental sleep deprivation in which nocturnal ghrelin levels were also found to decrease (Dzaja et al., 2004
). In the current study, insomnia patients had ghrelin levels that were approximately 30% lower than healthy controls, a difference similar in magnitude to those found when comparing obese (Tschop et al., 2001
) or type 2 diabetic adults (Poykko et al., 2003
) with healthy controls.
Leptin levels were higher at 200 h than the other two time points in both groups; however, across the night, leptin levels did not differ between the groups. Like ghrelin and leptin levels rise shortly after sleep onset and this increase is blunted during experimental sleep deprivation (Mullington et al., 2003
). Although mean values for leptin were lower in insomnia patients, these values were not significantly different from healthy controls.
Decreased nocturnal ghrelin in insomnia may be driven by the autonomic nervous system (ANS). Decreases in efferent vagal activity and/or blockade of vagal signaling are associated with decreased ghrelin expression (Williams et al., 2003
; Broglio et al., 2004
; Maier et al., 2004
). Insomnia patients have decreased efferent vagal activity, as measured by decreased heart rate variability (Bonnet and Arand, 1998
), along with heightened sympathetic activity, evidenced by increased circulating catecholamines (Irwin et al., 2003
). However, the effects of sympathetic activity on ghrelin are less clear; changes in circulating epinephrine do not affect ghrelin levels, yet short-term sympathetic nerve stimulation boosts ghrelin expression (Mundinger et al., 2006
). Similarly, sympathetic response to short-term psychological stress is not associated with ghrelin responsivity (Rouach et al., 2007
The findings from the current study suggest an underlying disruption in ghrelin expression that may be important not just for sleep but also for energy balance. Although the current study did not address weight gain, our findings suggest that ghrelin may be important to examine as a mediator or moderator relating poor sleep to body weight. Chronic insomnia is prospectively associated with weight gain (Janson et al., 2001
; Hasler et al., 2004
) and is cross-sectionally associated with obesity (Foley et al., 1995
; Taheri et al., 2004
). Future prospective studies are needed to examine whether ghrelin mediates the relationship between poor sleep and weight gain in insomnia patients.
This study had a number of limitations. The sample was small and comprised entirely of men; the nocturnal profile of leptin and ghrelin in female insomnia patients is unknown. Recent work suggests that gender plays an important role in regulating energy balance with sleep processes (Schuessler et al., 2005
). In one study with only women participants, ghrelin administration provoked the expected increase in growth hormone, but no changes in sleep parameters (Kluge et al., 2007a
). Thus larger studies incorporating male and female insomnia patients are needed. In addition, the number of nocturnal time points was limited in this study and future studies that incorporate more frequent blood draws both at night and during the day are needed. Future work may also elucidate the complex interactions between the course of insomnia, behavior, mood and food intake with energy balance. Lastly, it is unclear whether these findings reflect state or trait changes in hormone regulation. Future work examining ghrelin and leptin and treatment of insomnia (e.g. medication management or behavior therapy) may help determine whether energy balance regulation in insomnia patients can be adjusted with treatment.
Although the number of studies examining ghrelin and leptin continues to increase dramatically, the mechanisms as to how these hormones coordinate both appetitive drives and sleep processes are unclear. Decreased ghrelin in insomnia patients reflects altered endocrine energy balance and indicates that in addition to short-term, experimental sleep loss, long-term sleep difficulties are also associated with altered ghrelin expression.