The role of ghrelin in the regulation of sleep, hormone secretion and appetite
The peptide ghrelin is an endogenous ligand of the growth-hormone secretagogue (GHS) receptor. It participates in the regulation of hormone secretion and of the energy balance. We showed that repetitive administration of 4 x 50 µg ghrelin between 22 h and 1 h to young normal men results in increases of slow wave sleep, slow wave activity, GH, cortisol and prolactin levels. The response of GH to ghrelin was most distinct after the first injection and lowest after the fourth injection. In contrast cortisol showed an inverse pattern of response. The effects of ghrelin on sleep and GH are similar to those of growth hormone-releasing hormone (GHRH) in young male subjects. Cortisol, however, is stimulated after ghrelin (and the synthetic GHSs growth hormone-releasing peptide 6 and hexarelin) whereas it is blunted after GHRH. We suggest that ghrelin is an endogenous sleep-promoting factor. Furthermore we hypothesise that ghrelin acts as an interface of the hypothalamo-pituitary-somatotropic and the hypothalamo-pituitary-adrenocortical systems.
Fig. 1. Effects of ghrelin on delta power activity. Accumulated delta power (± SEM) for time in bed after injection of 4 × 50 µg ghrelin compared with placebo (n = 7). Grey area, significant changes after ghrelin administration. (Am J Physiol Endocrinol Metab 284: E407-415, 2003 Weikel et al Fig 1, Copyright by The American Physiological Society, used with permission).
Fig. 2. Time course of nocturnal plasma hormone concentrations. Nocturnal secretions of growth hormone (ACTH), cortisol, and prolactin (means ± SEM) after iv injection of 4 × 50 µg of ghrelin compared with placebo (n = 7). Arrows, times of injections. (Am J Physiol Endocrinol Metab 284: E407-415, 2003 Weikel et al Fig 2, Copyright by The American Physiological Society, used with permission).
In contrast sleep remained unchanged in young normal male subjects, when 4 x 50 µg ghrelin were injected hourly during the early morning between 4 h and 7 h, whereas GH and cortisol increased. This finding suggests that the effect of ghrelin on sleep depends on the time of administration. Similarly GHRH does not affect sleep after injection in the early morning. In young healthy women sleep EEG remained unchanged after ghrelin, whereas similar to the effect in male subjects, GH and cortisol increased. Obviously there is a gender difference in the effect of ghrelin on sleep, similar to the sexual dimorphism of sleep-EEG changes after GHRH.
Partly different gender differences were observed after ghrelin in drugfree patients with depression. Administration of 4 x 50 µg ghrelin improved sleep in male patients. Furthermore a trend was found of improved scores in a selfrating scale (Befindlichkeits-Skala). In female patients the amount of REM sleep decreased. The pattern of cortisol secretion after ghrelin differed between female and male patients.
In order to study the interaction between nocturnal ghrelin levels, sleep and the nocturnal secretion of GH, adrenocorticotropic hormone (ACTH) and cortisol, we examined simultaneously sleep EEG and nocturnal hormone secretion in healthy female and male subjects. Significant interaction between gender and the course of ghrelin concentration was observed in the interval between 20 h and sleep onset (23 h). In males a continuous increase of ghrelin levels before sleep onset was found. In females however a rise of ghrelin during the night was missed. We found a trend suggesting a lower time spent in shallow sleep in subjects with high nocturnal ghrelin levels. Systemic interactions between ghrelin, sleep EEG and other hormones were not found. Particularly there was no peak in plasma ghrelin levels resembling the nocturnal GH surge. In another study we compared ghrelin levels between the nights before and after 40 hours of sleep deprivation. Compared to baseline ghrelin increased earlier after sleep deprivation and a trend occurred suggesting higher ghrelin secretion in the first half of the night. This finding supports the view that ghrelin is a sleep-promoting substance.
Fig. 3. Nocturnal ghrelin secretion (mean ± SEM) at baseline and after sleep deprivation. (Reprinted from Psychoneuroendocrinology (31), Schüssler et al., Nocturnal ghrelin, ACTH, GH and cortisol secretion after sleep deprivation in humans, Fig 1 b, p. 915-923, Copyright 2006, used with permission from Elsevier).
Ghrelin affects the hypothalamic-pituitary-gonadal axis in various nonhuman mammals, predominantly by suppressing the secretion of luteinizing hormone (LH). We studied the effects of ghrelin on secretion of LH and testosterone in young normal male subjects. After ghrelin both LH and testosterone levels decreased. Ghrelin induced both delay and suppression of the amplitude of LH pulses. The decrease of testosterone occurred about one hour after the LH changes. Therefore it appears likely that testosterone suppression is secondary to the changes of LH secretion.
In order to elucidate the interaction of ghrelin, GHRH and corticotropin-releasing hormone (CRH) in sleep regulation, young normal male controls underwent four treatments according to randomized schedule: A) placebo, B) ghrelin alone, C) ghrelin + GHRH, D) ghrelin + CRH. When compared to placebo nonREM sleep decreased after all other three conditions, whereas the amount of REM sleep decreased. Interestingly the increase of nonREM sleep was most distinct after ghrelin and CRH. Sleep promotion after this combination was also evident by decrease of intermittent wakefulness. Furthermore REM latency decreased. CRH enhanced the ghrelin-induced cortisol secretion, but had no relevant effect on GH secretion. In turn, GHRH enhanced the ghrelin-induced GH secretion but had no effect on cortisol secretion. This study confirmed the sleep-promoting effect of ghrelin in young men. This effect was enhanced by both GHRH and CRH. The sleep promotion after CRH combined with ghrelin comes as a surprise, since in previous studies CRH alone impaired sleep.
In one subject we observed a distinct increase of hunger after 100 µg ghrelin given at bedtime. After a single iv injection of 100 µg ghrelin in the morning the appetite was enhanced in 8 of 9 young normal women and men. The subjects reported a vivid lasting image of their preferred meal. Leptin, which appears to inhibit food intake, remained unchanged. Our findings suggest that the role of ghrelin in the regulation of human eating is more complex than suspected so far. In addition to stimulation of appetite, cognitive functions appear to be involved. Exogenous ghrelin appears to be capable in promoting appetite independently from acute action on leptin. Interestingly in one female patient with night eating syndrome nocturnal ghrelin levels were distinctly higher than in healthy women.
Research groups involved:
RG Axel Steiger: Petra Schüssler, Michael Kluge
Kluge, M., Schüssler, P., Dresler, M., Schmidt, D., Yassouridis, A., Uhr, M., Steiger, A.: Effects of ghrelin on psychopathology, sleep and secretion of cortisol and growth hormone in patients with major depression. Journal of Psychiatric Research 45 (2011) 421-426
Steiger, A., Dresler, M., Schüssler, P., Kluge, M.: Ghrelin in mental health, sleep, memory. Molecular and Cellular Endocrinology 340 (2011) 88-96
Kluge M., Gazea M., Schüssler P., Genzel L., Dresler M., Kleyer S., Uhr M., Yassouridis A., Steiger A. (2010) Ghrelin increases slow wave sleep and stage 2 sleep and decreases stage 1 sleep and REM sleep in elderly men but does not affect sleep in elderly women. Psychoneuroendocrinology 35:297-304.
Kluge M., Riedl S., Uhr M., Schmidt D., Zhang X., Yassouridis A., Steiger A. (2010) Ghrelin affects the hypothalamus-pituitary-thyroid (HPT) axis in humans by increasing free thyroxine and decreasing TSH in plasma. European Journal of Endocrinology 162:1059-65.
Kluge M., Schüssler P., Schmid D., Uhr M., Kleyer S., Yassouridis A., Steiger A. (2009) Ghrelin plasma levels are not altered in major depression. Neuropsychobiology, 59, 199-204
Kluge M., Uhr M., Bleninger P., Yassouridis A., Steiger A. (2009) Ghrelin suppresses secretion of follicle stimulating hormone (FSH) in males. Clin. Endocrinol. 70:920-3
Kluge M., Schüssler P., Bleninger P., Kleyer S., Uhr M., Weikel J.C., Yassouridis A., Zuber V., Steiger A. (2008) Ghrelin alone or co-administered with GHRH or CRH increases non-REM sleep and decreasesREM sleep in young males. Psychoneuroendocrinology, 33, 497-506
Kluge M., Schüssler P., Uhr M., Yassouridis A., Steiger A. (2007) Ghrelin suppresses secretion of luteinizing hormone in humans. Journal of Clinical Endocrinology & Metabolism, 92, 3202-3205
Kluge M., Schüssler P., Zuber V., Kleyer S., Yassouridis A., Dresler M., Uhr M., Steiger A. (2007) Ghrelin enhances the nocturnal secretion of cortisol and growth hormone in young females without influencing sleep. Psychoneuroendocrinology 32, 1079-1085
Steiger A. (2007) Ghrelin and sleep-wake regulation. American Journal of Physiology - Regulatory Integrative & Comparative Physiology, 292, 2006-2007
Kluge M., Schüssler P., Zuber V., Yassouridis A., Steiger A. (2007) Ghrelin administered in the early morning increases secretion of cortisol and growth hormone without affecting sleep. Psychoneuroendocrinology, 32, 287-292
Schüssler P., Uhr M., Ising M., Weikel J.C., Schmid D.A., Held K., Mathias S., Steiger A. (2006) Nocturnal ghrelin, ACTH, GH and cortisol secretion after sleep deprivation in humans. Psychoneuroendocrinology, 31, 915-923
Rosenhagen M.C., Uhr M., Schüssler P., Steiger A. (2005) Elevated plasma ghrelin levels in night-eating syndrome. Am. J. Psychiatry, 162, 813
Schmid D.A., Held K., Ising M., Uhr M., Weikel J.C., Steiger A. (2005) Ghrelin stimulates appetite, imagination of food, GH, ACTH and cortisol, but does not affect leptin in normal controls. Neuropsychopharmacology, 30, 1187-1192
Schüssler P., Uhr M., Ising M., Schmid D., Weikel J., Steiger A. (2005) Nocturnal ghrelin levels - relationship to sleep EEG, the levels of growth hormone, ACTH and cortisol - and gender differences. J. Sleep Res., 14, 329-336
Frieboes R.M., Antonijevic I.A., Held K., Murck H., Pollmächer T., Uhr M., Steiger A. (2004) Hexarelin decreases slow-wave sleep and stimulates the sleep-related secretion of GH, ACTH, cortisol and prolactin during sleep in healthy volunteers. Psychoneuroendocrinology, 29, 851-860
Steiger A. (2004) Eating and sleeping-their relationship to ghrelin and leptin. Am J Physiol Regul. Integr. Comp. Physiol., 287, 1031-31032
Weikel J.C., Wichniak, A., Ising M., Brunner H., Friess E., Held K., Mathias S., Schmid D.A., Uhr M., Steiger A. (2003) Ghrelin promotes slow-wave sleep in humans. Am. J. Physiol, 284, 407-415