Ghrelin promotes slow-wave sleep in humans.

Ghrelin, an endogenous ligand of the growth hormone (GH) secretagogue (GHS) receptor, stimulates GH release, appetite, and weight gain in humans and rodents. Synthetic GHSs modulate sleep electroencephalogram (EEG) and nocturnal hormone secretion. We studied the effect of 4 x 50 microg of ghrelin administered hourly as intravenous boluses between 2200 and 0100 on sleep EEG and the secretion of plasma GH, ACTH, cortisol, prolactin, and leptin in humans (n = 7). After ghrelin administration, slow-wave sleep was increased during the total night and accumulated delta-wave activity was enhanced during the second half of the night. Rapid-eye-movement (REM) sleep was reduced during the second third of the night, whereas all other sleep EEG variables remained unchanged. Furthermore, GH and prolactin plasma levels were enhanced throughout the night, and cortisol levels increased during the first part of the night (2200-0300). 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. Leptin levels did not differ between groups. Our data show a distinct action of exogenous ghrelin on sleep EEG and nocturnal hormone secretion. We suggest that ghrelin is an endogenous sleep-promoting factor. This role appears to be complementary to the already described effects of the peptide in the regulation of energy balance. Furthermore, ghrelin appears to be a common stimulus of the somatotropic and hypothalamo-pituitary-adrenocortical systems. It appears that ghrelin is a sleep-promoting factor in humans.

[1]  A. Steiger,et al.  The hypothalamic-pituitary-adrenocortical system and sleep in man. , 1995, Advances in neuroimmunology.

[2]  M. Fujimiya,et al.  A Role of Ghrelin in Neuroendocrine and Behavioral Responses to Stress in Mice , 2001, Neuroendocrinology.

[3]  K. Nakao,et al.  Ghrelin strongly stimulates growth hormone release in humans. , 2000, The Journal of clinical endocrinology and metabolism.

[4]  M. Opp.  Rat Strain Differences Suggest a Role for Corticotropin-Releasing Hormone in Modulating Sleep , 1997, Physiology & Behavior.

[5]  S. Henriksen,et al.  Effects of corticotropin-releasing factor and growth hormone-releasing factor on sleep and activity in rats. , 1986, Neuroendocrinology.

[6]  D. Kupfer,et al.  Hypothalamic peptide modulation of EEG sleep in depression: A further application of the S-process hypothesis , 1987, Biological Psychiatry.

[7]  R. Batterham,et al.  Ghrelin causes hyperphagia and obesity in rats. , 2001, Diabetes.

[8]  Márta Korbonits,et al.  The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans. , 2002, The Journal of clinical endocrinology and metabolism.

[9]  Patrick R. Griffin,et al.  A Receptor in Pituitary and Hypothalamus That Functions in Growth Hormone Release , 1996, Science.

[10]  J. Kamegai,et al.  Chronic central infusion of ghrelin increases hypothalamic neuropeptide Y and Agouti-related protein mRNA levels and body weight in rats. , 2001, Diabetes.

[11]  P. Linkowski,et al.  Effects of intravenous catheter on sleep in healthy men and in depressed patients. , 1989, Sleep.

[12]  A. Steiger,et al.  Neuropeptides and human sleep. , 1997, Sleep.

[13]  G. Frost,et al.  Ghrelin enhances appetite and increases food intake in humans. , 2001, The Journal of clinical endocrinology and metabolism.

[14]  A. Steiger,et al.  Effects of growth hormone-releasing hormone and somatostatin on sleep EEG and nocturnal hormone secretion in male controls. , 1992, Neuroendocrinology.

[15]  C. Tomasetto,et al.  Printed in U.S.A. Copyright © 2002 by The Endocrine Society Ultradian Rhythmicity of Ghrelin Secretion in Relation with GH, Feeding Behavior, and Sleep-Wake Patterns in Rats , 2022 .

[16]  M. Korbonits,et al.  The growth hormone secretagogue hexarelin stimulates the hypothalamo-pituitary-adrenal axis via arginine vasopressin. , 1999, The Journal of clinical endocrinology and metabolism.

[17]  F. Casanueva,et al.  Ghrelin-induced growth hormone secretion in humans. , 2000, European journal of endocrinology.

[18]  C. Guilleminault,et al.  EEG arousals: scoring rules and examples: a preliminary report from the Sleep Disorders Atlas Task Force of the American Sleep Disorders Association. , 1992, Sleep.

[19]  A. Steiger,et al.  Enhanced slow wave sleep in patients with prolactinoma. , 1998, The Journal of clinical endocrinology and metabolism.

[20]  S. Dickson,et al.  Systemic Administration of Ghrelin Induces Fos and Egr‐1 Proteins in the Hypothalamic Arcuate Nucleus of Fasted and Fed Rats , 2000, Journal of neuroendocrinology.

[21]  M. Opp,et al.  Blockade of corticotropin-releasing hormone receptors reduces spontaneous waking in the rat. , 1998, American journal of physiology. Regulatory, integrative and comparative physiology.

[22]  A. Steiger,et al.  Neuropeptide Y promotes sleep and inhibits ACTH and cortisol release in young men , 2000, Neuropharmacology.

[23]  Wallace B. Mondeison.  Studies of human growth hormone secretion in sleep and waking. , 1982 .

[24]  A. Steiger,et al.  VIP decelerates non-REM-REM cycles and modulates hormone secretion during sleep in men. , 1996, The American journal of physiology.

[25]  Y. Taché,et al.  Peripheral ghrelin selectively increases Fos expression in neuropeptide Y – synthesizing neurons in mouse hypothalamic arcuate nucleus , 2002, Neuroscience Letters.

[26]  J. Vincent,et al.  Effects of chronic icv infusion of vasopressin on sleep-waking cycle of rats. , 1989, American Journal of Physiology.

[27]  W. Mendelson.  Studies of human growth hormone secretion in sleep and waking. , 1982, International review of neurobiology.

[28]  J. Wakerley,et al.  Central oxytocin potentiates excitatory responses of oxytocin neurones to stimulation of the dorsomedial hypothalamic nucleus in the suckled rat , 2002, Neuroscience Letters.

[29]  A. Steiger,et al.  Somatostatin Impairs Sleep in Elderly Human Subjects , 1997, Neuropsychopharmacology.

[30]  M. Lancel,et al.  Sleep and Its Modulation by Drugs That Affect GABA(A) Receptor Function. , 1999, Angewandte Chemie.

[31]  S. Bloom,et al.  The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion. , 2000, Endocrinology.

[32]  A. Steiger.  Sleep and the hypothalamo-pituitary-adrenocortical system. , 2002, Sleep medicine reviews.

[33]  A. Steiger,et al.  Growth hormone-releasing peptide-6 stimulates sleep, growth hormone, ACTH and cortisol release in normal man. , 1995, Neuroendocrinology.

[34]  C. Ehlers,et al.  Electrophysiological Actions of Neuropeptide Y and Its Analogs: New Measures for Anxiolytic Therapy? , 1997, Neuropsychopharmacology.

[35]  M. Tschöp,et al.  Ghrelin induces adiposity in rodents , 2000, Nature.

[36]  E. Arvat,et al.  Effects of Dexamethasone and Alprazolam, a Benzodiazepine, on the Stimulatory Effect of Hexarelin, a Synthetic GHRP, on ACTH, Cortisol and GH Secretion in Humans , 1998, Neuroendocrinology.

[37]  E. van Cauter,et al.  Prolonged oral treatment with MK-677, a novel growth hormone secretagogue, improves sleep quality in man. , 1997, Neuroendocrinology.

[38]  T. Horvath,et al.  0013-7227/01/$03.00/0 Endocrinology 142(10):4163–4169 Printed in U.S.A. Copyright © 2001 by The Endocrine Society Minireview: Ghrelin and the Regulation of Energy , 2022 .

[39]  M. Kerkhofs,et al.  Evidence against a role for the growth hormone-releasing peptide axis in human slow-wave sleep regulation. , 1998, American journal of physiology. Endocrinology and metabolism.

[40]  J. Krueger,et al.  The somatotropic axis and sleep. , 2001, Revue neurologique.

[41]  M. Papotti,et al.  The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A. Copyright © 2001 by The Endocrine Society Endocrine Activities of Ghrelin, a Natural Growth Hormone Secretagogue (GHS), in Humans: Comparison and Interactions with Hexarelin, a Nonnatura , 2022 .

[42]  A. Rechtschaffen.  A manual of standardized terminology, techniques and scoring system for sleep of human subjects , 1968 .

[43]  C. Tomasetto,et al.  In vivo and in vitro Effects of Ghrelin/Motilin-Related Peptide on Growth Hormone Secretion in the Rat , 2001, Neuroendocrinology.

[44]  E. Wolpert.  A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects. , 1969 .

[45]  J. Krueger,et al.  Central administration of the somatostatin analog octreotide induces captopril-insensitive sleep responses. , 1999, American journal of physiology. Regulatory, integrative and comparative physiology.

[46]  A. Steiger,et al.  Neurosteroid pregnenolone induces sleep-EEG changes in man compatible with inverse agonistic GABAA-receptor modulation , 1993, Brain Research.

[47]  A. Steiger,et al.  Effects of intravenous corticotropin-releasing hormone upon sleep-related growth hormone surge and sleep EEG in man. , 1988, Neuroendocrinology.

[48]  K. C. Yeh,et al.  A comparison of numerical integrating algorithms by trapezoidal, Lagrange, and spline approximation , 1978, Journal of Pharmacokinetics and Biopharmaceutics.

[49]  M. Nakazato,et al.  A role for ghrelin in the central regulation of feeding , 2001, Nature.

[50]  J. Krueger,et al.  Corticotropin-releasing factor attenuates interleukin 1-induced sleep and fever in rabbits. , 1989, The American journal of physiology.

[51]  M. Nakazato,et al.  Ghrelin is a growth-hormone-releasing acylated peptide from stomach , 1999, Nature.

[52]  K. Hosoda,et al.  Ghrelin, an endogenous growth hormone secretagogue, is a novel orexigenic peptide that antagonizes leptin action through the activation of hypothalamic neuropeptide Y/Y1 receptor pathway. , 2001, Diabetes.

[53]  J. Krueger,et al.  Sleep in mice with nonfunctional growth hormone-releasing hormone receptors. , 2003, American journal of physiology. Regulatory, integrative and comparative physiology.