Ghrelin promotes slow-wave sleep in humans

Abstract

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.

Ghrelin Stimulates Appetite, Imagination of Food, GH, ACTH, and Cortisol, but does not Affect Leptin in Normal Controls

“…Subsequently, he had a large meal (Weikel et al, 2003). This observation fits with various studies from our laboratory and others showing that repetitive (Steiger and Holsboer, 1997;Weikel et al, 2003) and single (Kerkhofs et al, 1993;Antonijevic et al, 1999a) i.v. bolus injections of neuropeptides modulate human behavior, and in the latter experiments, modulate sleep.…”

“…Similarly, we found increases of nocturnal GH, ACTH, and cortisol levels after ghrelin (Weikel et al, 2003) and after the synthetic GHS, GH-releasing peptide-6 (GHRP-6) (Frieboes et al, 1999) and hexarelin (Frieboes et al, 2004).…”

“…bolus injections of neuropeptides modulate human behavior, and in the latter experiments, modulate sleep. After a lower dose of ghrelin, 4 Â 50 mg given in a pulsatile manner between 2200 and 0100 to young normal male controls, appetite and leptin levels remained unchanged, whereas slow wave sleep (SWS), GH, cortisol, and prolactin secretion increased (Weikel et al, 2003). In a similar protocol, we found previously opposite effects of GH-releasing hormone (GHRH) in normal women and men.…”

“…The effects of ghrelin appear to be dose dependent. After 4 Â 50 mg ghrelin given in hourly injections between 2200 and 0100, appetite remained unchanged, whereas SWS, GH, cortisol, and prolactin increased (Weikel et al, 2003). In a single case observation, 100 mg ghrelin given at 2200 prompted a distinct increase of hunger and food intake (Weikel et al, 2003).…”

“…Obviously, the observed acute behavioral effects of ghrelin are not mediated by leptin. Similarly, nocturnal leptin concentrations remained unchanged after repetitive administration of 40 Â 50 mg ghrelin, a dose which did not affect appetite (Weikel et al, 2003), and after the synthetic GHS, hexarelin in young normal men (Frieboes et al, 2004). Furthermore, injection of leptin into nonobese humans had no effects on the cardiovascular or autonomic nervous systems and no evident effects on weight control (Mackintosh and Hirsch, 2001).…”