Elsevier

Sleep Medicine Reviews

Volume 18, Issue 1, February 2014, Pages 89-97
Sleep Medicine Reviews

Physiological review
Ghrelin and its interactions with growth hormone, leptin and orexins: Implications for the sleep–wake cycle and metabolism

https://doi.org/10.1016/j.smrv.2013.04.003Get rights and content

Summary

Several studies have shown that ghrelin administration promotes wakefulness in rodents, while in human males it induces sleep but has no effect in women. Ghrelin also plays an important role in metabolism and appetite regulation, and as described in this review may participate in the energy balance during sleep. In this review, we summarize some of the effects induced by ghrelin administration on the sleep–wake cycle in relation to the effects of other hormones, such as growth hormone, leptin, and orexin. Finally we discuss the relationship between sleep deprivation, obesity and ghrelin secretion pattern.

Introduction

Ghrelin's role in appetite and energy balance regulation is well documented. In recent years new evidence has emerged demonstrating the role of ghrelin in the sleep–wake cycle, both in animals and humans. This topic has been addressed in two excellent reviews published by the group of A. Steiger.1, 2 However, to our knowledge there are no reviews addressing the role of ghrelin regulating both behaviors. In this review we summarize some of the effects induced by ghrelin administration on the sleep–wake cycle in experimental animals and humans. We also discuss the possible interactions of ghrelin with growth hormone, leptin, and orexins in the regulation of the sleep–feeding circuit, emphasizing ghrelin's potential role on the energy balance during sleep. Finally, we address how the lack of sleep could be a trigger for the development of obesity and whether ghrelin is part of it.

Ghrelin is a 28 amino acid peptide secreted mainly by the stomach and is an endogenous ligand for the growth hormone secretagogue receptor 1a (GHS-R1a).3 GHS-R1a is a G protein-coupled receptor widely expressed in peripheral tissues, as well as in various brain regions, such as the hypothalamus, thalamus, cortex, hippocampus and the pituitary gland.4, 5 The hypothalamus is the main brain region of ghrelin synthesis,6 although overall peptide brain levels are much lower than those found in the stomach.

Ghrelin is derived from a preprohormone called preproghrelin, which generates, by post-translational cleavage, a second peptide of 26 amino acid called obestatin,7 and a third peptide of 60 amino acids, called C-ghrelin (reviewed by Seim et al.8). In addition, the primary mRNA encoded by the ghrelin gene can also generate multiple transcripts by alternative splicing, some of them may encode peptides of unknown function.8 Ghrelin is involved in growth hormone release, metabolism and appetite regulation (reviewed by Chen et al.9), as well as in the sleep–wake cycle regulation as described1, 2 and in this review. Obestatin was initially reported as a ligand for the orphan G protein-coupled receptor GPR39, involved in satiety and decreased food intake7; however there is controversy on these findings, and the role of this peptide is not well established (reviewed by Seim et al.10). Obestatin also induces sleep when centrally administered to rats.11 On the other hand, C-ghrelin circulates at high levels in plasma; however, its function and putative receptor are unknown.8

Despite its widespread and important physiological actions, ghrelin gene precise transcriptional and translational regulatory mechanisms remain ambiguous. Further studies on the biogenesis, expression and functions of C-ghrelin and obestatin, and the identification of their receptors are required.8

Before entering to this reviews' topic, we consider important to describe the phenomenology of the sleep–wake cycle. According to a simple behavioral definition, sleep is a reversible behavioral state of perceptual disengagement and unresponsiveness to the environment.12 Today it is universally accepted that mammals present at least two basic stages of sleep: non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep. The electrographic signals of cortical activity (electroencephalogram (EEG)), eye movements and muscle tone (electromyogram (EMG)) are the major signals, which determine a given sleep stage.12 In humans, NREM sleep has been further divided into N1, N2 and N3 stages based on specific EEG patterns. The N2 and N3 stages have been characterized by the presence of slow (delta) waves in the EEG and thus, referred also as slow-wave sleep (SWS).13 However, in the animal literature, the terms SWS and NREM sleep have been used interchangeably and often refer to the same sleep stage (non-REM sleep).14

NREM sleep in humans is associated with fragmented mental activity. REM sleep, by contrast, is defined by EEG activation, muscle atonia, and episodic burst of rapid eye movements. The mental activity during REM sleep is associated with dreaming, based on vivid dream recall reported after approximately 80% of arousals from this sleep state.

There is a large body of evidence demonstrating that sleep is influenced by a number of hormones and peptides, referred to as sleep-regulatory substances (SRS). Some of these peptides tend to accumulate within the brain and cerebrospinal fluid. Cerebrospinal or brain extracts taken from a sleep-deprived animal or from animals in the sleep-intense part of the cycle, promote sleep when injected into the ventricles of a normal animal, as demonstrated by several groups.15, 16, 17 Thus, chemicals of different molecular sizes have been suggested to function as neurotransmitters, neuromodulators or neurohormones, providing the possibility for short-to-long acting molecules that could participate collectively in the generation and maintenance of the sleep–wake cycle.17, 18, 19 Among these SRS, interleukin-1β, tumor necrosis factor α, growth hormone releasing hormone (GHRH), prolactin, and nitric oxide, are currently the best characterized; and many of their downstream biochemical mechanisms are also implicated in sleep regulation, e.g., adenosine, nitric oxide, prostaglandins, and others.17 However, as discussed below, ghrelin, although it does not meet all the criteria established for SRS,17, 18 is significantly involved in regulating the sleep–wake cycle, in addition to its role in metabolism regulation.

Section snippets

Ghrelin's role on the sleep–wake cycle

Studies conducted in rodents indicate that central administration of ghrelin to rats and mice increases wakefulness, but the effects of systemic ghrelin administration are less clear, and depend on the species, the dose and route of administration (Table 1). On the other hand, the effects of ghrelin administration to humans depend on the gender and time of administration. Repeated intravenous administration of ghrelin increases NREM sleep in young and elderly men, but has no effect on women (

Integration of ghrelin in the sleep–feeding circuit

Taking into account its role in the feeding behavior, the main function of ghrelin in sleep could be related to the maintenance of metabolic homeostasis during this process. Sleep perturbations are frequently associated with alterations in feeding behavior, like hyperphagia and pathologies such as obesity and diabetes.45 In this sense, ghrelin could interact with a series of molecules regulating the feeding–sleep circuit, among which GH, leptin, and orexins (hypocretins) are of importance. In

Ghrelin and GH

Although it is obvious that sleep plays an important role in energy balance, the role of sleep in modulating caloric intake is, in fact, very limited. Ghrelin stimulates the release of GH from pituitary cells,46, 47 as well as that of GHRH and SST, which inhibit its secretion. GHRH is mainly expressed in the arcuate nucleus of the hypothalamus (ARC); whereas SST is maximally expressed in the periventricular (PeN) nucleus of the hypothalamus.

The ultradian secretion of GH is linked to the

Ghrelin and leptin

Leptin is a protein of 167 amino acids, produced mainly by the adipose tissue.55 Initial studies, investigating the physiologic role of leptin in mice, demonstrated that this protein was directly involved in the regulation of satiety, energy and feeding behavior.56 The ob/ob mice, which do not produce functional leptin, become obese when they are fed ad libitum.57 Administration of leptin reversed this weight gain.57 However this encouraging result did not extrapolate to obese humans, because

Ghrelin and orexins (hypocretins)

From the evidence described above, it is clear that there is a neuronal circuit regulating both sleep and metabolism, where ghrelin plays an important role. The hypothalamus is an important brain area that regulates several homeostatic processes, including energy balance. Neurons in the arcuate nucleus of the hypothalamus act as sensors of circulating hormones. A group of arcuate neurons co-expresses NPY and agouti-related peptide (AgRP), while another group co-expresses proopiomelanocortin

Sleep restriction, leptin–ghrelin balance and obesity

Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems.77 Obesity is a rapidly spreading epidemic in the majority of developed countries.78 Obesity adversely affects health by increasing the risk for various associated conditions including the metabolic syndrome, type 2 diabetes, coronary artery disease, and hypertension; all of them are associated

Conclusions

The findings discussed in this review suggest that the physiological effects of ghrelin depend on the route and time of administration, the dose injected, the species, and gender. In rodents, central administration of ghrelin induces wakefulness, whereas the effects of systemic administration are less clear. A single dose of intraperitoneal (ip) ghrelin administration had no effect in rodents, while repeated iv injections induced wakefulness in rats. In human males, on the contrary, repeated iv

Acknowledgment

This work was supported by a grant from CONACYT-133178 to FGG. All authors have read and have abided by the Authorship Responsibility, Financial Disclosure, and Acknowledgment Form.

References (90)

  • E. Szentirmai et al.

    Ghrelin-induced sleep responses in ad libitum fed and food-restricted rats

    Brain Res

    (2006)
  • J. Danguir et al.

    Somatostatin antiserum blocks carbachol-induced increase of paradoxical sleep in the rat

    Brain Res Bull

    (1988)
  • J. Toppila et al.

    Intracerebroventricular and locus coeruleus microinjections of somatostatin antagonist decrease REM sleep in rats

    Pharmacol Biochem Behav

    (2000)
  • S. Takano et al.

    Electrophysiological effects of ghrelin on laterodorsal segmental neurons in rats: an in vitro study

    Peptides

    (2009)
  • J. Kim et al.

    Electrophysiological effects of ghrelin on pedunculopontine tegmental neurons in rats: an in vitro study

    Peptides

    (2009)
  • M. Kluge et al.

    Ghrelin alone or co-administered with GHRH or CRH increases non-REM sleep and decreases REM sleep in young males

    Psychoneuroendocrinology

    (2008)
  • M. Kluge et al.

    Ghrelin administered in the early morning increases secretion of cortisol and growth hormone without affecting sleep

    Psychoneuroendocrinology

    (2007)
  • P. Schüssler et al.

    Nocturnal ghrelin, ACTH, GH and cortisol secretion after sleep deprivation in humans

    Psychoneuroendocrinology

    (2006)
  • M. Kluge et al.

    Ghrelin enhances the nocturnal secretion of cortisol and growth hormone in young females without influencing sleep

    Psychoneuroendocrinology

    (2007)
  • M. Kluge et al.

    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

    (2010)
  • F. Obal et al.

    GHRH and sleep

    Sleep Med Rev

    (2004)
  • J.E. Reseland et al.

    Effect of long-term changes in diet and exercise on plasma leptin concentrations

    Am J Clin Nutr

    (2001)
  • A. Adamantidis et al.

    Sleep and metabolism: shared circuits, new connections

    Trends Endocrinol Metab

    (2008)
  • D.W. Haslam et al.

    Obesity

    Lancet

    (2005)
  • L. Brondel et al.

    Acute partial sleep deprivation increases food intake in healthy men

    Am J Clin Nutr

    (2010)
  • M. Kojima et al.

    Ghrelin is a growth-hormone-releasing acylated peptide from stomach

    Nature

    (1999)
  • J.V. Zhang et al.

    Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake

    Science

    (2005)
  • C.Y. Chen et al.

    Ghrelin gene products and the regulation of food intake and gut motility

    Pharmacol Rev

    (2009)
  • M. Carskadon et al.

    Normal human sleep: an overview

  • M.H. Silber et al.

    The visual scoring of sleep in adult

    J Clin Sleep Med

    (2007)
  • F. Obal et al.

    Biochemical regulation of non-rapid-eye-movement sleep

    Front Biosci

    (2003)
  • F. García-García et al.

    Sleep-inducing factors

    CNS Neurol Disord Drug Targets

    (2009)
  • J.M. Clinton et al.

    Biochemical regulation of sleep and sleep biomarkers

    J Clin Sleep Med

    (2011)
  • F. Garcia-Garcia et al.

    Nutritional impact on sleep-wake cycle

  • E. Szentirmai et al.

    Ghrelin microinjection into forebrain sites induces wakefulness and feeding in rats

    Am J Physiol Regul Integr Comp Physiol

    (2007)
  • É. Szentirmai

    Central but not systemic administration of ghrelin induces wakefulness in mice

    PLoS One

    (2012)
  • V. Tolle et al.

    Ultradian rhythmicity of ghrelin secretion in relation with GH, feeding behavior, and sleep-wake patterns in rats

    Endocrinology

    (2002)
  • F. Obal et al.

    Sleep in mice with nonfunctional growth hormone-releasing hormone receptors

    Am J Physiol Regul Integr Comp Physiol

    (2003)
  • R.W. McCarley

    Mechanisms and models of REM sleep control

    Arch Ital Biol

    (2004)
  • E. Szentirmai et al.

    Spontaneous sleep and homeostatic sleep regulation in ghrelin knockout mice

    Am J Physiol Regul Integr Comp Physiol

    (2007)
  • E. Szentirmai et al.

    The preproghrelin gene is required for the normal integration of thermoregulation and sleep in mice

    Proc Natl Acad Sci U S A

    (2009)
  • M. Esposito et al.

    Impaired wake-promoting mechanisms in ghrelin receptor-deficient mice

    Eur J Neurosci

    (2012)
  • B. Bodosi et al.

    Rhythms of ghrelin, leptin, and sleep in rats: effects of the normal diurnal cycle, restricted feeding, and sleep deprivation

    Am J Physiol Regul Integr Comp Physiol

    (2004)
  • E. Szentirmai et al.

    Restricted feeding-induced sleep, activity, and body temperature changes in normal and preproghrelin-deficient mice

    Am J Physiol Regul Integr Comp Physiol

    (2010)
  • J.C. Weikel et al.

    Ghrelin promotes slow-wave sleep in humans

    Am J Physiol Endocrinol Metab

    (2003)
  • Cited by (0)

    The most important references are denoted by an asterisk.

    View full text