Physiological reviewGhrelin and its interactions with growth hormone, leptin and orexins: Implications for the sleep–wake cycle and metabolism
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)
Neurochemical regulation of sleep
J Psychiatr Res
(2007)- et al.
Ghrelin in mental health, sleep, memory
Mol Cell Endocrinol
(2011) - et al.
Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues
Brain Res Mol Brain Res
(1997) - et al.
Ghrelin-containing neuron in cerebral cortex and hypothalamus linked with the DVC of brainstem in rat
Regul Pept
(2006) - et al.
Immunocytochemical observation of ghrelin-containing neurons in the rat arcuate nucleus
Neurosci Lett
(2002) - et al.
New insights into the molecular complexity of the ghrelin gene locus
Cytokine Growth Factor Rev
(2009) - et al.
The expanding roles of the ghrelin-gene derived peptide obestatin in health and disease
Mol Cell Endocrinol
(2011) - et al.
Obestatin alters sleep in rats
Neurosci Lett
(2006) - et al.
Sleep and obesity: a focus on animal models
Neurosci Biobehav Rev
(2012) - et al.
Endogenous and exogenous factors on sleep-wake cycle regulation
Prog Neurobiol
(1999)
Ghrelin-induced sleep responses in ad libitum fed and food-restricted rats
Brain Res
Somatostatin antiserum blocks carbachol-induced increase of paradoxical sleep in the rat
Brain Res Bull
Intracerebroventricular and locus coeruleus microinjections of somatostatin antagonist decrease REM sleep in rats
Pharmacol Biochem Behav
Electrophysiological effects of ghrelin on laterodorsal segmental neurons in rats: an in vitro study
Peptides
Electrophysiological effects of ghrelin on pedunculopontine tegmental neurons in rats: an in vitro study
Peptides
Ghrelin alone or co-administered with GHRH or CRH increases non-REM sleep and decreases REM sleep in young males
Psychoneuroendocrinology
Ghrelin administered in the early morning increases secretion of cortisol and growth hormone without affecting sleep
Psychoneuroendocrinology
Nocturnal ghrelin, ACTH, GH and cortisol secretion after sleep deprivation in humans
Psychoneuroendocrinology
Ghrelin enhances the nocturnal secretion of cortisol and growth hormone in young females without influencing sleep
Psychoneuroendocrinology
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
GHRH and sleep
Sleep Med Rev
Effect of long-term changes in diet and exercise on plasma leptin concentrations
Am J Clin Nutr
Sleep and metabolism: shared circuits, new connections
Trends Endocrinol Metab
Obesity
Lancet
Acute partial sleep deprivation increases food intake in healthy men
Am J Clin Nutr
Ghrelin is a growth-hormone-releasing acylated peptide from stomach
Nature
Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake
Science
Ghrelin gene products and the regulation of food intake and gut motility
Pharmacol Rev
Normal human sleep: an overview
The visual scoring of sleep in adult
J Clin Sleep Med
Biochemical regulation of non-rapid-eye-movement sleep
Front Biosci
Sleep-inducing factors
CNS Neurol Disord Drug Targets
Biochemical regulation of sleep and sleep biomarkers
J Clin Sleep Med
Nutritional impact on sleep-wake cycle
Ghrelin microinjection into forebrain sites induces wakefulness and feeding in rats
Am J Physiol Regul Integr Comp Physiol
Central but not systemic administration of ghrelin induces wakefulness in mice
PLoS One
Ultradian rhythmicity of ghrelin secretion in relation with GH, feeding behavior, and sleep-wake patterns in rats
Endocrinology
Sleep in mice with nonfunctional growth hormone-releasing hormone receptors
Am J Physiol Regul Integr Comp Physiol
Mechanisms and models of REM sleep control
Arch Ital Biol
Spontaneous sleep and homeostatic sleep regulation in ghrelin knockout mice
Am J Physiol Regul Integr Comp Physiol
The preproghrelin gene is required for the normal integration of thermoregulation and sleep in mice
Proc Natl Acad Sci U S A
Impaired wake-promoting mechanisms in ghrelin receptor-deficient mice
Eur J Neurosci
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
Restricted feeding-induced sleep, activity, and body temperature changes in normal and preproghrelin-deficient mice
Am J Physiol Regul Integr Comp Physiol
Ghrelin promotes slow-wave sleep in humans
Am J Physiol Endocrinol Metab
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The most important references are denoted by an asterisk.