Ultradian Rhythmicity of Ghrelin Secretion in Relation with GH, Feeding Behavior, and Sleep-Wake Patterns in Rats (original) (raw)
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European Journal of Endocrinology, 2005
Objective: Ghrelin stimulates GH release and causes weight gain through increased food intake and reduced fat utilization. Ghrelin levels were shown to rise in the preprandial period and decrease shortly after meal consumption, suggesting a role as a possible meal initiator. However, ghrelin secretion in fasting subjects has not yet been studied in detail. Design: 24-h ghrelin profiles were studied in six healthy volunteers (three females; 25.5 years; body mass index 22.8 kg/m 2 ) and compared with GH, insulin and glucose levels.
Regulation of Ghrelin Secretion and Action
Endocrine, 2003
The pulsatile release of growth hormone (GH) from anterior pituitary gland is regulated by the interplay of at least two hypothalamic hormones, GH-releasing hormone (GHRH) and somatostatin, via their engagement with specific cell surface receptors on the anterior pituitary somatotroph. Furthermore, release of GH in vivo may also be controlled by a third type of receptor, the growth hormone secretagogue receptor, a G-proteincoupled receptor, called GHS receptor type 1a (GHS-R1a), which was identified in the pituitary and the hypothalamus in humans using a nonpeptidyl growth hormone secretagogue (MK-0677). Ghrelin, the endogenous ligand for the GHS-R1a, is a 28-amino-acid peptide isolated from human stomach that is modified by a straight chain octanoyl group covalently linked to Ser 3 , which is essential for its endocrine activity. This hormone, predominantly expressed and secreted by the stomach, has a dual action on GH secretion and food intake, showing interdependency between these actions. The finding that fasting and food intake, respectively, increase and decrease the secretion of ghrelin suggests that this hormone may be the bridge connecting somatic growth and body composition with energy metabolism, and appears to play a role in the alteration of energy homeostasis and body weight in pathophysiological states such as hypothyroidism and hyperthyroidism. Despite this, little is known about the intracellular signaling through which ghrelin exerts its regulatory actions. Activation of intracellular calcium mobilization is one of the earliest known cellular signals elicited by ghrelin. In HEK-293 cells expressing the GHS-R1a, ghrelin induces a biphasic cytosolic calcium elevation characterized by a spike phase of the response, which reflects Ins(1,4,5)P 3dependent calcium mobilization of intracellular stores, and a sustained phase of the response, which is due to calcium influx across the plasma membrane triggered by aperture of capacitative calcium channels (store-operated calcium channels). Upon repeated administration, ghrelin showed a marked suppression of ghrelin-mediated elevations of intracellular calcium. This homologous desensitization represents an important physiological mechanism that modulates receptor responsiveness and acts as an information filter for intracellular signaling system. The discovery of ghrelin adds a new component to the complex machinery responsible for regulation of GH secretion in connection with the regulation of appetite and energy homeostasis.
Ghrelin elicits a marked stimulatory effect on GH secretion in freely-moving rats
European Journal of Endocrinology, 2000
Ghrelin is a growth hormone-releasing acylated peptide from stomach. The purified peptide consist of 28 amino acids in which the serine 3 residue is n-octanoylated. Ghrelin has been reported to increase in vitro GH secretion as well as in vivo plasma GH levels in pentobarbital anaesthetized rats. The aim of this work was to characterize the stimulatory effect of Ghrelin on in vivo GH secretion in freely-moving rats. Furthermore, we compare the effect of Ghrelin with GHRH.
Direct Stimulation of Ghrelin Secretion by Sympathetic Nerves
Endocrinology, 2006
The hormone ghrelin is secreted mainly from the gut, rises in peripheral plasma before meals, and is implicated in stimulating hunger, initiating meals, and developing obesity. We hypothesize that activation of the sympathetic nervous system contributes to preprandial ghrelin surges. The present studies in isoflurane-anesthetized Wistar rats were designed to determine whether sympathetic nerves and neurohormones are capable of stimulating ghrelin secretion. We activated gut sympathetic nerves by two methods: electrical sympathetic nerve stimulation (SNS) and chemical sympathetic nerve activation with iv tyramine (TYR) administration. Portal venous blood was sampled before and during a 10-min sympathetic stimulation. Successful activation of gut sympathetic nerves was verified by increments in portal venous norepinephrine. SNS increased portal ghrelin by 206 ؎ 50%. In contrast, simply isolating gut sympathetic nerves without ap-plying current had a minimal effect on ghrelin levels. TYR also increased portal ghrelin [change (⌬), ؉52 ؎ 11%], whereas saline infusion had little effect. We next determined whether the neural stimulation of ghrelin secretion was mediated indirectly via the suppression of insulin secretion during SNS and TYR. Streptozotocin-induced diabetes prevented a fall in insulin during TYR, yet the portal ghrelin response (⌬ ؍ ؉47 ؎ 18%) was similar to that in nondiabetic rats. Lastly, to test for humoral stimulation of ghrelin, we infused the sympathetic neurohormone, epinephrine, to achieve levels found during severe stress. Epinephrine failed to stimulate ghrelin secretion (⌬ ؍ ؉4 ؎ 35%). We conclude that the neural, but not the neurohumoral, branch of the sympathetic nervous system can directly stimulate ghrelin secretion. (Endocrinology 147:
Regulation of ghrelin in physiologic and pathophysiologic states
The Journal of nutrition, 2005
Ghrelin, a ligand for the growth hormone secretagogue receptor, is an orexigenic hormone produced in the gastrointestinal tract. In humans and other animals, circulating ghrelin levels fluctuate over the course of the day in relation to food intake. If circulating ghrelin plays a role in determining food intake from meal to meal, it will be important to understand the factors that regulate plasma ghrelin levels in relation to feeding. Circulating ghrelin levels also appear to reflect body weight changes over the longer term, raising the possibility that ghrelin functions as an adiposity signal. This review discusses some of the factors known to affect ghrelin levels, including nutrient stimulation of the gastrointestinal tract, diet composition, and weight loss. We also consider potential hormonal and neural mediators of the effects of nutrients and weight change on ghrelin levels.
Biological rhythm of saliva ghrelin in humans
Biological Rhythm …, 2006
Background: We previously reported that ghrelin in saliva, orexigenic hormone that induces NPY release, was produced and released by salivary glands in humans. The purpose of this study was to investigate a possible circadian rhythm in saliva ghrelin concentration in human subjects as a function of time and meal. Saliva samples were collected at three-hour intervals throughout a 24-h period in 12 healthy volunteer males and ten healthy volunteer females who were provided with meals on a fixed schedule, and saliva collections were made within 15 minutes after each meal. Saliva ghrelin levels were measured by using a commercial radioimmunoassay (RIA) kit that uses 125 I-labeled bioactive ghrelin as a tracer and a rabbit polyclonal antibody raised against full-length octanoylated human ghrelin. Immunohistochemical analysis of salivary glands was also performed. The results of this investigation indicated the following. (1) The saliva ghrelin level was slightly higher in female subjects in comparison with male subjects. (2) Saliva ghrelin levels were elevated before each meal and fell to trough levels after eating. (3) Saliva ghrelin levels showed a circadian rhythm that rose throughout the day to a zenith at 0300, then dropped at 0600 -0900. (4) Saliva ghrelin also weakly correlated with BMI. (5) Immunohistochemical analysis showed that ghrelin was localized in the striated and excretory ducts of salivary glands of human. The present work is the first report of the circadian rhythm of saliva ghrelin level in human subjects as a function of time and meal. Meal plays an important role in lowering saliva ghrelin concentration in humans. However, present data did not exclude whether the circadian changes in saliva ghrelin expression were regulated by the biological clock or by food intake.
Mediation of the behavioral, endocrine and thermoregulatory actions of ghrelin
Hormones and Behavior, 2006
The action of ghrelin on telemetrically recorded motor activity and the transmission of the effects of this neuropeptide on spontaneous and exploratory motor activity and some related endocrine and homeostatic parameters were investigated. Different doses (0.5-5 μg) of ghrelin administered intracerebroventricularly caused significant increases in both square crossing and rearing activity in the "open-field" apparatus, while only the dose of 5 μg evoked a significant increase in the spontaneous locomotor activity recorded by telemetry. Ghrelin also induced significant increases in corticosterone release and core temperature. To determine the transmission of these neuroendocrine actions, the rats were pretreated with different antagonists, such as a corticotropin-releasing hormone (CRH) antagonist (α-helical CRH 9-41 ), the nitric oxide synthase inhibitor Nω-nitro-L-arginine-methyl ester (L-NAME), haloperidol, cyproheptadine or the cyclooxygenase inhibitor noraminophenazone (NAP). The openfield and biotelemetric observations revealed that the motor responses were diminished by pretreatment with the CRH antagonist and haloperidol. In the case of HPA (hypothalamic pituitary adrenal) activation, only cyproheptadine pretreatment proved effective; haloperidol and L-NAME did not modify the corticosterone response. NAP had only a transient, while cyproheptadine elicited a more permanent impact on the hyperthermic response evoked by ghrelin; the other antagonists proved to be ineffective. The present data suggest that both CRH release and dopaminergic transmission may be involved in the ghrelin-evoked behavioral responses. On the other hand, ghrelin appears to have an impact on the HPA response via a serotonergic pathway and on the hyperthermic response via a cyclooxygenase and a serotonergic pathway.
Endogenous Circulating Ghrelin Does Not Mediate Growth Hormone Rhythmicity or Response to Fasting
The Journal of Clinical Endocrinology & Metabolism, 2005
GH secretory profiles in humans are pulsatile and exhibit nocturnal elevation during the early hours of sleep. Fasting augments GH output and rhythmicity. Ghrelin was suggested to exhibit nocturnal increases and to rise in response to nutritional deprivation. We examined whether ghrelin may be an underlying mechanism of GH rhythmicity and response to fasting. We studied nine young healthy subjects during normal feeding and after 2 d of complete fasting. Plasma GH was measured every 10 min, and plasma total and active ghrelins were measured every 20 min. Fasting augmented mean daily plasma GH (1.47 ؎ 0.25 vs. 3.30 ؎ 0.6 g/liter; P ؍ 0.012). Neither mean daily total ghrelin (4.19 ؎ 0.64 vs. 4.35 ؎ 0.74 g/liter; P ؍ 0.75) nor mean daily active ghrelin (0.13 ؎ 0.02 vs. 0.13 ؎ 0.02 g/liter; P ؍ 0.34) changed as a result of fasting. All subjects exhibited nocturnal augmentation of GH secretion; there were no corresponding nocturnal increases in either total or active ghrelin concentrations. Similarly, cross-correlation analysis failed to find any relation between GH and ghrelin pulses. We conclude that ghrelin is unlikely to be of importance in the generation of rhythmic or nutritionally mediated GH secretion. (J Clin Endocrinol Metab 90: 2982-2987, 2005)
Ghrelin deficiency does not influence feeding performance
Regulatory Peptides, 2008
Ghrelin is an endogenous ligand for the growth hormone secretagogue receptor that is synthesized predominantly in the stomach. Previous studies demonstrated that ghrelin stimulates growth hormone release and food intake. These data suggested that antagonism of ghrelin could serve as a useful treatment for eating disorders and obesity. To study the role of endogenous ghrelin in feeding performance further, we generated ghrelin-deficient (ghrl −/− ) mice. Unexpectedly, ghrl −/− mice exhibited normal growth, cumulative food intake, reproduction, histological characters, and serum parameters. There were no differences in feeding patterns between ghrl +/+ and ghrl −/− mice. Ghrl −/− mice displayed normal responses to scheduled feedings as seen for ghrl +/+ mice. Memory-related feeding performances of ghrl −/− mice were indistinguishable from ghrl +/+ littermates. These data indicate that ghrelin is not critical for feeding performance.