HORMONES 2016, 15(2):186-196
DOI:10.14310/horm.2002.1672
Review
Laura Mihalache,1 Andreea Gherasim,1 Otilia Niță,1 Maria Christina Ungureanu,1 Sergiu Serghei Pădureanu,2 Radu Sebastian Gavril,1 Lidia Iuliana Arhire 1
1 Department of Internal Medicine, 2 Department of Surgery, “Grigore T. Popa” University of Medicine and Pharmacy, Iassy, Romania
Ghrelin is a gut peptide composed of 28 amino acids mostly secreted in the gastric fundus mucosa. It was isolated and described in 1999 by Kojima et al. and only three years later its specific receptor, GHSR1a, was also identified. Ghrelin, the endogenous ligand for the GH secretagogue receptor, is the only peripheral orexigenic hormone that activates the receptors to be found especially in the appetite center (hypothalamus and pituitary gland). Ghrelin is present in human plasma in two forms: an inactive form known as deacylated ghrelin, and an active form called acylated ghrelin synthesized under the action of ghrelin O-acyltransferase enzyme (GOAT). The literature even mentions an extremely complex ghrelin/GOAT/GHSR system involved in the regulation of human energy, metabolism and adaptation of energy homeostasis to environmental changes. In humans, there is a preprandial rise and a postprandial fall in plasma ghrelin levels, which strongly suggest that the peptide plays a physiological role in meal initiation and may be employed in determining the amount and quality of ingested food. Besides the stimulation of food intake, ghrelin determines a decrease in energy expenditure and promotes the storage of fatty acids in adipocytes. Thus, in the human body ghrelin induces a positive energy balance, an increased adiposity gain, as well as an increase in caloric storage, seen as an adaptive mechanism to caloric restriction conditions. In the current world context, when we are witnessing an increasing availability of food and a reduction of energy expenditure to a minimum level, these mechanisms have become pathogenic. As a consequence, the hypothesis that ghrelin is involved in the current obesity epidemic has been embraced by many scholars and researchers.
Keywords
Appetite, Energy balance, Ghrelin
Ghrelin is a gut peptide composed of 28 amino acids mostly secreted by the gastric fundus mucosa. It was isolated and described in 1999 by Kojima et al and three years later its specific receptor, GH secretagogue receptor 1a (GHSR1a), was identified. Ghrelin, the endogenous ligand for GHSR1a, is the only peripheral orexigenic hormone that activates receptors localized in the appetite centers in hypothalamus. Ghrelin is present in human plasma in two forms: an inactive form known as deacylated ghrelin, and an active form, the acylated ghrelin synthesized under the action of ghrelin O-acyltransferase enzyme (GOAT). The literature additionally mentions an extremely complex ghrelin/GOAT/GHSR system involved in the regulation of human energy and metabolism and the adaptation of energy homeostasis to environmental changes. In humans, there is a preprandial rise and a postprandial fall in plasma ghrelin levels, which strongly suggest that the peptide plays a physiological role in meal initiation, while it is also employed in determining the amount and quality of ingested food. Besides the stimulation of food intake, ghrelin brings about a decrease in energy expenditure and promotes the storage of fatty acids in adipocytes. Thus, in the human body ghrelin induces a positive energy balance, an increased adiposity gain, as well as an increase in caloric storage, seen as an adaptive mechanism to caloric restriction conditions. In the current global context when we are witnessing an increasing availability of food and a reduction of energy expenditure to a minimum level, these mechanisms have become pathogenic. As a consequence, the hypothesis that ghrelin is involved in the current obesity epidemic has been embraced by many scholars and researchers. This review aims to analyze currently existing data on ghrelin involvement in regulating the human body energy balance.
It is known and has been abundantly demonstrated that in both animals and human subjects, ghrelin increases appetite and stimulates food intake in a GH-independent manner 1 through its specific receptor GHSR1a.2 Numerous data in the literature have supported findings providing evidence that, besides exerting an orexigenic effect, this ghrelin/GOAT/GHSR system is involved in regulating energy metabolism and its adjustment to energy balance changes.3 The circulating levels of ghrelin are elevated during fasting and before meals 4-6 and decline postprandially,5-7 which implies that ghrelin plays a significant role in initiating food intake.8 The increased level of ghrelin during fasting 9 is a unique phenomenon in human physiology, which contrasts with the secretion levels of most gut hormones that increase during nutrient intake and decrease during fasting.8 Another peculiarity of ghrelin is that although it is a peripherally-secreted peptide in the gastrointestinal tract, it has major effects upon the central nervous system (CNS).1 Ghrelin is synthesized and secreted primarily in the stomach 10 (oxintic mucosa X/A-like cells are immunoreactive cells for ghrelin, being more numerous in the gastric fundus and progressively decreasing towards the pylorus 11), but low levels of ghrelin expression can also be found in other tissues such as the bowel, pancreas, kidney, ovary or brain.12 Accordingly, positive immunoreactivity for ghrelin was described in the hypothalamic arcuate nucleus,1 an extremely important region for appetite control, and in the internuclear space of the lateral hypothalamus, hypothalamic arcuate, ventromedial, dorsomedial and paraventricular nuclei and ependymal layer of the third ventricle.13 To exert its orexigenic action, ghrelin reaches the hypothalamus in three different ways: systemically by crossing the blood-brain barrier, via the vagal afferents and via local hypothalamic synthesis and secretion, thereby exerting paracrine actions.14
In humans initiating meals voluntarily without time- and food-related cues, plasma ghrelin levels increase before meals and display a temporal profile similar to hunger scores,15 once again confirming the hypothesis that ghrelin is a physiological meal initiator. Food intake or gastric/enteral feeding causes the suppression of circulating ghrelin levels.16 Moreover, the composition of ingested foods appears to influence ghrelin secretion, albeit the published studies report conflicting results in this regard. In fact, two different situations have been observed: more significantly decreased levels of ghrelin after the ingestion of proteins and carbohydrates than those observed after the ingestion of lipids;17,18 lower ghrelin levels after lipids that after carbohydrate or protein intake.19
However, most research teams have concluded that the circulating levels of ghrelin decrease after meals regardless of the type of nutrients consumed (carbohydrates and proteins still remaining the most potent inhibitors),20 these interprandial changes in circulating ghrelin levels being found only in normal weight individuals.21 Ghrelin is the only currently known orexigenic gastrointestinal peptide which, in addition to appetite stimulation, increases the number of meals and also shortens latency to eat.20 Ghrelin-induced hyperphagia was hence considered as one of the mechanisms involved in the development of overweight.
Recent studies have demonstrated that ghrelin also acts on the dopaminergic regions of the limbic system.22 Moreover, ghrelin stimulates brain activity in certain regions involved in controlling eating behaviour, such as the amygdale and the orbitofrontal cortex.23-25 Thus, besides the demonstrated classic effect of appetite stimulation through hypothalamic circuits, ghrelin may be involved in regulating eating behaviour.16
Ghrelin stimulates food intake in an acute manner, inducing meal initiation.26 Initially, many experimental studies on laboratory animals showed that the administration of ghrelin increased the urge to eat and look for food,27 without influencing the hedonic aspects of eating. But at the central level there are nuclei expressing ghrelin receptors that are associated with the intake of high-palatability foods. This may explain why in a food preference test the central administration of ghrelin shifts food choice towards a hyperlipid diet.28 Therefore, ghrelin stimulates the intake of high energy density, high-fat, high-palatability foods, regardless of the type of nutrient normally preferred.20 Ghrelin administration in laboratory mice caused increasing intake of palatable saccharin solutions and preference for food with saccharin.29 In normal human subjects, ghrelin administration, besides increasing appetite and caloric intake, also stimulates imagination of favourite meals 30 and external visual stimuli represented by hedonic foods increases ghrelin levels.31 In addition to meal initiation, ghrelin increases meal duration and size in the context of regularly scheduled meals.32 The distribution of specific receptors for ghrelin as well as the study of MRI images confirm the hypothesis that ghrelin not only stimulates appetite but is also involved in regulating the hedonic aspects of eating: the preference for palatable foods, the motivation to obtain one’s preferred foods, the reward value/effect of one’s preferred foods and the actual purchase of foods.33,34 Recent data indicate that ghrelin also influences behaviours related to motivational aspects of eating. Thus, currently existing evidence suggests that the ghrelin/GOAT/GHSR1a system is closely linked to pathways involved in reward aspects of food intake, additionally and partially separated from those determining food intake initiation.35 Mediation of this eating behaviour response by ghrelin is accomplished through the dopaminergic neural network extending from the ventral tegmental area and other brain nuclei and finally resulting in food intake depending on its reward aspects.36
Hence, at the mesolimbic level, ghrelin would produce increased hedonic aspects of eating and increase motivation to seek and procure food, initiating anticipatory activity and foraging behaviours.35 Based on these aspects, some researchers have proposed the clinical use of ghrelin in cases in which increased levels of food intake may be beneficial, such as elderly patients with nutritional deficiencies 37 or with anorexia associated with different consumption diseases.38
Ghrelin is considered an orexigenic signal (gut-brain) for the control of appetite and energy balance in healthy individuals. GHSR1a, the ghrelin-specific receptor, binds acylated ghrelin and mainly induces the release of the growth hormone from the somatotropic cells in the anterior pituitary gland. Via the vagus nerve or directly at the central level, ghrelin activates the neurons in the arcuate nucleus (ARC nucleus) secreting orexigenic peptides—neuropeptide Y (NPY) and agouti-related peptide (AgRP)39—and inhibits the anorexigenic neurons secreting pro-opiomelanocortin and α-melanocyte-stimulating hormone. Orexigenic signals act via adenosine monophosphate-activated protein kinase (AMPK) and increase the dopaminergic transmission from the ventral tegmental area to the nucleus accumbens, enhancing the reward signals.40 Therefore, the binding of ghrelin to its specific receptor GHSR1a will lead to an increase in intracellular calcium concentration, with consequent activation of CaMKK2 (calmodulin kinase-kinase 2), which will phosphorylate AMPK.41 In its turn, AMPK will phosphorylate and inhibit acetyl-coenzyme A carboxylase, resulting in decreased levels of malonyl-CoA and subsequent activation of carnitine-palmitoyltransferase-1.42 The end result of this long series of enzymatic reactions is increased mitochondrial β-oxidation, with the generation of reactive oxygen species and stimulation of uncoupling protein 2 (UCP2),43 which will stimulate NPY/AgRP transcription.44
In pathologic states, ghrelin may be decreased (in obesity) or increased (in anorexia nervosa, cachexia or Prader-Willi syndrome), which promotes speculation about the therapeutic applications of both ghrelin agonists and antagonists in these states.45 It is hence evident that the metabolic status plays a key role in ghrelin function. Ghrelin activates NPY/agouti-related protein (AgRP) neurons through fatty acid oxidation and maintains NPY/AgRP cell function during extended periods of negative energy balance. Meanwhile, ghrelin is also required to maintain normal blood sugar levels during severe caloric restriction. Ghrelin is a key modulator of energy metabolism during starvation or long periods of negative energy balance. Recent studies have shown that in patients with diet-induced obesity (DIO) there is resistance to ghrelin in the arcuate NPY/AgRP neurons. In this case, the level of circulating ghrelin, the overall level of ghrelin as well as that of the GOAT mRNA in the stomach and that of the GHSR in the hypothalamus are all decreased.46
Acylated ghrelin is a potent stimulator of gastric secretion and motility.47 On the one hand, ghrelin stimulates the secretion of gastric acid and digestive enzymes in the digestive organs within the digestive/gastrointestinal (GI) tract (stomach, intestine, and pancreas).48,49 On the other hand, ghrelin reduces the gastrointestinal transit time of ingested nutrients, accelerating gastric emptying and stimulating the motility in the small intestine and colon.50 These prokinetic and prosecretory effects, coupled with the modulation of eating behaviour actually facilitate digestion and absorption processes.8 However, by decreasing the intestinal transit time, ghrelin limits the feedback from digestive tract/GI satiety signals, which should determine termination of food intake.20
The energy homeostasis/balance of the human body and therefore its weight stability is reached when there is a balance between energy intake and expenditure, the two arms of the energy balance. As a result, weight loss will occur when the caloric intake is decreased and/or the energy expenditure is increased, while weight gain will occur when the caloric intake is increased and/or the energy expenditure is reduced. Due to its appetite stimulating effect, ghrelin is an enteroendocrine peptide that induces weight gain and adiposity.51,52 Interestingly enough, there is also a preferential effect on fat intake that has recently been demonstrated.28 Additionally, ghrel
