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Ghrelin, Appetite Regulation, and Food Reward: Interaction with Chronic Stress

Ghrelin, Appetite Regulation, and Food Reward: Interaction with Chronic Stress Hindawi Publishing Corporation International Journal of Peptides Volume 2011, Article ID 898450, 11 pages doi:10.1155/2011/898450 Review Article Ghrelin, Appetite Regulation, and Food Reward: Interaction with Chronic Stress Yolanda Diz-Chaves Instituto Cajal, CSIC, Avenida Doctor Arce 37, 28002 Madrid, Spain Correspondence should be addressed to Yolanda Diz-Chaves, ydiz@cajal.csic.es Received 30 May 2011; Accepted 24 July 2011 Academic Editor: A. Inui Copyright © 2011 Yolanda Diz-Chaves. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Obesity has become one of the leading causes of illness and mortality in the developed world. Preclinical and clinical data provide compelling evidence for ghrelin as a relevant regulator of appetite, food intake, and energy homeostasis. In addition, ghrelin has recently emerged as one of the major contributing factors to reward-driven feeding that can override the state of satiation. The corticotropin-releasing-factor system is also directly implicated in the regulation of energy balance and may participate in the pathophysiology of obesity and eating disorders. This paper focuses on the role of ghrelin in the regulation of appetite, on its possible role as a hedonic signal involved in food reward, and on its interaction with the corticotropin-releasing-factor system and chronic stress. 1. Introduction hormonal, and vegetative systems that are engaged to reestablish homeostasis in the face of the stress perturbation, Obesity and related disorders are among the leading causes either real or perceived, of the internal and/or external of illness and mortality in the developed world, and it environment [9]. In human beings, many obese patients tend became a severe epidemic problem not only in adults to eat more when they are emotionally tense or depressed but also in younger generations [1]. To better understand or simply bored. Sadness favored eating of high fat/sweet, the pathophysiological mechanism that underlies metabolic hedonically rewarding foods, whereas intake during a happy disorders, increasing attention has been paid to central regu- state favored dried fruit [1]. In addition, it has been described latory elements in energy homeostasis, including food intake that visceral overweight subjects showed stress-induced food and energy expenditure. The discovery of ghrelin and its intake in the absence of hunger, resulting in an increased influence on appetite, fuel utilization, body weight, and body energy intake [10]. composition adds yet another component to the complexity Increasing evidence suggests an interplay between the in the central regulation of energy balance [2]. In addition, CRF and ghrelin systems. However, it is unknown wether recently it has been described that ghrelin may be implicated this interacion plays a role in the pathophysiology of obesity. in food reward [3], since ghrelin directly targets the ventral tegmental area to increase food motivation [4]. However, 2. Ghrelin and the Regulation of Energy Balance it remains to be determined whether the central ghrelin signaling system has a role in the pathophysiology of obesity. Small synthetic molecules called growth hormone secret- The corticotropin releasing factor (CRF) system is agogues (GHSs) stimulate the release of growth hormone directly implicated in the regulation of energy balance [5, 6]. (GH) from the pituitary. They act through the GHS-receptor In addition, it may participate in the pathophysiology of (GHS-R), which has been cloned for different groups [11, obesity and eating disorders [7, 8]. Considerable evidence 12]. Despite intensive searches by different groups, in 1999, has accumulated to demonstrate that feeding behavior is was purified and identified the endogenous specific ligand influenced by stress. Stress triggers a physiological response for GHS-R [13]. This ligand is a molecule of 28 amino that involves the coordinated control of multiple motor, acids called ghrelin in which the serine residue 3 was 2 International Journal of Peptides n-octanoylated. The minimum core of ghrelin residing in the prompt significant orexigenic response was the paraven- N-terminal tetrapeptide and the acylation of the peptide had tricular nucleus (PVN), but the stimulation of food intake been supposed critical to cross the blood-brain barrier but was significantly less than the one seen in the ARC [47]. is also essential for binding the GHS-1a receptor and for its Studies with confocal laser microscopy have analyzed the GH releasing and other endocrine actions [13–15]. Recently, effect of ghrelin on the expression of c-fos, a marker of the enzyme responsible for the acylation of ghrelin was neuronal activation. These studies have shown that i.p. identified by two independent groups [16, 17]. The ghrelin administration of ghrelin induces c-fos immunoreactivity in O-acetyltransferase (GOAT) is the specific acyl transferase (i) the ARC and medioparvocellular part of the PVN [52, that activates ghrelin [16, 17] and belongs to the super family 53], (ii) the dorsomedial and lateral hypothalamic nuclei, of membrane-bound O-acyltransferases (MBOATs) [17–19]. and (iii) two regions of the brainstem, the nucleus of the In humans, GOAT expression is high in stomach and gut, tractus solitarius and the area postrema [53]. In addition, the major ghrelin-secreting tissues, and in the pituitary, in after i.c.v. ghrelin administration, c-fos immunoreactivity which ghrelin is known to show autocrine and paracrine was found in neuronal populations of primary importance effects [16, 20]. GOAT is regulated by nutrient availability, in the regulation of feeding, including NPY neurons, AgRP depends on specific dietary lipids as acylation substrates neurons [42, 48], and orexin-containing neurons (in the and links ingested lipids to energy expenditure and body fat lateral hypothalamus) [53]. Furthermore, antibodies and mass [21]. Although devoid of neuroendocrine activity, also antagonist of NPY and AgRP abolish ghrelin-induced feed- unacylated ghrelin, its most abundant circulating form, is an ing [54]. Ghrelin increases NPY and AgRP mRNA expression active molecule. This evidence agrees with the existence of levels [42, 48–50, 55] independently of the nutritional status GHS-R subtypes that are activated by ghrelin independently [56] and blocked leptin-induced feeding reduction [48]. of its acylation [13, 22]. Furthermore, the orexigenic effect of ghrelin is abolished In humans, the stomach is a major source of circu- by i.c.v. coinjection of Y1 receptor antagonist, indicating lating ghrelin. It has been shown that plasma ghrelin- that ghrelin increases food intake at least partly through the like immunoreactivity levels in gastrectomized patients still activation of the hypothalamic NPY/Y1 pathway [50, 55]. remain 35% of those in normal subjects, suggesting that Endogenous ghrelin secretion is pulsatile and directly tissues other than the stomach contribute to a certain related to feeding behavior [57]; after fasting, ghrelin amount of circulating ghrelin [23]. The peptide is produced secretion is augmented in the form of high frequency, high prevalently in the stomach by the X/A-like cells within amplitude episodes [58, 59]. Ghrelin concentrations in the the oxyntic glands of the gastric fundus mucosa [13, 24– blood and mRNA levels were increased by fasting and 27], with substantially lower amounts derived from the decreased by feeding in the stomach [23, 51, 60]. The plasma bowel [24, 27–29], pancreas [28, 30], lymphocytes [28], levels of ghrelin inversely correlate with body mass index chondrocytes [31], kidney [28, 32], placenta [33], lung [28], (BMI), thus, ghrelin levels are modified in patients with testis [28, 34], ovary [35, 36], adrenal cortex [37, 38], anorexia nervosa and obesity. Ghrelin secretion is increased pituitary (lactotrophs, somatotrophs, and thyrotrophs cells) in anorexia and cachexia, reduced in obesity, and normalized [39, 40], and hypothalamus [40–42]. by recovery of idealbodyweight[23, 61, 62]. The paradoxical Ghrelin is strongly involved in the regulation of energy situation of increased basal plasma ghrelin concentrations homeostasis. The group of Ghigo and coworkers published observed in subjects with long-term energy deficit and for the first time the involvement of ghrelin in the regulation decreased food intake such as in restrictive anorexia nervosa of appetite. They described that 3 out of 4 healthy volunteers [63] suggests the existence of ghrelin resistance that may reported hunger following ghrelin administration as a “side be relevant to the decreased effects of ghrelin to promote effect” in a clinical study analyzing GH release, and this a positive energy balance [64]. In addition, plasma ghrelin effect has been confirmed in more studies [43, 44]. In levels regulation could be influenced by ghrelin reactive animal studies, it has been shown that ghrelin increased food autoantibodies (autoAbs), since it had been demonstrated intake of rats, when it was administered either into central the presence of autoAbs reactive with ghrelin in healthy nervous system or peripherally [45–47], in both satiated and subjects and rats [65, 66]. Furthermore, a role of autoAbs feeding conditions [48]. The i.c.v. administration generated against appetite-regulating neuropeptides in eating disorders a dose-dependent increase in food intake and body weight has emerged [65]. In this regard, it had been described [49–51]. The time course and magnitude of this effect decreased plasma levels of acyl ghrelin IgG autoAbs present was similar to neuropeptide Y (NPY) [46, 49]. Also, it as free or total immunoglobulins in patients with anorexia has been shown a significant increase of the food intake nervosa, suggesting that altered production of ghrelin reac- after the systemic administration of ghrelin, occurring at tive autoAbs is associated with persistently elevated plasma plasma ghrelin levels within normal fasting range [47, 52]. In ghrelin and eventually ghrelin resistance in anorexia nervosa rodents, ghrelin-induced gain weight is based on accretion of [67]. fat mass gain by reducing fat utilization, without changes in Furthermore, a negative association between body mass longitudinal skeletal growth and without an increase in lean and ghrelin secretion in Prader-Willi syndrome exists, where [51]. obesity is associated with ghrelin hypersecretion [68]. In Very low doses (30 pmol) of ghrelin injected into the obese humans, food intake (including 60% of carbohydrates) arcuate nucleus (ARC) potently stimulated food intake. with postprandially increased insulin response fails to sup- Another hypothalamic nucleus that showed a similarly press ghrelin levels sufficiently [69], suggesting that ghrelin International Journal of Peptides 3 may be involved in some of the multiple pathophysiological apposition to NPY and GABA axon terminals in the ARC and mechanisms leading to obesity and type 2 diabetes [70]. PVH. In the paraventricular hypothalamic nucleus (PVN), The reduction in plasma ghrelin levels with high-fat diet some of ghrelin axons innervated CRF cells [70, 78, 79]. agreed with the low circulating levels of ghrelin in obese Therefore, the final effects of ghrelin are likely to reflect humans and db/db reflected a physiological adaptation to complex interactions of GHRH, CRF, AVP, NPY, and other the positive energy balance associated with obesity [23, 62, hypothalamic neuronal circuits [80]. 71, 72]. In addition, high-fat diet causes ghrelin resistance by In addition, it has been recently described that ghrelin reducing NPY/agouti-related peptide (AgRP) responsiveness is implicated in certain rewarding aspects of eating that are to plasma ghrelin and suppressing the neuroendocrine separated from eating-associated body weight homeostasis ghrelin axis to limit further food intake [73]. Indeed, ghrelin and that require the presence of intact orexin signaling [81]. secretion increases with a low-protein diet and decreases with Growth hormone secretagogue receptors are expressed in a high-fat diet [26]. It has been shown that sugar intake, but tegmental and mesolimbic areas, such as the ventral tegmen- not stomach expansion, reduced serum ghrelin levels [51]. tal area (VTA) and laterodorsal tegmental areas (LDTg), It is clear that several molecular mediators are involved in involved with reward processing [82]. Ghrelin binds to the control of energy homeostasis. This is a highly complex neurons in VTA, where increases dopamine neuronal activity process that involves several brain regions, ranging from and dopamine turnover in the nucleus accumbens [83]. The cortex to brainstem. However, an important effort has been neurotransmitter dopamine is of primary importance for paid to understand the role of hypothalamus on this process, incentive motivation [3]. Furthermore, ghrelin signaling at since numerous neural circuits involved in the homeostatic the level of the VTA appears to be important for feeding control are located in this brain region. Discrete neuronal effects as intra-VTA injection of ghrelin increases the intake populations in the hypothalamus are regulated by specific of palatable food [84]. signals of nutritional state and express neurotransmitters that mediate particular effects on food intake and/or energy 3. CRF Components and the Regulation of expenditure. These neuronal populations were considered Energy Homeostasis to mediate “feeding” or “satiety” responses [74]. Currently, it seems likely that the effects that are causing a positive The mammalian CRF family comprises several peptides energy balance are mediated via leptin-responsive neurons such as CRF, urocortin (Ucn), UcnII, and UcnIII [85]. In in specific regions of the hypothalamus [2, 48, 50]. By in situ addition to integrate endocrine and autonomic and behav- hybridization procedure, it has been shown that the effect of ioral responses to stress via activation of the hypothalamic- food intake on NPY neurons is mediated by the direct action pituitary-adrenal (HPA) axis [86, 87], considerable evidence of leptin via Ob-Rb receptors expressed by these NPY cells. suggests a role for the CRF system in the regulation of energy The expression of these receptors is a defining phenotypic balance [88]. In recent years, vast new endogenous functions characteristic of the subset of NPY arcuate neurons that are have been attributed to this family, including regulation activated by fasting and play an adaptive response to negative of food intake and satiety, gastrointestinal motility, vascu- energy balance [75]. Leptin reduces food intake, body weight, lar tone and development, hearing, and cardiac function, and hypothalamic NPY mRNA expression, and these effects demonstrating the ubiquitous importance of the CRF family are reversed by the simultaneous administration of ghrelin [89]. through the activation of hypothalamic NPY/Y1 receptor The CRF system is involved in energy homeostasis via pathway [48, 50, 55, 60]. However, although the leptin- direct central actions independent of HPA axis control induced decrease in hypothalamic NPY mRNA expression is [90], with dysfunctions of CRF system hypothesized to completely abolished by i.c.v. coinjection of ghrelin, the sati- participate in the pathophysiology of obesity and eating ety effect of leptin is only partially reversed by ghrelin. This disorders [7, 10, 91]. Most pharmacological data concerning suggests the involvement of other orexigenic or anorexigenic the regulation of energy balance by the CRF system have systems in the antagonism of leptin action by ghrelin [50]. been obtained during acute administration of CRF and Ucns Information of both anorexigenic systems, mainly which dose-dependently inhibits food intake [5]. However, including melanocortin-derived peptides and orexigenic whereas central administration of CRF has an effect on peptidergic systems containing NPY and AgRP, seem to feeding behavior that is rather short (1–6 h) in duration, converge in PVN [76]. Ghrelin injected peripherally induces central administration of Ucn has an effect that persists c-fos expression in arcuate NPY-positive neurons that 12 or 24 hours [92]. In addition, urocortin was found to project to the medioparvocellular part of PVN [77]. Cowley have the most potent and prolonged inhibitory effect on et al. showed that ghrelin is expressed in a previously decreasing food intake among the CRF family peptides, when uncharacterized group of neurons in the hypothalamus. administered peripherally [93, 94]. Also Ucn II and Ucn III These neurons lie in the space between the lateral, arcuate, play an important role in regulating food intake [94, 95]. ventromedial, dorsomedial, and PVN hypothalamic nuclei Furthermore, the feeding stimulatory effect of NPY is and they send projections to several of these nuclei as attenuated by administration of CRF [88]. Different studies well as outside of the hypothalamus [41]. Ghrelin boutons suggests that CRF is a hypothalamic regulatory factor that established synaptic contacts on cell bodies and dendrites inhibits feeding induced by NPY [88, 96]. I.c.v. pretreatment of NPY/AgRP and Proopiomelanocortin (POMC) neurons with a CRF receptor antagonist, α-helical CRF [9–41], in the arcuate nucleus. Also, ghrelin boutons were in direct potentiated feeding induced by NPY, suggesting that brain 4 International Journal of Peptides CRF systems attenuate intake under conditions of evoked which express CRFR1, can be sites of the anorectic effects of appetite [88, 96]. CRF-related peptides [88]. In addition to energy intake, there is evidence that Several lines of evidence indicate that CRF-induced anx- CRF and Ucn also affect energy expenditure. Chronic iogenic effects, ACTH secretion, and locomotor activation administration of CRF and Ucn dose-dependently decreases are mediated by the activation of CRF receptor type 1 body weight, with a great impact of CRF [94]. Acute [103, 104]. Bradbury et al. have reported that stress-induced administration of CRF activates the sympathetic nervous anorexia may involve stimulation of CRFR1 during the first system (SNS), brown fat tissue (BAT) thermogenesis [5, 97], hours of the response; a similar reduction in the amount elevates norepinephrine release in several brain areas [98, of food and water consumed following the treatment with 99], increased uncoupling protein-1 in BAT [100], increases urocortin was observed in CRFR1 KO mice [105]. Moreover, body temperature [101], and reduces carcass fat [6]. In this a decrease in food-water intake was observed in CRFR1 regard, central infusion of CRF induces a state of negative KO and wt mice following i.c.v CRF treatment [103]. In energy balance that is partially a function of its effects on addition, CRFR1 KO mice appear to exhibit normal food food intake and partially a function of its activating effects on intake over a 24 h period relative to wild-type controls, the sympathetic nervous system. In contrast, UCN appears further suggesting that receptors in brain other than CRFR1 to induce a less dramatic state of negative energy balance that regulate normal food intake [106]. CRFR2 may mediate the is primarily dependent on changes in food intake and does appetite-suppressing effects of CRF-like peptides [103], since not appear to involve sympathetic nervous system activation the selective downregulation of CRFR2 mRNA with an anti- [102]. Consistent with this idea, brown adipose fat pad sense oligonucleotide attenuates CRF-induced anorexia. The weights and adrenal tissue weights increased in CRF-treated demonstration that expression of the CRFR2 gene is reduced rats. Furthermore, chronic central administration of CRF in obese, diabetic, and food-deprived rats and increased resulted in elevated corticosterone, cholesterol, triglycerides, following i.c.v. infusions of leptin is also consistent with a and free fatty acids (FFA), all of those suggesting SNS- role for the CRFR2 in the regulation of energy balance [88]. induced lipolysis. When a selective antagonist of the CRFR2 TheroleofCRFR2 receptor in energy balancemay receptor, antisauvagine-30 (ASV-30), was administrated, primarily mediate the appetite suppressing effects of CRF it could clearly attenuated the effects of both UCN and rather than the metabolic effects of this peptide [102]. CRF on food intake, but it did not affect the SNS or Genetic deletion of CRF2 receptors increased food intake HPA variables that were altered by chronic CRF-infusion. during the dark phase of the light/dark cycle. Microstructural Interestingly, ASV-30 alone also increased food intake and analyses indicated that this orexigenic effect was due to glucose levels, providing the evidence that antagonism of increased meal size. CRF2 pathway endogenously reinforces endogenous CRF can result in increased feeding [102]. The the satiating value of food at the circadian time of greatest effects of the urocortin on the microstructure of ingestive spontaneous intake. This suggests that the CRF2 pathway behavior are analogous to those of the dexfenfluramine, a might be involved in the processing of gut-derived satiation serotoninergic agonist which suppresses appetite. Anorexic signals or might potentiate their action [107, 108]. and thermogenic properties of serotonin receptor agonist Studies conducted in the rat suggest that CRFergic activ- have been shown to be dependent on brain [88]. ity is reduced in obesity and food-deprived rats [109]. The The distribution and regulation of both known subtypes obese Zucker rat is more sensitive than its lean counterpart to of CRF receptor, CRFR1, and CRFR2 further support the the effects of a central infusion of CRF [85]. There is evidence relevance of brain CRF systems in energy balance regulation. that the expression of CRF-binding protein (CRF-BP) is In particular, CRFR1 receptor are broadly distributed in reduced in the medial preoptic area and the basolateral brain with high densities observed in cortical and limbic complex of the amygdala in obese and food-deprived rats. In regions relevant for regulation of hypophysiotropic secretion addition, obesity and food deprivation reduce the expression and sympathetic outflow mediated by brainstem autonomic of CRFR2 receptor mRNA within the VMH [88]. In fact, nuclei, and the CRF2 receptors are focally distributed with obese rodents readily react to stressful and food deprivation high densities in subcortical regions such as the olfactory which can even induce, in genetically obese animals, a bulb, lateral septum, and ventromedial hypothalamus. More- neurogenic-stress-like response that strongly stimulates the over, levels of protein and message for CRF itself and both CRF system. Nonetheless, there are adaptations of the CRF CRF receptors are altered by experimental conditions such system in obesity (or following food deprivation). Food as anorexic drug treatment or fasting which disturbs energy deprivation could concur to reduce the CRF tone [85]. homeostasis [88]. However, there is increasing evidence that, in humans, Experiments conducted in rats have suggested that abdominal obesity phenotype may be characterized by a paraventricular hypothalamic nucleus is the site of the hyperactivation or hyperresponsiveness of the HPA axis anorexic effect, but the observations that PVH lesions do [110]. In the Cushing syndrome, hypercortisolism results in not prevent the CRF-mediated anorexic effects are consistent abdominal obesity [109]. with the view that the anoretic actions of CRF and urocortin can be exerted at extra PVH sites. The chronic infusion 3.1. Stress Response: Activation of the Hypothalamic-Pituitary- of urocortin into the arcuate-ventromedial region causes Adrenal Axis and Glucocorticoids (Gcs) Feedback. Stress trig- anorexia suggests that both the ventromedial hypothalamic gers a physiological response that involves the coordinated nucleus, which express the CRFR2, and the arcuate nucleus, control of multiple motor, hormonal, and vegetative systems International Journal of Peptides 5 that are engaged to reestablish homeostasis in the face hypothalamus of rats and mice [85, 112, 116]and hasa of the stress perturbation, either real or perceived, of the potent ACTH-releasing activity [43]. Functional interactions internal and/or external environment. The neuroendocrine between these systems in the control of gastrointestinal component of the stress response is characterized by the motility [116] have been demonstrated. In addition, ghrelin activation of the hypothalamic-pituitary-adrenal axis which has anxiety-like effects [117–119]. results in high levels of glucocorticoids in the blood [6, 9, 10]. Furthermore, the CRF system interacts with ghrelin. The resulting stress levels of circulating glucocorticoids Following acute stress, a rise in either gastric ghrelin mRNA give rise to multiple, complex physiological effects with or total plasma ghrelin has been observed, also tail pinch highly variable kinetics throughout the whole organism, stress significantly increased ghrelin mRNA expression including effects on glucose metabolism and mobilization [116, 120], although, recently, it has been demonstrated in different tissues, regulation of immune and inflammatory that increasing ghrelin through caloric restriction decreases responses, cardiovascular effects, neuroendocrine actions, anxiety and depressive-like behavior via GHS-R1a signaling and effects on cognition [9]. [119]. A main feedback effect of glucocorticoids is to suppress Indeed, Ucn increased acylated and desacylated ghrelin the activation of the HPA axis, inhibiting HPA hormone levels in the gastric body and decreased their levels in plasma, secretion and precipitating the termination of the neuroen- and decreased preproghrelin mRNA levels in the gastric docrine stress response. These inhibitory feedback effects on body. In addition, Ucn-induced reduction of plasma ghrelin HPA axis activation are thought to occur in the hippocam- andfoodintakewererestoredbyCRFR2 butnot CRFR1 pus, the hypothalamus, and the pituitary gland [9, 111]. and Ucn-induced reduction of food intake was restored by Acutely, glucocorticoids increase utilizable energy by exogenous ghrelin [91]. promoting glycogen and protein metabolism in liver and Endogenously as well as exogenously induced hypercor- muscle, respectively, along with enhancing catecholamine- tisolism leads to a significant decrease in plasma ghrelin induced lipolysis in adipose tissue [112]. levels in humans, indicating a possible feedback mechanism Acutely (within hours) glucocorticoids directly inhibit between gastric ghrelin secretion and the activity levels of the further activity in the hypothalamo-pituitary-adrenal axis, HPA [121]. but the chronic actions (across days) of these steroids on Within the brain, the expression of GHS-R1a is remark- brain are directly excitatory. Chronically high concentrations ably high in the hypothalamus-pituitary unit, in agreement of Gcs act in three ways that are functionally congruent. (i) with its impact on anterior pituitary function as well as Gcs increase the expression of CRF mRNA in the central with its influence in the control of appetite, food intake, and nucleus of the amygdala, a critical node in the emotional energy balance [61, 82]. But, mRNA encoding the GHS-R brain. CRF enables recruitment of a chronic stress-response was also expressed in several other discrete regions of the network. (ii) Gcs increase the salience of pleasurable or com- brain (rat), such as dentate gyrus, CA2 and CA3 regions of pulsive activities (ingesting sucrose, fat, and drugs, or wheel- the hippocampal formation, thalamic regions, and several running). This motivates ingestion of “comfort food.” (iii) nuclei within the brainstem including pars compacta of Gcs act systemically to increase abdominal fat depots [113]. the substantia nigra, ventral tegmental area, median and As glucocorticoids increase, insulin secretion also dorsal raphe nuclei, Edinger-Westphal nucleus, laterodorsal increases, as it is well known from the strong association nucleus, and facial nerve [82]. It looks like that a relationship of Cushing’s syndrome with type 2 diabetes. It appears that between ghrelin and the CRF system exists, since ghrelin insulin plays a profound role in food selection whereas Gcs receptor has been detected in the paraventricular nucleus, the determine the motivation for selecting these foods, perhaps principal source of CRF, and in the Edinger-Westphal nuclei, thought their actions on dopamine secretion in the nucleus the primary site of urocortin expression. accumbens [1]. 4.1. Brain Circuitry in the Hypothalamus: Connecting Ghrelin. Ghrelin activates Agrp/NPY neurons, thereby stimulating 4. Ghrelin and CRF System food intake. GHSreceptormRNAisexpressedin94% Ghrelin and CRF have opposed functions in the control of arcuate neurons that express NPY [122]. The ARC- of food intake. Ghrelin is a hunger signal, released by the NPY/Agrp neurons project dorsally and anteriorly into stomach into the circulation and produced in a subset of the perifornical lateral hypothalamic area, paraventriculat hypothalamic neurons [70]. Its secretion is triggered to nucleus, dorsomedial nucleus of the hypothalamus, and counteract further deficit of storage and to prevent starva- medial preoptic area [74]. NPY projections to the PVH tion. CRF causes anorexia and also activates the sympathetic are derived from the arcuate nucleus and the brainstem, nervous system in addition to its role as a major regulator of and synaptic contacts between NPY terminals and CRF the hypothalamic-pituitary-adrenal axis [114]. neurons have been demonstrated. Available pharmacological However, increasing evidence suggests an interplay evidence suggests that NPY exerts a stimulatory effect on between the CRF and ghrelin systems. Ghrelin expression CRF neurons. It is possible that under normal conditions, is present in afferents to CRF-expressing neurons [41]. In brief activation of the ARC NPY system might not only addition, peripheral and i.c.v. ghrelin injection increases CRF trigger a feeding response, but also activate counteracting mRNA expression in vivo in the hypothalamus of rats [115] mechanism as the CRF system [123]. Although no con- and mice [116] in vitro [82]“in vivo”and “in vitro”, in the vincing Y1 receptor staining wasfound in CRF cell bodies, 6 International Journal of Peptides Y1-positive fibers made close appositions on CRF cell bodies the OFC to DA neurons and NAc are involved in conditioned in the parvocellular nucleus as well as in the periventricular responses to food [128, 134]. zone. So, NPY may be able to indirectly modulate CRF neuronal activity by acting on presynaptic Y1 receptors to 5.2. Ghrelin as a Hedonic Signal? Chronic stress induces modulate the secretion of neurotransmitters or neuromodu- changes in mood, feeding, and metabolism by a poorly lators, which in turn modulate CRF neuronal activity [123]. understood neurobiological mechanism. Elevated stress hor- The group of Smith has discovered the presence of CRFR1 mones and palatable food intake and the consequent accre- colocalized to NPY neurons in the ARC, and it provided a tion of fat can serve as feedback signals that reduce perceived potential neuroanatomical circuit by which CRF may inhibit stress, thus reinforcing stress-induced feeding behavior [1]. NPY signaling by direct modulation of NPY neurons [124]. Stress not only increases glucocorticoid levels through One possible effect of ghrelin is to increase the release of the cellular actions of CRF in the hypothalamic-pituitary- NPY onto GABAergic nerve terminals, disinhibiting the CRF adrenal axis, but also induces the release of CRF in extrahy- neuron and thus stimulating greater CRF release into the pothalamic brain regions, such as VTA [135, 136], where pituitary-hypophyseal portal circulation, driving increased stimulates CRFR1 on VTA dopamine neurons and activates ACTH secretion from the pituitary [41]. The CRF receptor a protein-kinase-C- (PKC-) dependent enhancement of Ih, antagonist α-helical CRF9-41 significantly inhibited ghrelin- which led to increased cell firing [137]. This activation may induced anxiogenic effects, so this behavior effect includes a be implicated in the interaction between stress, dopamine, mechanism of action involving CRF [116]. and motivation which is important for many behaviors and psychiatric disorders such as depression [138–140]drug 5. Stress and Obesity: Ghrelin as abuse [136, 141], and schizophrenia [138, 142]. Ghrelin has recently emerged as one of the major con- aHedonic Signal? tributing factors to reward-driven feeding that can override 5.1. Reward System and the Control of Food Intake. Reward the state of satiation [3, 81, 84, 143]. The ghrelin receptor, is often conceptualized as if it were a single psychological GHS-R1A, is also expressed in tegmental and mesolimbic process or a unitary feature of a reinforcing stimulus. It is areas involved in reward, such as the VTA and laterodorsal sometimes identified with the pleasure or hedonic impact of tegmental areas (LDTg). Intracerebroventricular injection a stimulus and is viewed by some as necessarily subjective in of ghrelin has been shown to stimulate food intake [144], nature. However, reward is not a unitary process, but instead especially the intake of palatable food [84]. Moreover, the a constellation of multiple processes many of which can be effects of peripheral ghrelin on food intake were blunted by separately identified in behavior, especially after the compo- intra-VTA administration of a GHS-R1A antagonist [83]. nent processes are dissociated by brain manipulations [125]. Consistent with this, peripheral treatment with a GHS- Certain foods, particularly those rich in sugars and fat, R1A antagonist decreased preference for palatable food, are potent rewards that promote eating [126, 127]and suppressed the ability of sweet treats to condition a place triggered learned associations between the stimulus and preference [84], and suppressed motivated behavior for the reward (conditioning) [128]. Several neurotransmitters, rewarding foods, both sweet [3, 84, 143] and high-fat including DA, as well neuropeptides involved in homeostatic foods [81]. Collectively these data support the idea that regulation of food intake, are implicated in the rewarding the physiological role of ghrelin is to increase the incentive effects of food. Dopamine is a key neurotransmitter mod- motivation for natural rewards such as food. ulating reward, which it does mainly through its projections The central ghrelin signaling system emerges as a novel from the ventral tegmental area (VTA) [128]. and interesting therapeutic target as studies in rodents have The VTA dopamine (DA) projection to nucleus accum- shown that ghrelin antagonists suppress the mesoaccumbal bens (NAcc) has been implicated in the control of behaviors dopamine system, suppress the intake of (and preference motivated by rewards [129–131]. The VTA also contains for) palatable food, suppress the ability of rewarding foods DA neurons that project to medial prefrontal cortex (PFC), to condition a place preference, and decrease operant a structure linked functionally to temporal organization of responding for rewarding foods [3]. The CRF system is goal-directed behaviors [131]. directly implicated in the regulation of energy balance [5, 6] The mesolimbic dopamine projections, originating from and may participate in the pathophysiology of obesity and neuronal cell populations in the VTA and terminating in eating disorders. Additionally, increasing evidence suggests the ventral striatum and the prefrontal cortex, are linked an interplay between the CRF and ghrelin systems. Further to anticipatory, appetitive, or approach phases of motivated studies should determine whether ghrelin plays a role in the behavior and are important for anticipatory food reward and feeding behavior associated with stress. food-seeking behavior [132]. The extensive glutamatergic afferents to DA neurons References from regions involved with sensory (insula or primary gus- tatory cortex), homeostatic (hypothalamus), reward (NAc), [1] M. F. 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Ghrelin, Appetite Regulation, and Food Reward: Interaction with Chronic Stress

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Copyright © 2011 Yolanda Diz-Chaves. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Hindawi Publishing Corporation International Journal of Peptides Volume 2011, Article ID 898450, 11 pages doi:10.1155/2011/898450 Review Article Ghrelin, Appetite Regulation, and Food Reward: Interaction with Chronic Stress Yolanda Diz-Chaves Instituto Cajal, CSIC, Avenida Doctor Arce 37, 28002 Madrid, Spain Correspondence should be addressed to Yolanda Diz-Chaves, ydiz@cajal.csic.es Received 30 May 2011; Accepted 24 July 2011 Academic Editor: A. Inui Copyright © 2011 Yolanda Diz-Chaves. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Obesity has become one of the leading causes of illness and mortality in the developed world. Preclinical and clinical data provide compelling evidence for ghrelin as a relevant regulator of appetite, food intake, and energy homeostasis. In addition, ghrelin has recently emerged as one of the major contributing factors to reward-driven feeding that can override the state of satiation. The corticotropin-releasing-factor system is also directly implicated in the regulation of energy balance and may participate in the pathophysiology of obesity and eating disorders. This paper focuses on the role of ghrelin in the regulation of appetite, on its possible role as a hedonic signal involved in food reward, and on its interaction with the corticotropin-releasing-factor system and chronic stress. 1. Introduction hormonal, and vegetative systems that are engaged to reestablish homeostasis in the face of the stress perturbation, Obesity and related disorders are among the leading causes either real or perceived, of the internal and/or external of illness and mortality in the developed world, and it environment [9]. In human beings, many obese patients tend became a severe epidemic problem not only in adults to eat more when they are emotionally tense or depressed but also in younger generations [1]. To better understand or simply bored. Sadness favored eating of high fat/sweet, the pathophysiological mechanism that underlies metabolic hedonically rewarding foods, whereas intake during a happy disorders, increasing attention has been paid to central regu- state favored dried fruit [1]. In addition, it has been described latory elements in energy homeostasis, including food intake that visceral overweight subjects showed stress-induced food and energy expenditure. The discovery of ghrelin and its intake in the absence of hunger, resulting in an increased influence on appetite, fuel utilization, body weight, and body energy intake [10]. composition adds yet another component to the complexity Increasing evidence suggests an interplay between the in the central regulation of energy balance [2]. In addition, CRF and ghrelin systems. However, it is unknown wether recently it has been described that ghrelin may be implicated this interacion plays a role in the pathophysiology of obesity. in food reward [3], since ghrelin directly targets the ventral tegmental area to increase food motivation [4]. However, 2. Ghrelin and the Regulation of Energy Balance it remains to be determined whether the central ghrelin signaling system has a role in the pathophysiology of obesity. Small synthetic molecules called growth hormone secret- The corticotropin releasing factor (CRF) system is agogues (GHSs) stimulate the release of growth hormone directly implicated in the regulation of energy balance [5, 6]. (GH) from the pituitary. They act through the GHS-receptor In addition, it may participate in the pathophysiology of (GHS-R), which has been cloned for different groups [11, obesity and eating disorders [7, 8]. Considerable evidence 12]. Despite intensive searches by different groups, in 1999, has accumulated to demonstrate that feeding behavior is was purified and identified the endogenous specific ligand influenced by stress. Stress triggers a physiological response for GHS-R [13]. This ligand is a molecule of 28 amino that involves the coordinated control of multiple motor, acids called ghrelin in which the serine residue 3 was 2 International Journal of Peptides n-octanoylated. The minimum core of ghrelin residing in the prompt significant orexigenic response was the paraven- N-terminal tetrapeptide and the acylation of the peptide had tricular nucleus (PVN), but the stimulation of food intake been supposed critical to cross the blood-brain barrier but was significantly less than the one seen in the ARC [47]. is also essential for binding the GHS-1a receptor and for its Studies with confocal laser microscopy have analyzed the GH releasing and other endocrine actions [13–15]. Recently, effect of ghrelin on the expression of c-fos, a marker of the enzyme responsible for the acylation of ghrelin was neuronal activation. These studies have shown that i.p. identified by two independent groups [16, 17]. The ghrelin administration of ghrelin induces c-fos immunoreactivity in O-acetyltransferase (GOAT) is the specific acyl transferase (i) the ARC and medioparvocellular part of the PVN [52, that activates ghrelin [16, 17] and belongs to the super family 53], (ii) the dorsomedial and lateral hypothalamic nuclei, of membrane-bound O-acyltransferases (MBOATs) [17–19]. and (iii) two regions of the brainstem, the nucleus of the In humans, GOAT expression is high in stomach and gut, tractus solitarius and the area postrema [53]. In addition, the major ghrelin-secreting tissues, and in the pituitary, in after i.c.v. ghrelin administration, c-fos immunoreactivity which ghrelin is known to show autocrine and paracrine was found in neuronal populations of primary importance effects [16, 20]. GOAT is regulated by nutrient availability, in the regulation of feeding, including NPY neurons, AgRP depends on specific dietary lipids as acylation substrates neurons [42, 48], and orexin-containing neurons (in the and links ingested lipids to energy expenditure and body fat lateral hypothalamus) [53]. Furthermore, antibodies and mass [21]. Although devoid of neuroendocrine activity, also antagonist of NPY and AgRP abolish ghrelin-induced feed- unacylated ghrelin, its most abundant circulating form, is an ing [54]. Ghrelin increases NPY and AgRP mRNA expression active molecule. This evidence agrees with the existence of levels [42, 48–50, 55] independently of the nutritional status GHS-R subtypes that are activated by ghrelin independently [56] and blocked leptin-induced feeding reduction [48]. of its acylation [13, 22]. Furthermore, the orexigenic effect of ghrelin is abolished In humans, the stomach is a major source of circu- by i.c.v. coinjection of Y1 receptor antagonist, indicating lating ghrelin. It has been shown that plasma ghrelin- that ghrelin increases food intake at least partly through the like immunoreactivity levels in gastrectomized patients still activation of the hypothalamic NPY/Y1 pathway [50, 55]. remain 35% of those in normal subjects, suggesting that Endogenous ghrelin secretion is pulsatile and directly tissues other than the stomach contribute to a certain related to feeding behavior [57]; after fasting, ghrelin amount of circulating ghrelin [23]. The peptide is produced secretion is augmented in the form of high frequency, high prevalently in the stomach by the X/A-like cells within amplitude episodes [58, 59]. Ghrelin concentrations in the the oxyntic glands of the gastric fundus mucosa [13, 24– blood and mRNA levels were increased by fasting and 27], with substantially lower amounts derived from the decreased by feeding in the stomach [23, 51, 60]. The plasma bowel [24, 27–29], pancreas [28, 30], lymphocytes [28], levels of ghrelin inversely correlate with body mass index chondrocytes [31], kidney [28, 32], placenta [33], lung [28], (BMI), thus, ghrelin levels are modified in patients with testis [28, 34], ovary [35, 36], adrenal cortex [37, 38], anorexia nervosa and obesity. Ghrelin secretion is increased pituitary (lactotrophs, somatotrophs, and thyrotrophs cells) in anorexia and cachexia, reduced in obesity, and normalized [39, 40], and hypothalamus [40–42]. by recovery of idealbodyweight[23, 61, 62]. The paradoxical Ghrelin is strongly involved in the regulation of energy situation of increased basal plasma ghrelin concentrations homeostasis. The group of Ghigo and coworkers published observed in subjects with long-term energy deficit and for the first time the involvement of ghrelin in the regulation decreased food intake such as in restrictive anorexia nervosa of appetite. They described that 3 out of 4 healthy volunteers [63] suggests the existence of ghrelin resistance that may reported hunger following ghrelin administration as a “side be relevant to the decreased effects of ghrelin to promote effect” in a clinical study analyzing GH release, and this a positive energy balance [64]. In addition, plasma ghrelin effect has been confirmed in more studies [43, 44]. In levels regulation could be influenced by ghrelin reactive animal studies, it has been shown that ghrelin increased food autoantibodies (autoAbs), since it had been demonstrated intake of rats, when it was administered either into central the presence of autoAbs reactive with ghrelin in healthy nervous system or peripherally [45–47], in both satiated and subjects and rats [65, 66]. Furthermore, a role of autoAbs feeding conditions [48]. The i.c.v. administration generated against appetite-regulating neuropeptides in eating disorders a dose-dependent increase in food intake and body weight has emerged [65]. In this regard, it had been described [49–51]. The time course and magnitude of this effect decreased plasma levels of acyl ghrelin IgG autoAbs present was similar to neuropeptide Y (NPY) [46, 49]. Also, it as free or total immunoglobulins in patients with anorexia has been shown a significant increase of the food intake nervosa, suggesting that altered production of ghrelin reac- after the systemic administration of ghrelin, occurring at tive autoAbs is associated with persistently elevated plasma plasma ghrelin levels within normal fasting range [47, 52]. In ghrelin and eventually ghrelin resistance in anorexia nervosa rodents, ghrelin-induced gain weight is based on accretion of [67]. fat mass gain by reducing fat utilization, without changes in Furthermore, a negative association between body mass longitudinal skeletal growth and without an increase in lean and ghrelin secretion in Prader-Willi syndrome exists, where [51]. obesity is associated with ghrelin hypersecretion [68]. In Very low doses (30 pmol) of ghrelin injected into the obese humans, food intake (including 60% of carbohydrates) arcuate nucleus (ARC) potently stimulated food intake. with postprandially increased insulin response fails to sup- Another hypothalamic nucleus that showed a similarly press ghrelin levels sufficiently [69], suggesting that ghrelin International Journal of Peptides 3 may be involved in some of the multiple pathophysiological apposition to NPY and GABA axon terminals in the ARC and mechanisms leading to obesity and type 2 diabetes [70]. PVH. In the paraventricular hypothalamic nucleus (PVN), The reduction in plasma ghrelin levels with high-fat diet some of ghrelin axons innervated CRF cells [70, 78, 79]. agreed with the low circulating levels of ghrelin in obese Therefore, the final effects of ghrelin are likely to reflect humans and db/db reflected a physiological adaptation to complex interactions of GHRH, CRF, AVP, NPY, and other the positive energy balance associated with obesity [23, 62, hypothalamic neuronal circuits [80]. 71, 72]. In addition, high-fat diet causes ghrelin resistance by In addition, it has been recently described that ghrelin reducing NPY/agouti-related peptide (AgRP) responsiveness is implicated in certain rewarding aspects of eating that are to plasma ghrelin and suppressing the neuroendocrine separated from eating-associated body weight homeostasis ghrelin axis to limit further food intake [73]. Indeed, ghrelin and that require the presence of intact orexin signaling [81]. secretion increases with a low-protein diet and decreases with Growth hormone secretagogue receptors are expressed in a high-fat diet [26]. It has been shown that sugar intake, but tegmental and mesolimbic areas, such as the ventral tegmen- not stomach expansion, reduced serum ghrelin levels [51]. tal area (VTA) and laterodorsal tegmental areas (LDTg), It is clear that several molecular mediators are involved in involved with reward processing [82]. Ghrelin binds to the control of energy homeostasis. This is a highly complex neurons in VTA, where increases dopamine neuronal activity process that involves several brain regions, ranging from and dopamine turnover in the nucleus accumbens [83]. The cortex to brainstem. However, an important effort has been neurotransmitter dopamine is of primary importance for paid to understand the role of hypothalamus on this process, incentive motivation [3]. Furthermore, ghrelin signaling at since numerous neural circuits involved in the homeostatic the level of the VTA appears to be important for feeding control are located in this brain region. Discrete neuronal effects as intra-VTA injection of ghrelin increases the intake populations in the hypothalamus are regulated by specific of palatable food [84]. signals of nutritional state and express neurotransmitters that mediate particular effects on food intake and/or energy 3. CRF Components and the Regulation of expenditure. These neuronal populations were considered Energy Homeostasis to mediate “feeding” or “satiety” responses [74]. Currently, it seems likely that the effects that are causing a positive The mammalian CRF family comprises several peptides energy balance are mediated via leptin-responsive neurons such as CRF, urocortin (Ucn), UcnII, and UcnIII [85]. In in specific regions of the hypothalamus [2, 48, 50]. By in situ addition to integrate endocrine and autonomic and behav- hybridization procedure, it has been shown that the effect of ioral responses to stress via activation of the hypothalamic- food intake on NPY neurons is mediated by the direct action pituitary-adrenal (HPA) axis [86, 87], considerable evidence of leptin via Ob-Rb receptors expressed by these NPY cells. suggests a role for the CRF system in the regulation of energy The expression of these receptors is a defining phenotypic balance [88]. In recent years, vast new endogenous functions characteristic of the subset of NPY arcuate neurons that are have been attributed to this family, including regulation activated by fasting and play an adaptive response to negative of food intake and satiety, gastrointestinal motility, vascu- energy balance [75]. Leptin reduces food intake, body weight, lar tone and development, hearing, and cardiac function, and hypothalamic NPY mRNA expression, and these effects demonstrating the ubiquitous importance of the CRF family are reversed by the simultaneous administration of ghrelin [89]. through the activation of hypothalamic NPY/Y1 receptor The CRF system is involved in energy homeostasis via pathway [48, 50, 55, 60]. However, although the leptin- direct central actions independent of HPA axis control induced decrease in hypothalamic NPY mRNA expression is [90], with dysfunctions of CRF system hypothesized to completely abolished by i.c.v. coinjection of ghrelin, the sati- participate in the pathophysiology of obesity and eating ety effect of leptin is only partially reversed by ghrelin. This disorders [7, 10, 91]. Most pharmacological data concerning suggests the involvement of other orexigenic or anorexigenic the regulation of energy balance by the CRF system have systems in the antagonism of leptin action by ghrelin [50]. been obtained during acute administration of CRF and Ucns Information of both anorexigenic systems, mainly which dose-dependently inhibits food intake [5]. However, including melanocortin-derived peptides and orexigenic whereas central administration of CRF has an effect on peptidergic systems containing NPY and AgRP, seem to feeding behavior that is rather short (1–6 h) in duration, converge in PVN [76]. Ghrelin injected peripherally induces central administration of Ucn has an effect that persists c-fos expression in arcuate NPY-positive neurons that 12 or 24 hours [92]. In addition, urocortin was found to project to the medioparvocellular part of PVN [77]. Cowley have the most potent and prolonged inhibitory effect on et al. showed that ghrelin is expressed in a previously decreasing food intake among the CRF family peptides, when uncharacterized group of neurons in the hypothalamus. administered peripherally [93, 94]. Also Ucn II and Ucn III These neurons lie in the space between the lateral, arcuate, play an important role in regulating food intake [94, 95]. ventromedial, dorsomedial, and PVN hypothalamic nuclei Furthermore, the feeding stimulatory effect of NPY is and they send projections to several of these nuclei as attenuated by administration of CRF [88]. Different studies well as outside of the hypothalamus [41]. Ghrelin boutons suggests that CRF is a hypothalamic regulatory factor that established synaptic contacts on cell bodies and dendrites inhibits feeding induced by NPY [88, 96]. I.c.v. pretreatment of NPY/AgRP and Proopiomelanocortin (POMC) neurons with a CRF receptor antagonist, α-helical CRF [9–41], in the arcuate nucleus. Also, ghrelin boutons were in direct potentiated feeding induced by NPY, suggesting that brain 4 International Journal of Peptides CRF systems attenuate intake under conditions of evoked which express CRFR1, can be sites of the anorectic effects of appetite [88, 96]. CRF-related peptides [88]. In addition to energy intake, there is evidence that Several lines of evidence indicate that CRF-induced anx- CRF and Ucn also affect energy expenditure. Chronic iogenic effects, ACTH secretion, and locomotor activation administration of CRF and Ucn dose-dependently decreases are mediated by the activation of CRF receptor type 1 body weight, with a great impact of CRF [94]. Acute [103, 104]. Bradbury et al. have reported that stress-induced administration of CRF activates the sympathetic nervous anorexia may involve stimulation of CRFR1 during the first system (SNS), brown fat tissue (BAT) thermogenesis [5, 97], hours of the response; a similar reduction in the amount elevates norepinephrine release in several brain areas [98, of food and water consumed following the treatment with 99], increased uncoupling protein-1 in BAT [100], increases urocortin was observed in CRFR1 KO mice [105]. Moreover, body temperature [101], and reduces carcass fat [6]. In this a decrease in food-water intake was observed in CRFR1 regard, central infusion of CRF induces a state of negative KO and wt mice following i.c.v CRF treatment [103]. In energy balance that is partially a function of its effects on addition, CRFR1 KO mice appear to exhibit normal food food intake and partially a function of its activating effects on intake over a 24 h period relative to wild-type controls, the sympathetic nervous system. In contrast, UCN appears further suggesting that receptors in brain other than CRFR1 to induce a less dramatic state of negative energy balance that regulate normal food intake [106]. CRFR2 may mediate the is primarily dependent on changes in food intake and does appetite-suppressing effects of CRF-like peptides [103], since not appear to involve sympathetic nervous system activation the selective downregulation of CRFR2 mRNA with an anti- [102]. Consistent with this idea, brown adipose fat pad sense oligonucleotide attenuates CRF-induced anorexia. The weights and adrenal tissue weights increased in CRF-treated demonstration that expression of the CRFR2 gene is reduced rats. Furthermore, chronic central administration of CRF in obese, diabetic, and food-deprived rats and increased resulted in elevated corticosterone, cholesterol, triglycerides, following i.c.v. infusions of leptin is also consistent with a and free fatty acids (FFA), all of those suggesting SNS- role for the CRFR2 in the regulation of energy balance [88]. induced lipolysis. When a selective antagonist of the CRFR2 TheroleofCRFR2 receptor in energy balancemay receptor, antisauvagine-30 (ASV-30), was administrated, primarily mediate the appetite suppressing effects of CRF it could clearly attenuated the effects of both UCN and rather than the metabolic effects of this peptide [102]. CRF on food intake, but it did not affect the SNS or Genetic deletion of CRF2 receptors increased food intake HPA variables that were altered by chronic CRF-infusion. during the dark phase of the light/dark cycle. Microstructural Interestingly, ASV-30 alone also increased food intake and analyses indicated that this orexigenic effect was due to glucose levels, providing the evidence that antagonism of increased meal size. CRF2 pathway endogenously reinforces endogenous CRF can result in increased feeding [102]. The the satiating value of food at the circadian time of greatest effects of the urocortin on the microstructure of ingestive spontaneous intake. This suggests that the CRF2 pathway behavior are analogous to those of the dexfenfluramine, a might be involved in the processing of gut-derived satiation serotoninergic agonist which suppresses appetite. Anorexic signals or might potentiate their action [107, 108]. and thermogenic properties of serotonin receptor agonist Studies conducted in the rat suggest that CRFergic activ- have been shown to be dependent on brain [88]. ity is reduced in obesity and food-deprived rats [109]. The The distribution and regulation of both known subtypes obese Zucker rat is more sensitive than its lean counterpart to of CRF receptor, CRFR1, and CRFR2 further support the the effects of a central infusion of CRF [85]. There is evidence relevance of brain CRF systems in energy balance regulation. that the expression of CRF-binding protein (CRF-BP) is In particular, CRFR1 receptor are broadly distributed in reduced in the medial preoptic area and the basolateral brain with high densities observed in cortical and limbic complex of the amygdala in obese and food-deprived rats. In regions relevant for regulation of hypophysiotropic secretion addition, obesity and food deprivation reduce the expression and sympathetic outflow mediated by brainstem autonomic of CRFR2 receptor mRNA within the VMH [88]. In fact, nuclei, and the CRF2 receptors are focally distributed with obese rodents readily react to stressful and food deprivation high densities in subcortical regions such as the olfactory which can even induce, in genetically obese animals, a bulb, lateral septum, and ventromedial hypothalamus. More- neurogenic-stress-like response that strongly stimulates the over, levels of protein and message for CRF itself and both CRF system. Nonetheless, there are adaptations of the CRF CRF receptors are altered by experimental conditions such system in obesity (or following food deprivation). Food as anorexic drug treatment or fasting which disturbs energy deprivation could concur to reduce the CRF tone [85]. homeostasis [88]. However, there is increasing evidence that, in humans, Experiments conducted in rats have suggested that abdominal obesity phenotype may be characterized by a paraventricular hypothalamic nucleus is the site of the hyperactivation or hyperresponsiveness of the HPA axis anorexic effect, but the observations that PVH lesions do [110]. In the Cushing syndrome, hypercortisolism results in not prevent the CRF-mediated anorexic effects are consistent abdominal obesity [109]. with the view that the anoretic actions of CRF and urocortin can be exerted at extra PVH sites. The chronic infusion 3.1. Stress Response: Activation of the Hypothalamic-Pituitary- of urocortin into the arcuate-ventromedial region causes Adrenal Axis and Glucocorticoids (Gcs) Feedback. Stress trig- anorexia suggests that both the ventromedial hypothalamic gers a physiological response that involves the coordinated nucleus, which express the CRFR2, and the arcuate nucleus, control of multiple motor, hormonal, and vegetative systems International Journal of Peptides 5 that are engaged to reestablish homeostasis in the face hypothalamus of rats and mice [85, 112, 116]and hasa of the stress perturbation, either real or perceived, of the potent ACTH-releasing activity [43]. Functional interactions internal and/or external environment. The neuroendocrine between these systems in the control of gastrointestinal component of the stress response is characterized by the motility [116] have been demonstrated. In addition, ghrelin activation of the hypothalamic-pituitary-adrenal axis which has anxiety-like effects [117–119]. results in high levels of glucocorticoids in the blood [6, 9, 10]. Furthermore, the CRF system interacts with ghrelin. The resulting stress levels of circulating glucocorticoids Following acute stress, a rise in either gastric ghrelin mRNA give rise to multiple, complex physiological effects with or total plasma ghrelin has been observed, also tail pinch highly variable kinetics throughout the whole organism, stress significantly increased ghrelin mRNA expression including effects on glucose metabolism and mobilization [116, 120], although, recently, it has been demonstrated in different tissues, regulation of immune and inflammatory that increasing ghrelin through caloric restriction decreases responses, cardiovascular effects, neuroendocrine actions, anxiety and depressive-like behavior via GHS-R1a signaling and effects on cognition [9]. [119]. A main feedback effect of glucocorticoids is to suppress Indeed, Ucn increased acylated and desacylated ghrelin the activation of the HPA axis, inhibiting HPA hormone levels in the gastric body and decreased their levels in plasma, secretion and precipitating the termination of the neuroen- and decreased preproghrelin mRNA levels in the gastric docrine stress response. These inhibitory feedback effects on body. In addition, Ucn-induced reduction of plasma ghrelin HPA axis activation are thought to occur in the hippocam- andfoodintakewererestoredbyCRFR2 butnot CRFR1 pus, the hypothalamus, and the pituitary gland [9, 111]. and Ucn-induced reduction of food intake was restored by Acutely, glucocorticoids increase utilizable energy by exogenous ghrelin [91]. promoting glycogen and protein metabolism in liver and Endogenously as well as exogenously induced hypercor- muscle, respectively, along with enhancing catecholamine- tisolism leads to a significant decrease in plasma ghrelin induced lipolysis in adipose tissue [112]. levels in humans, indicating a possible feedback mechanism Acutely (within hours) glucocorticoids directly inhibit between gastric ghrelin secretion and the activity levels of the further activity in the hypothalamo-pituitary-adrenal axis, HPA [121]. but the chronic actions (across days) of these steroids on Within the brain, the expression of GHS-R1a is remark- brain are directly excitatory. Chronically high concentrations ably high in the hypothalamus-pituitary unit, in agreement of Gcs act in three ways that are functionally congruent. (i) with its impact on anterior pituitary function as well as Gcs increase the expression of CRF mRNA in the central with its influence in the control of appetite, food intake, and nucleus of the amygdala, a critical node in the emotional energy balance [61, 82]. But, mRNA encoding the GHS-R brain. CRF enables recruitment of a chronic stress-response was also expressed in several other discrete regions of the network. (ii) Gcs increase the salience of pleasurable or com- brain (rat), such as dentate gyrus, CA2 and CA3 regions of pulsive activities (ingesting sucrose, fat, and drugs, or wheel- the hippocampal formation, thalamic regions, and several running). This motivates ingestion of “comfort food.” (iii) nuclei within the brainstem including pars compacta of Gcs act systemically to increase abdominal fat depots [113]. the substantia nigra, ventral tegmental area, median and As glucocorticoids increase, insulin secretion also dorsal raphe nuclei, Edinger-Westphal nucleus, laterodorsal increases, as it is well known from the strong association nucleus, and facial nerve [82]. It looks like that a relationship of Cushing’s syndrome with type 2 diabetes. It appears that between ghrelin and the CRF system exists, since ghrelin insulin plays a profound role in food selection whereas Gcs receptor has been detected in the paraventricular nucleus, the determine the motivation for selecting these foods, perhaps principal source of CRF, and in the Edinger-Westphal nuclei, thought their actions on dopamine secretion in the nucleus the primary site of urocortin expression. accumbens [1]. 4.1. Brain Circuitry in the Hypothalamus: Connecting Ghrelin. Ghrelin activates Agrp/NPY neurons, thereby stimulating 4. Ghrelin and CRF System food intake. GHSreceptormRNAisexpressedin94% Ghrelin and CRF have opposed functions in the control of arcuate neurons that express NPY [122]. The ARC- of food intake. Ghrelin is a hunger signal, released by the NPY/Agrp neurons project dorsally and anteriorly into stomach into the circulation and produced in a subset of the perifornical lateral hypothalamic area, paraventriculat hypothalamic neurons [70]. Its secretion is triggered to nucleus, dorsomedial nucleus of the hypothalamus, and counteract further deficit of storage and to prevent starva- medial preoptic area [74]. NPY projections to the PVH tion. CRF causes anorexia and also activates the sympathetic are derived from the arcuate nucleus and the brainstem, nervous system in addition to its role as a major regulator of and synaptic contacts between NPY terminals and CRF the hypothalamic-pituitary-adrenal axis [114]. neurons have been demonstrated. Available pharmacological However, increasing evidence suggests an interplay evidence suggests that NPY exerts a stimulatory effect on between the CRF and ghrelin systems. Ghrelin expression CRF neurons. It is possible that under normal conditions, is present in afferents to CRF-expressing neurons [41]. In brief activation of the ARC NPY system might not only addition, peripheral and i.c.v. ghrelin injection increases CRF trigger a feeding response, but also activate counteracting mRNA expression in vivo in the hypothalamus of rats [115] mechanism as the CRF system [123]. Although no con- and mice [116] in vitro [82]“in vivo”and “in vitro”, in the vincing Y1 receptor staining wasfound in CRF cell bodies, 6 International Journal of Peptides Y1-positive fibers made close appositions on CRF cell bodies the OFC to DA neurons and NAc are involved in conditioned in the parvocellular nucleus as well as in the periventricular responses to food [128, 134]. zone. So, NPY may be able to indirectly modulate CRF neuronal activity by acting on presynaptic Y1 receptors to 5.2. Ghrelin as a Hedonic Signal? Chronic stress induces modulate the secretion of neurotransmitters or neuromodu- changes in mood, feeding, and metabolism by a poorly lators, which in turn modulate CRF neuronal activity [123]. understood neurobiological mechanism. Elevated stress hor- The group of Smith has discovered the presence of CRFR1 mones and palatable food intake and the consequent accre- colocalized to NPY neurons in the ARC, and it provided a tion of fat can serve as feedback signals that reduce perceived potential neuroanatomical circuit by which CRF may inhibit stress, thus reinforcing stress-induced feeding behavior [1]. NPY signaling by direct modulation of NPY neurons [124]. Stress not only increases glucocorticoid levels through One possible effect of ghrelin is to increase the release of the cellular actions of CRF in the hypothalamic-pituitary- NPY onto GABAergic nerve terminals, disinhibiting the CRF adrenal axis, but also induces the release of CRF in extrahy- neuron and thus stimulating greater CRF release into the pothalamic brain regions, such as VTA [135, 136], where pituitary-hypophyseal portal circulation, driving increased stimulates CRFR1 on VTA dopamine neurons and activates ACTH secretion from the pituitary [41]. The CRF receptor a protein-kinase-C- (PKC-) dependent enhancement of Ih, antagonist α-helical CRF9-41 significantly inhibited ghrelin- which led to increased cell firing [137]. This activation may induced anxiogenic effects, so this behavior effect includes a be implicated in the interaction between stress, dopamine, mechanism of action involving CRF [116]. and motivation which is important for many behaviors and psychiatric disorders such as depression [138–140]drug 5. Stress and Obesity: Ghrelin as abuse [136, 141], and schizophrenia [138, 142]. Ghrelin has recently emerged as one of the major con- aHedonic Signal? tributing factors to reward-driven feeding that can override 5.1. Reward System and the Control of Food Intake. Reward the state of satiation [3, 81, 84, 143]. The ghrelin receptor, is often conceptualized as if it were a single psychological GHS-R1A, is also expressed in tegmental and mesolimbic process or a unitary feature of a reinforcing stimulus. It is areas involved in reward, such as the VTA and laterodorsal sometimes identified with the pleasure or hedonic impact of tegmental areas (LDTg). Intracerebroventricular injection a stimulus and is viewed by some as necessarily subjective in of ghrelin has been shown to stimulate food intake [144], nature. However, reward is not a unitary process, but instead especially the intake of palatable food [84]. Moreover, the a constellation of multiple processes many of which can be effects of peripheral ghrelin on food intake were blunted by separately identified in behavior, especially after the compo- intra-VTA administration of a GHS-R1A antagonist [83]. nent processes are dissociated by brain manipulations [125]. Consistent with this, peripheral treatment with a GHS- Certain foods, particularly those rich in sugars and fat, R1A antagonist decreased preference for palatable food, are potent rewards that promote eating [126, 127]and suppressed the ability of sweet treats to condition a place triggered learned associations between the stimulus and preference [84], and suppressed motivated behavior for the reward (conditioning) [128]. Several neurotransmitters, rewarding foods, both sweet [3, 84, 143] and high-fat including DA, as well neuropeptides involved in homeostatic foods [81]. Collectively these data support the idea that regulation of food intake, are implicated in the rewarding the physiological role of ghrelin is to increase the incentive effects of food. Dopamine is a key neurotransmitter mod- motivation for natural rewards such as food. ulating reward, which it does mainly through its projections The central ghrelin signaling system emerges as a novel from the ventral tegmental area (VTA) [128]. and interesting therapeutic target as studies in rodents have The VTA dopamine (DA) projection to nucleus accum- shown that ghrelin antagonists suppress the mesoaccumbal bens (NAcc) has been implicated in the control of behaviors dopamine system, suppress the intake of (and preference motivated by rewards [129–131]. The VTA also contains for) palatable food, suppress the ability of rewarding foods DA neurons that project to medial prefrontal cortex (PFC), to condition a place preference, and decrease operant a structure linked functionally to temporal organization of responding for rewarding foods [3]. The CRF system is goal-directed behaviors [131]. directly implicated in the regulation of energy balance [5, 6] The mesolimbic dopamine projections, originating from and may participate in the pathophysiology of obesity and neuronal cell populations in the VTA and terminating in eating disorders. Additionally, increasing evidence suggests the ventral striatum and the prefrontal cortex, are linked an interplay between the CRF and ghrelin systems. Further to anticipatory, appetitive, or approach phases of motivated studies should determine whether ghrelin plays a role in the behavior and are important for anticipatory food reward and feeding behavior associated with stress. food-seeking behavior [132]. The extensive glutamatergic afferents to DA neurons References from regions involved with sensory (insula or primary gus- tatory cortex), homeostatic (hypothalamus), reward (NAc), [1] M. F. 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