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Spexin (SPX) and galanin (GAL) are two neuropeptides widely expressed in the central nervous system as well as within peripheral tissues in humans and other species. SPX and GAL mediate their biological actions through binding and activation of galanin receptors (GALR), namely GALR1, GALR2 and GLAR3. GAL appears to trigger all three galanin receptors, whereas SPX interacts more specifically with GALR2 and GLAR3. Whilst the biological effects of GAL have been well-described over the years, in-depth knowledge of physiological action profile of SPX is still in its preliminary stages. However, it is recognised that both peptides play a significant role in modulating overall energy homeostasis, suggesting possible therapeutically exploitable benefits in diseases such as obesity and type 2 diabetes mellitus. Accordingly, although both peptides activate GALR's, it appears GAL may be more useful for the treatment of eating disorders such as anorexia and bulimia, whereas SPX may find therapeutic application for obesity and obesity-driven forms of diabetes. This short narrative review aims to provide an up-to-date account of SPX and GAL biology together with putative approaches on exploiting these peptides for the treatment of metabolic disorders. • Galanin (GAL) and spexin (SPX) are neuropeptides that bind to GALR1, GALR2 and GLAR3 galanin receptors. • GAL activates all galanin receptors, whereas SPX interacts with GALR2 and GLAR3. • GAL and SPX appear to have beta-cell resting actions at the level of the endocrine pancreas. • Both peptides augment insulin action and GAL induces food intake, whereas SPX inhibits appetite. • GAL and SPX related peptides could have therapeutic applicability for type 2 diabetes and related disorders. [ABSTRACT FROM AUTHOR]

Highlights • Mechanisms of appetite suppression and reproductive control in mouthbrooding tilapia is unknown. • Telencephalic NPY neurons may primarily control appetite during mouthbrooding. • GnRH1 and GnRH3 neurons may control reproductive functions during mouthbrooding. Abstract A cichlid fish, the Nile tilapia (Oreochromis niloticus), is a maternal mouthbrooder, which exhibits minimum energy expenditure and slower ovarian cycles during mouthbrooding. The objective of this study was to observe changes in the gene expression of key neuropeptides involved in the control of appetite and reproduction, including neuropeptide Y a (NPYa), reproductive neuropeptides: gonadotropin-releasing hormone (GnRH1, GnRH2 and GnRH3) and kisspeptin (Kiss2) during mouthbrooding (4- and 12-days), 12-days of food restriction and 12-days of food restriction followed by refeeding. The food restriction regime showed a significant increase in npya mRNA levels in the telencephalon. However, there were no significant alterations in npya mRNA levels during mouthbrooding. gnrh1 mRNA levels were significantly lower in mouthbrooding female as compared with females with food restriction. gnrh3 mRNA levels were also significantly lower in female with 12-days of mouthbrooding, 12-days of food restriction followed by 12-days of refeeding when compared with controls. There were no significant differences in gnrh2 and kiss2 mRNA levels between groups under different feeding regimes. No significant changes were observed in mRNA levels of receptors for peripheral metabolic signaling molecules: ghrelin (GHS-R1a and GHS-R1b) and leptin (Lep-R). These results suggested that unaffected npya mRNA levels in the telencephalon might contribute to suppression of appetite in mouthbrooding female tilapia. Furthermore, lower gnrh1 and gnrh3 mRNA levels may influence the suppression of reproductive functions such as progression of ovarian cycle and reproductive behaviours, while GnRH2 and Kiss2 may not play a significant roles in reproduction under food restriction condition. [ABSTRACT FROM AUTHOR]

Highlights • I.p. injection of nesfatin-1 remarkable inhibited the feeding behavior of Siberian sturgeon. • Co-injection of nesfatin-1 and CCK8 significantly decreased the food intake of Siberian sturgeon as a synergistic effect. • Nesfatin-1 acts on CCK then primarily through CCK1R to inhibit the appetite of Siberian sturgeon. Abstract Nesfatin-1 is an 82-amino acid protein derived from nucleobindin 2 (NUCB2), which could inhibit food intake in fish and mammals. However, the neuroendocrine mechanism of nesfatin-1 in animal appetite regulation is unclear. To explore the feeding mechanism of nesfatin-1 in Siberian sturgeon (Acipenser baerii), intraperitoneal injections of nesfatin-1 and sulfated cholecystokinin octapeptide (CCK8), Lorglumide (CCK1R selective antagonist), or LY 225,910 (CCK2R selective antagonist) were performed. Co-injection of nesfatin-1 and CCK8 synergistically significantly decreased the food intake in 1 h. Lorglumide reversed the anorectic effect of nesfatin-1, but LY 225,910 had no effect. Moreover, Lorglumide could also reverse the expressions of appetite factors including nucb2 , cck , unc3 , cart , apelin , pyy , and npy induced by nesfatin-1 in the brain, stomach, and liver, while LY 225,910 partially reversed these changes. These results indicate that nesfatin-1 inhibits the appetite of Siberian sturgeon mainly through the CCK−CCK1R signaling pathway. [ABSTRACT FROM AUTHOR]

Despite its limited ability to cross the blood-brain barrier, peripherally administered oxytocin (OT) acutely decreases food intake, most likely via the brainstem and hypothalamic mechanisms. Studies performed to date have focused mainly on the effects of subcutaneous or intraperitoneal OT on the consumption of only solid calorie-dense diets (either standard or high-fat), whereas it is unknown whether, similarly to central OT, peripherally administered peptide reduces intake of calorie-dilute and non-caloric palatable solutions. In this project, we established that 0.1 μg/kg intravenous (IV) OT is the lowest anorexigenic dose, decreasing deprivation-induced standard chow intake by ca. 40% in rats and its effect does not stem from aversion. We then used this dose in paradigms in which effects of centrally acting OT ligands on consumption of palatable solutions had been previously reported. We found that IV OT did not change episodic intake of individually presented palatable solutions containing 10% sucrose, 0.1% saccharin, combined 10% sucrose-0.1% saccharin or 4.1%. Intralipid and it failed to affect daily scheduled consumption of a sucrose solution in non-deprived rats. In a two-bottle choice test, IV OT did not shift animals’ preference from sucrose to Intralipid. Finally, OT injected IV prior to the simultaneous presentation chow and a sucrose solution in food-deprived rats significantly decreased chow intake, whereas sugar water consumption remained unchanged. We conclude that IV OT reduces deprivation-induced chow intake without causing aversion, but the dose effective in decreasing energy-driven consumption of high-calorie food fails to affect consumption of palatable calorie-dilute solutions. [ABSTRACT FROM AUTHOR]

There is a well-documented association between cyclic changes to food intake and the changing ovarian hormone levels of the reproductive cycle in female mammals. Limited research on appetite-controlling gastrointestinal peptides has taken place in females, simply because regular reproductive changes in steroid hormones present additional experimental factors to account for. This study focussed directly on the roles that gastrointestinal-secreted peptides may have in these reported, naturally occurring, changes to food intake during the rodent estrous cycle and aimed to determine whether peripheral changes occurred in the anorexigenic (appetite-reducing) hormones peptide-YY (PYY) and glucagon-like peptide-1 (GLP-1) in female Wistar rats (32-44 weeks of age). Total forms of each peptide were measured in matched fed and fasted plasma and descending colon tissue samples for each animal during the dark (feeding) phase. PYY concentrations did not significantly change between defined cycle stages, in either plasma or tissue samples. GLP-1 concentrations in fed plasma and descending colon tissue were significantly increased during proestrus, just prior to a significant reduction in fasted stomach contents at estrus, suggesting increased satiety and reduced food intake at this stage of the cycle. Increased proestrus GLP-1 concentrations could contribute to the reported reduction in food intake during estrus and may also have biological importance in providing the optimal nutritional and metabolic environment for gametes at the potential point of conception. Additional analysis of the findings demonstrated significant interactions of ovarian cycle stage and fed/fasted status with age on GLP-1, but not PYY plasma concentrations. Slightly older females had reduced fed plasma GLP-1 suggesting that a relaxation of regulatory control of this incretin hormone may also take place with increasing age in reproductively competent females. [ABSTRACT FROM AUTHOR]

Knowledge about neuroendocrine mechanisms regulating appetite in fish, including the role of leptin, is inconclusive. We investigated leptin mRNA abundance in various tissues, plasma leptin levels and the hypothalamic gene expression of putative orexigenic (neuropeptide Y and agouti-regulated peptide) and anorexigenic (melanocortin receptor, proopiomelanocortins ( POMCs ), cocaine- and amphetamine-regulated transcript and corticotropin-releasing factor) neuropeptides in relation to feeding status in rainbow trout ( Oncorhynchus mykiss ). Blood and tissues were first (Day 1) sampled from trout that had been fed or fasted for 4 months and the day after (Day 2) from fasted fish after they had been given a large meal, and their continuously fed counterparts. The fasted fish ate vigorously when they were presented a meal. There were no differences between fed, fasted and re-fed fish in hypothalamic neuropeptide transcript levels, except for pomca1 and pomcb , which were higher in fasted fish than in fed fish at Day 1, and which, for pomcb , decreased to the level in fed fish after the meal at Day 2. Plasma leptin levels did not differ between fasted, re-fed and fed fish. A higher leptina1 transcript level was seen in the belly flap of fasted fish than in fed fish, even after re-feeding on Day 2. The data do not reveal causative roles of the investigated brain neuropeptides, or leptin, in appetite regulation. It is suggested that the elevated pomc transcript levels provide a satiety signal that reduces energy expenditure during prolonged fasting. The increase in belly flap leptin transcript with fasting, which did not decrease upon re-feeding, indicates a tissue-specific role of leptin in long-term regulation of energy homeostasis. [ABSTRACT FROM AUTHOR]

Context CCK is understood to play a major role in appetite regulation. Difficulties in measuring CCK have limited the potential to assess its profile in relation to food-induced satiety. Improvements in methodology and progress in theoretical understanding of satiety/satiation make it timely for this to be revisited. Objective First, examine how physiologically relevant postprandial CCK8/33(s) profiles are influenced by fat (HF) or carbohydrate (HCHO) meals. Second, to examine relationships between postprandial CCK and profiles of satiety (hunger/fullness) and satiation (meal size). Participants and design Sixteen overweight/obese adults (11 females/5 males) participated in a randomised-crossover study (46 years, 29.8 kg/m 2 ) in a university research centre. Plasma was collected preprandially and for 180 min postprandially. Simultaneously, ratings of hunger/fullness were tracked for 180 min before an ad libitum lunch was provided. Results CCK8/33(s) levels increased more rapidly and reached a higher peak following HF compared to HCHO breakfast ( F (1,15) = 14.737, p < 0.01). Profiles of hunger/fullness did not differ between conditions ( F (1,15) = 0.505, p = 0.488; F (1,15) = 2.277, p = 0.152). There was no difference in energy intake from the ad libitum meal (HF-3958 versus HCHO-3925 kJ; t (14) = 0.201, p = 0.844). CCK8/33(s) profiles were not associated with subjective appetite during early and late phases of satiety; nor was there an association between CCK8/33(s) and meal size. Conclusions These results demonstrate CCK levels were higher after HF meal compared to HCHO isocaloric meal. There was no association between CCK levels and intensity of satiety, or with meal size. Under these circumstances, CCK does not appear to play a unique independent role in satiety/satiation. CCK probably acts in conjunction with other peptides and the action of the stomach. [ABSTRACT FROM AUTHOR]

Ghrelin, a gut and brain peptide, has recently been shown to be involved in motivated behavior and regulation of the sleep and wakefulness cycle. The laterodorsal tegmental nucleus (LDT) is involved in appetitive behavior and control of the arousal state of an organism, and accordingly, behavioral actions of ghrelin could be mediated by direct cellular actions within this nucleus. Consistent with this interpretation, postsynaptically mediated depolarizing membrane actions of ghrelin on LDT neurons have been reported. Direct actions were ascribed solely to closure of a potassium conductance however this peptide has been shown in other cell types to lead to rises in calcium via release of calcium from intracellular stores. To determine whether ghrelin induced intracellular calcium rises in mouse LDT neurons, we conducted calcium imaging studies in LDT brain slices loaded with the calcium binding dye, Fura-2AM. Ghrelin elicited TTX-insensitive changes in dF/F indicative of rises in calcium, and a portion of these rises were independent of membrane depolarization, as they persisted in conditions of high extracellular potassium solutions and were found to involve SERCA-pump mediated intracellular calcium stores. Involvement of the ghrelin receptor (GHR-S) in these actions was confirmed. Taken together with other studies, our data suggest that ghrelin has multiple cellular actions on LDT cells. Ghrelin's induction of calcium via intracellular release in the LDT could play a role in behavioral actions of this peptide as the LDT governs processes involved in stimulation of motivated behavior and control of cortical arousal. [ABSTRACT FROM AUTHOR]

Orexins, apelin, melanin-concentrating hormone (MCH), neuropeptide Y (NPY) and cocaine and amphetamine regulated transcript (CART) are important appetite-regulating factors produced by the brain of both mammals and fish. These peptide systems and their target areas are widely distributed within the central nervous system. Although morphological connections between some of these systems have been demonstrated in the brain, little is known about the functional interactions between these systems, in particular in fish. In order to better understand the interactions between appetite-related peptides, the effects of in vitro treatments of hindbrain, forebrain and hypothalamus – a major feeding regulating area – fragments with MCH, apelin and orexin on the expression of MCH, apelin, orexin, CART (forms 1 and 2) and NPY were assessed. Overall, the apelin and orexin systems stimulate each other and stimulate the NPY system while inhibiting the CART system, which is consistent with the known orexigenic actions of these two peptides. The actions of MCH remain unclear: although it appears to interact positively with orexigenic systems – as it stimulates both the orexin and apelin systems and its expression is increased by apelin – it also increases the hypothalamic expression of CART2 – but not CART1 – an anorexigenic factor, and inhibits the NPY system in all brain regions examined. This study suggests that MCH, apelin, orexin, CART and NPY do influence each other within the brain of goldfish and that these interactions might differ in nature and strength according to the peptide form and the brain region considered. [ABSTRACT FROM AUTHOR]

Highlights: [•] Apelin, CCK, CART, PYY and orexin were cloned in red-bellied piranha. [•] All peptides are widely expressed within piranha brain and peripheral tissues. [•] Fasting increased apelin and orexin, and decreased CART brain mRNA expressions. [•] Intestine PYY mRNA expression was lower in fasted compared to fed fish. [•] These peptides might play a major role in the regulation of feeding of piranha. [Copyright &y& Elsevier]

Highlights: [•] Blockade of δ-opioid receptors inhibits salt intake in sodium-depleted rats. [•] Interaction between δ-opioid receptors and angiotensin controlling salt appetite. [•] δ-Opioid receptors blockade does not change locomotor activity, palatability or blood pressure. [Copyright &y& Elsevier]

Highlights: [•] Central administration of GCGL in chicks suppressed food intake. [•] Plasma glucose level was significantly decreased by GCGL. [•] CRF receptor antagonist attenuated GCGL-suppressed food intake. [•] GCGL might be an anorexigenic peptide in the central nervous system of chicks. [Copyright &y& Elsevier]

Highlights: [•] This review focuses on angiotensin III, a physiologically relevant renin angiotensin system peptide. [•] Similar to angiotensin II, the peptide causes an increase in blood pressure, aldosterone release, vasopressin release and other effects. [•] Angiotensin III appears to be the main peptide involved in vasopressin release and atrial natriuretic peptide release. [•] We believe angiotensin III is a physiologically relevant peptide and its effects and molecular pathways should be further investigated. [Copyright &y& Elsevier]

Highlights: [•] Investigation of appetite hormone regulation of vagal afferent receptor expression. [•] Leptin, ghrelin and NPW have the ability to modulate their own and other receptors. [•] Their ability to modulate vagal receptor expression is diet dependent. [•] Diet induced changes in vagal afferent receptor regulation may affect appetite. [Copyright &y& Elsevier]

Highlights: [•] The adipokine omentin-1 stimulates feeding and leads to body weight gain. [•] The orexigenic effect could be related to decreased CART and CRH in the hypothalamus. [•] Omentin-1 also stimulates norepinephrine synthesis and release in the hypothalamus. [Copyright &y& Elsevier]

Abstract: Acute studies showed that ghrelin acts on the central nervous system (CNS) to reduce blood pressure (BP), heart rate (HR) and sympathetic activity. However, the long-term CNS cardiovascular actions of ghrelin are still unclear. We tested whether chronic intracerebroventricular (ICV) infusion of ghrelin causes sustained reductions in BP, HR and whether it alters baroreceptor sensitivity (BRS) and autonomic input to the heart. A cannula was placed in the lateral ventricle of male Sprague–Dawley (SD) rats for ICV infusions via osmotic minipump (0.5μl/h). BP and HR were measured 24-h/day by telemetry. After 5 days of control measurements, ghrelin (0.21nmol/h) or saline vehicle were infused ICV for 10 days followed by a 5-day post-treatment period. Chronic ICV ghrelin infusion increased food intake (22±3 to 26±1g/day) leading to ∼50g body weight gain. BP fell slightly during ghrelin infusion while HR decreased by ∼26bpm. In control animals BP and HR increased modestly. ICV Ghrelin infusion caused a 50% reduction in sympathetic tone to the heart but did not alter BRS. We also tested if the depressor responses to ICV ghrelin infusion were enhanced in spontaneously hypertensive rats (SHR) due to their high basal sympathetic tone. However, we observed similar BP and HR responses compared to normotensive rats. These results indicate that ghrelin, acting via direct actions on the CNS, has a sustained effect to lower HR and a modest impact to reduce BP in normotensive and hypertensive animals despite increasing appetite and body weight. [Copyright &y& Elsevier]

Abstract: The effects of metformin and pioglitazone on ghrelin, a physiologic regulator of appetite and food intake, have not been clearly established. In a randomized clinical trial, we randomly assigned 60 type 2 diabetic patients to either metformin (Group A; n =30) or pioglitazone (Group B; n =30) treatment groups. The groups were similar in their baseline characteristics. A standard fasting 75g oral glucose tolerance test was performed at time zero before starting metformin or pioglitazone, and 3 months later. After 3 months of treatment, pioglitazone, but not metformin, was significantly associated with weight gain. Both groups experienced a significant reduction in fasting plasma glucose (p <0.01), hemoglobin A1c (p <0.01 in Group A and p <0.05 in Group B), and insulin resistance (p <0.01). The effect of metformin on preprandial ghrelin and its response to glucose challenge was not significant, while the pioglitazone group had a significant reduction in preprandial ghrelin levels after treatment (p <0.05). The effect of pioglitazone on ghrelin was independent of changes in body weight, body mass index, glucose control, insulin resistance, and plasma insulin. In conclusion, treatment with pioglitazone is associated with a decrease in preprandial ghrelin levels and therefore, the weight gain and increased food intake related to pioglitazone use cannot be explained by its effects on ghrelin. The effect of pioglitazone on ghrelin is independent of changes in body weight, body mass index, plasma insulin, insulin resistance, or glucose control. [Copyright &y& Elsevier]

Abstract: GLP-1, a peptidergic endocrine hormone, which associate with appetite control, glucose homeostasis and satiety. It might play an important role in the gustatory system. We tried to investigate the expression of GLP-1 in von Ebner''s gland of diabetic and control rats, and the ultrastructure changes on von Ebner''s gland of diabetes rats. GLP-1 expression in von Ebner''s gland was evaluated by immunohistochemistry. The number of GLP-1 positive cells in diabetic rat von Ebner''s gland was significantly higher than that in normal controls. Electron micrographs showed that a series of pathologic changes in von Ebner''s gland of diabetes rats. The results suggest that GLP-1 have some effects within the gustatory systems, and elevated von Ebner''s gland GLP-1 expression may be one cause of diabetic taste impairment. [Copyright &y& Elsevier]

Abstract: Acute studies suggest that adiponectin may reduce sympathetic activity and blood pressure (BP) via actions on the central nervous system (CNS). However, the chronic effects of adiponectin on energy expenditure and cardiovascular function are still poorly understood. We tested if chronic intracerebroventricular (ICV) infusion of adiponectin (1 or 7μg/day) in Sprague-Dawley rats fed a high fat diet (HFD) for 8 weeks and at the high dose (7μg/day) in spontaneously hypertensive rats (SHRs), a hypertensive model associated with sympathetic overactivity, evoked chronic reductions in BP and heart rate (HR). We also determined if chronic ICV adiponectin infusion alters appetite, whole body oxygen consumption (VO2), and insulin and leptin levels. Neither dose of adiponectin infused for 7 days significantly altered BP or HR in the HFD group (115±2 to 112±2mmHg and 384±6 to 379±6bpm at 1μg/day; 109±3 to 111±3mmHg and 366±5 and 367±5bpm at 7μg/day). The higher dose slightly reduced food intake (14±1 to 11±1g/day), whereas VO2, insulin and leptin levels were not affected by the treatment. In SHRs, ICV adiponectin infusion reduced appetite (22±2 to 12±2g/day) and insulin levels (∼55%), but did not alter BP (162±4 to 164±3mmHg) or HR (312±5 to 322±8bpm). These results suggest that adiponectin, acting via its direct actions on the CNS, has a small effect to reduce appetite and insulin levels, but it has no long-term action to reduce BP or HR, or to alter whole body metabolic rate. [Copyright &y& Elsevier]

Abstract: Broiler chicks eat more food than layer chicks. However, the causes of the difference in food intake in the neonatal period between these strains are not clear. In this study, we examined the involvement of proopiomelanocortin (POMC)-derived melanocortin peptides α-, β- and γ-melanocyte-stimulating hormones (MSHs) in the difference in food intake between broiler and layer chicks. First, we compared the hypothalamic mRNA levels of POMC between these strains and found that there was no significant difference in these levels between broiler and layer chicks. Next, we examined the effects of central administration of MSHs on food intake in these strains. Central administration of α-MSH significantly suppressed food intake in both strains. Central administration of β-MSH significantly suppressed food intake in layer chicks, but not in broiler chicks, while central administration of γ-MSH did not influence food intake in either strain. It is therefore likely that the absence of the anorexigenic effect of β-MSH might be related to the increased food intake in broiler chicks. [Copyright &y& Elsevier]

Abstract: The rapid increase in the prevalence of overweight and obesity is becoming an important health problem. Overweight and obesity may cause several metabolic complications, including type 2 diabetes mellitus, hyperlipidemia, high cholesterol, coronary artery disease as well as hypertension. Prevention and treatment of obesity will benefit the treatment of these related diseases. Current strategies for treatment of obesity are not adequately effective and are frequently companied with many side effects. Thus, new ways to treat obesity are urgently needed. Galanin is undoubtedly involved in the regulation of food intake and body weight. The aim of this review is to provide up-to-date knowledge concerning the roles of central and peripheral galanin as well as its receptors in the regulation of metabolism, obesity and appetite. We also highlight the mechanisms of galanin and its receptors in experimental obesity, trying to establish a novel anti-obesity strategy. [Copyright &y& Elsevier]

Abstract: The present study examined the antimicrobial activity of the peptide ghrelin. Both major forms of ghrelin, acylated ghrelin (AG) and desacylated ghrelin (DAG), demonstrated the same degree of bactericidal activity against Gram-negative Escherichia coli (E. coli) and Pseudomonas aeruginosa (P. aeruginosa), while bactericidal effects against Gram-positive Staphylococcus aureus (S. aureus) and Enterococcus faecalis (E. faecalis) were minimal or absent, respectively. To elucidate the bactericidal mechanism of AG and DAG against bacteria, we monitored the effect of the cationic peptides on the zeta potential of E. coli. Our results show that AG and DAG similarly quenched the negative surface charge of E. coli, suggesting that ghrelin-mediated bactericidal effects are influenced by charge-dependent binding and not by acyl modification. Like most cationic antimicrobial peptides (CAMPs), we also found that the antibacterial activity of AG was attenuated in physiological NaCl concentration (150mM). Nonetheless, these findings indicate that both AG and DAG can act as CAMPs against Gram-negative bacteria. [Copyright &y& Elsevier]

Abstract: The effects of analogs of the diuretic peptides Locmi-DH, Dippu-DH46 and Dippu-DH31 on two aspects of appetitive behavior are investigated in previously food-deprived nymphs of Locusta migratoria. The analogs tested are the C-terminal 15-mer and nonapeptides and their corresponding cyclic analogs. At a nominal dose of 1pmol injected per nymph, the linear fragments and their cyclic analogs of Dippu-DH46 display no significant effects on the latency to feed or on the length of the first meal in nymphs. However, at the same dose, the linear fragments of Dippu-DH31 and their cyclic analogs, and analogs of Locmi-DH modulate appetitive behavior: they are anorexigenic in reducing the duration of the first meal, and generally increasing the latency to feed. The cyclic analogs of Dippu-DH31 are at least as effective as their linear counterparts in influencing these aspects of appetitive behavior in locust nymphs. [Copyright &y& Elsevier]

Abstract: The gut hormone and neuropeptide ghrelin was initially identified in the periphery as a compound released in the bloodstream in response to a negative energetic status. In the central nervous system (CNS), ghrelin mainly acts on the hypothalamus and the limbic system, with its best-known biological role being the regulation of appetitive functions. Recent research has shown that ghrelin is not an indispensable factor in the regulation of food intake. However, it plays a key role in the metabolic changes of lipids, mainly those involving hypothalamic NOS, AMPK, CaMKK2, CPT1 and UCP2 proteins. Ghrelin participates in the regulation of memory processes and the feeling of pleasure resulting from eating, both of which are metabolism-dependent and may be essential for the successful achievement of adaptive appetitive behavior. Ghrelin exerts its biological effect through a complicated network of neuroendocrine links, including the melanocortin and endocannabinoid systems. The activity of ghrelin is connected with circadian and annual fluctuations, which depend on seasons and food availability. [Copyright &y& Elsevier]

Abstract: Ghrelin is a peptide hormone secreted into circulation from the stomach. It has been postulated to act as a signal of hunger. Ghrelin administration acutely increases energy intake in lean and obese humans and chronically induces weight gain and adiposity in rodents. Circulating ghrelin levels are elevated by fasting and suppressed following a meal. Inhibiting ghrelin signaling therefore appears an attractive target for anti-obesity therapies. A number of different approaches to inhibiting the ghrelin system to treat obesity have been explored. Despite this, over a decade after its discovery, no ghrelin based anti-obesity therapies are close to reaching the market. This article discusses the role of ghrelin in appetite control in humans, examines different approaches to inhibiting the ghrelin system and assesses their potential as anti-obesity therapies. [Copyright &y& Elsevier]

Abstract: Ghrelin is a peptide hormone produced mainly by the stomach and has widespread physiological functions including increase in appetite. The stimulation of the ghrelin system represents a potential therapeutic approach in various disorders characterized by deficient ghrelin signaling or by low appetite. This stimulation may be achieved via pharmacological targeting of the ghrelin receptor with synthetic ghrelin or ghrelin mimetics or via increased endogenous ghrelin production. Recently, it was demonstrated that gastric electrical stimulation (GES) with Enterra parameters results in increased ghrelin production in rats. Furthermore, recent data revealed putative role of ghrelin-reactive immunoglobulins in the modulation of the ghrelin signaling which can be also stimulated by GES. Here, we review the links between GES and ghrelin in existing GES experimental and clinical applications for treatment of gastroparesis, functional dyspepsia or obesity and discuss if GES can be proposed as a non-pharmacological approach to improve ghrelin secretion in several pathological conditions characterized by low appetite, such as anorexia nervosa or anorexia–cachexia syndrome. [Copyright &y& Elsevier]

Abstract: Proopiomelanocortin (POMC, a precursor of melanocortin peptides) neurons in the hypothalamus play an important role in the central regulation of food intake in mammals. There is evidence that human melanocortin peptides alpha-, beta- and gamma2-melanocyte-stimulating hormone (α-, β- and γ2-MSH) significantly decreased food intake in chickens. However, the amino acid sequences of β- and γ2-MSH of chickens are different from those of humans whereas the amino acid sequence of α-MSH is conserved between these species. In the present study, we examined the effects of the central administration of α-, chicken β-, and chicken γ2-MSH on food intake in chicks. Central administration of α-MSH significantly suppressed food intake in chicks. In contrast, β- and γ2-MSH did not influence food intake in chicks. Central administration of HS014, a melanocortin 4 receptor antagonist, significantly reversed the anorexigenic action of α-MSH, suggesting that this action is mediated by the melanocortin 4 receptor in chicks as well as in mammals. These results suggest that α-MSH may play an important role in the regulation of food intake by the central melanocortin system in chicks. [Copyright &y& Elsevier]

Abstract: There are various forms of the satiety gut–brain peptide cholecystokinin (CCK), a short, widely utilized form or CCK-8, and a long, putatively more effective form or CCK-33. The issue of which of these forms is a more effective satiety peptide is not resolved. Here, we compared the satiety responses, including the sizes of the first three meals (MS) and intermeal intervals (IMI) as well as their calculated satiety ratios (SR), evoked by both peptides. CCK-8 and 33 (1, 3 and 5nmol/kg, i.p) reduced the size of the first meal similarly, only CCK-33 prolonged the first IMI and increased SR and both peptides failed to affect second and third MS and IMI. As such, CCK-33 is a more effective satiety peptide than CCK-8. The current results confirm previous findings which showed that both peptides reduce food intake by inhibiting meal size, whereas only CCK-33 reduces food intake by prolonging the intermeal interval. [Copyright &y& Elsevier]

Abstract: In recent years, there have been a large number of neuropeptides discovered that regulate food intake. Many of these peptides regulate food intake by increasing or decreasing nitric oxide (NO). In the current study, we compared the effect of the food modulators ghrelin, NPY and CCK in NOS KO mice. Satiated homozygous and heterozygous NOS KO mice and their wild type controls were administered ghrelin ICV. Food intake was measured for 2h post injection. Ghrelin did not increase food intake in the homozygous NOS KO mice compared to vehicle treated NOS KO mice, whereas food intake was increased in the wild type controls compared to vehicle treated wild type controls. NPY was administered ICV and food intake measured for 2h. Homozygous NOS KO mice showed no increase in food intake after NPY administration, whereas the wild type controls did. In our final study, we administered CCK intraperitoneally to homozygous and heterozygous NOS KO mice and their wild type controls after overnight food deprivation. Food intake was measured for 1h after injection. CCK inhibited food intake in wild type mice after overnight food deprivation, however, CCK failed to inhibit food intake in the NOS KO mice. The heterozygous mice showed partial food inhibition after the CCK. The current results add further support to the theory that NO is a central mediator in food intake. [Copyright &y& Elsevier]

Abstract: Neuronostatin, a recently discovered peptide derived from the somatostatin preprohormone, significantly inhibited both food and water intake when administered centrally in adult male rats. Because neuronostatin is highly produced in the hypothalamus, an area of the brain through which important feeding circuits, including the central melanocortin system, communicate, we sought to determine if the anorexigenic and antidipsogenic effects of neuronostatin would be reversed by pretreatment with the melanocortin 3/4 receptor antagonist, SHU9119. SHU9119 pretreatment reversed the effect of neuronostatin on both food and water intake. We have shown recently that the central oxytocin system is a potential downstream mediator of the anorexignic action of alpha-MSH. We therefore tested whether the effects of neuronostatin also were dependent upon central oxytocin receptors. Neuronostatin-induced anorexia was not reversed by pretreatment with the oxytocin receptor antagonist, OVT, suggesting that neuronostatin acts through a unique subset of POMC neurons that do not signal via central oxytocin receptors. [ABSTRACT FROM AUTHOR]

Abstract: Hypoxia in pregnancy may induce fetal growth restriction and cause functional abnormalities during development. The present study determined the long-term influence of hypoxia in fetal life on dipsogenic behavior linked to central angiotensin (Ang) network in the offspring rats. Fetal blood pO2 and body weight were decreased by hypoxia during pregnancy, followed by a postnatal “catch-up” growth. Subcutaneous hypertonic saline or intracerebroventricular Ang II significantly increased salt intake in the offspring prenatally exposed to hypoxia, while water intake was the same between the two groups. Ang II-induced c-fos expression was detected in the paraventricular nuclei, median preoptic nuclei, supraoptic nuclei, and subfornical organ in the brain, in association with reduced forebrain AT2 receptor protein abundance in the offspring prenatally exposed to hypoxia. Levels of central AT1 receptor protein were not changed between the two groups. Hypoxia during pregnancy could be linked to developmental problems related to behavioral dysfunctions in body fluid regulations in later life, in association with the change in central angiotensin II-mediated neural activation and expression of the Ang II receptor in the brain. [Copyright &y& Elsevier]

Abstract: Pancreatic polypeptide (PP) belongs to the neuropeptide Y (NPY) family of peptides and is released from pancreatic F cells postprandially. PP functions as a peptide hormone and has been associated with decreased food intake in humans and rodents. Our study describes the effects of PP on feeding behavior in dogs, whose mammalian order (Carnivora) is more distantly related to primates and rodents than these are to each other. Furthermore, obesity is becoming more prevalent in dogs which makes knowledge about their appetite regulation highly relevant. Repeated peripheral administration of physiological doses of PP (three injections of 30pmol/kg each that were administered within 30min) to six male beagle dogs prolonged the median time spent eating three servings of food by 19% but resulted in no reduction of food intake. In addition, PP decreased the duration of food-seeking behavior after the first serving by 71%. Thus, a physiological dose of PP seems to decrease both the appetitive and the consummatory drive in dogs. [Copyright &y& Elsevier]

Abstract: Neurochemicals that stimulate food foraging and hoarding in Siberian hamsters are becoming more apparent, but we do not know if cessation of these behaviors is due to waning of excitatory stimuli and/or the advent of inhibitory factors. Cholecystokinin (CCK) may be such an inhibitory factor as it is the prototypic gastrointestinal satiety peptide and is physiologically important in decreasing food intake in several species including Siberian hamsters. Systemic injection of CCK-33 in laboratory rats decreases food intake, doing so to a greater extent than CCK-8. We found minimal effects of CCK-8 on food foraging and hoarding previously in Siberian hamsters, but have not tested CCK-33. Therefore, we asked: Does CCK-33 decrease normal levels or food deprivation-induced increases in food foraging, hoarding and intake? Hamsters were housed in a wheel running-based foraging system with simulated burrows to test the effects of peripheral injections of CCK-33 (13.2, 26.4, or 52.8μg/kg body mass), with or without a preceding 56h food deprivation. The highest dose of CCK-33 caused large baseline reductions in all three behaviors for the 1st hour post-injection compared with saline; in addition, the intermediate CCK-33 dose was sufficient to curtail food intake and foraging during the 1st hour. In food-deprived hamsters, we used a 52.8μg/kg body mass dose of CCK-33 which decreased food intake, hoarding, and foraging almost completely compared with saline controls for 1h. Therefore, CCK-33 appears to be a potent inhibitor of food intake, hoarding, and foraging in Siberian hamsters. [Copyright &y& Elsevier]

Abstract: Melanin-concentrating hormone (MCH) has attracted considerable attention because of its effects on food intake and body weight and the MCH receptor (MCHR1) remains one of the viable targets for obesity therapy. This review summarizes the literature examining the effects of MCH on body weight, food intake and energy expenditure in rodent models, and the central sites where MCH acts in regulating energy homeostasis. Emphasis is given on the discrepancies between the genetic and pharmacologic models of MCHR1 inactivation. We propose some solutions to resolve these discrepancies and discuss some future directions in MCH research. [Copyright &y& Elsevier]

Abstract: Melanin-concentrating hormone (MCH), originally discovered in the teleost pituitary, is a hypothalamic neuropeptide involved in the regulation of body color in fish. Although MCH is also present in the mammalian brain, it has no evident function in providing pigmentation. Instead, this peptide is now recognized to be one of the key neuropeptides that act as appetite enhancers in mammals such as rodents and primates. Although there has been little information about the central action of MCH on appetite in fish, recent studies have indicated that, in goldfish, MCH acts as an anorexigenic neuropeptide, modulating the α-melanocyte-stimulating hormone signaling pathway through neuronal interaction. These observations indicate that there may be major differences in the mode of action of MCH between fish and mammals. This paper reviews what is currently known about the regulation of food intake by MCH in fish, especially the goldfish. [Copyright &y& Elsevier]

Abstract: Although its role in energy homeostasis is firmly established, the evidence accumulated over a decade linking the adipocyte leptin–hypothalamus axis in the pathogenesis of diabetes mellitus has received little attention in the contemporary thinking. In this context various lines of evidence are collated here to show that (1) under the direction of leptin two independent relays emanating from the hypothalamus restrain insulin secretion from the pancreas and mobilize peripheral organs – liver, skeletal muscle and brown adipose tissue – to upregulate glucose disposal, and (2), leptin insufficiency in the hypothalamus produced by either leptinopenia or restriction of leptin transport across the blood brain barrier due to hyperleptinemia of obesity and aging, initiate antecedent pathophysiological sequalae of diabetes type 1 and 2. Further, we document here the efficacy of leptin replenishment in vivo, especially by supplying it to the hypothalamus with the aid of gene therapy, in preventing the antecedent pathophysiological sequalae – hyperinsulinemia, insulin resistance and hyperglycemia – in various animal models and clinical paradigms of diabetes type 1 and 2 with or without attendant obesity. Overall, the new insights on the long-lasting antidiabetic potential of two independent hypothalamic relays engendered by central leptin gene therapy and the preclinical safety indicators in rodents warrant further validation in subhuman primates and humans. [Copyright &y& Elsevier]

Abstract: Apelin is a recently discovered peptide produced by several tissues including brain and adipose tissue. In mammals and zebrafish, apelin regulates cardiovascular functions. Recent evidence in mammals suggest that apelin might also regulate food intake. In this study, we cloned a cDNA encoding apelin and examined apelin mRNA distribution within the brain and in peripheral tissues. We also assessed the effects of fasting on apelin brain mRNA abundance. Apelin mRNA was expressed throughout the brain as well as in several peripheral tissues including brain, spleen, heart and fat. Apelin mRNA abundance in both hypothalamus and telencephalon was significant higher in fasted fish than in fed fish. In order to further characterize apelin in goldfish, we assessed the effects of central (intracerebroventricular, icv) and peripheral (intraperitoneal, ip) injections of apelin-13 on food intake in goldfish. Apelin injected ip at a dose of 100ng/g or icv at a dose of 10ng/g induced a significant increase in food intake compared to saline-injected fish. Our results suggest that apelin acts as an orexigenic factor in goldfish. Its widespread distribution in the brain and the periphery also suggests that apelin might have multiple physiological regulating roles in fish. [Copyright &y& Elsevier]

• Orally administered plant-derived bioactive peptides exhibit appetite-regulating effects. • Bioactive peptides are biochemically linked to hypothalamic signaling molecules in the regulation of appetite and energy homeostasis. • Bioactive peptides can interact with endogenous neuropeptides and hormonal peptides in controlling appetite and food intake. • Plant-derived bioactive peptides may be a novel target for facilitators of a healthy life expectancy. • Bioactive peptides from plant proteins are prominent candidates for achieving the Sustainable Development Goals (SDGs). Appetite is closely regulated not only by gut hormonal and neuronal peptides but also by exogenous peptides derived from food proteins. Food proteins are now recognized to contain many thousands of bioactive compounds that provide additional health benefits beyond their nutritional effects. Bioactive peptides are beneficial to the life and/or to regulate physiological functions. Although animal protein products have been widely applied in the food industry, exploring the possibilities of developing functional foods based on plant protein-derived peptides is considered attractive for achieving sustainable development goals. In addition, peptides from plant proteins have the potential to treat numerous diseases or risk factors and may therefore facilitate a healthy life expectancy. In this review, we discuss the identified plant-based bioactive peptides and their appetite regulating effects. Plant-based bioactive peptides may provide new opportunities to discover novel approaches that can improve and prevent diseases in a sustainable environment. [ABSTRACT FROM AUTHOR]

[Display omitted] • Thyroxine increased feeding behavior but not food intake in goldfish. • Negative feedback occurred to the pituitary but not hypothalamus in hyperthyroid fish. • Klotho is downregulated in the hypothalamus under a high thyroid load. • Propylthiouracil did not induce hypothyroidism or affect any parameter measured. • There is a poor association between thyroid state and appetite regulating peptides. There is poor evidence for an association between thyroidal state, feeding and appetite regulation in fish. We assessed how an altered thyroid state influences feeding behavior, food intake and expression of hypothalamic appetite-regulating peptides (Klotho-α and Klotho-β; orexin, OX; cholecystokinin, CCK; agouti-related peptide, AgRP; cannabinoid receptor 1, CB1) in goldfish. We also measured the expressions of hypothalamic, pituitary and liver transcripts that regulate the thyroid [thyrotropin-releasing hormone (TRH), thyrotropin-releasing hormone receptor (TRH-R) type 1, thyroid stimulating hormone beta (TSHβ), deiodinases (DIO2, DIO3), UDP-glucuronosyltransferase (UGT1A1), thyroid receptor alpha and beta (TRα, TRβ)], and circulating levels of total thyroxine (tT 4) and total triiodothyronine (tT 3). Goldfish were implanted with propylthiouracil (PTU) or T 4 osmotic pumps for 12 days. T 4 - treatment increased feeding behavior but not food intake, increased central TSHβ and DIO2, and hepatic DIO2 transcript expression and increased central DIO3 mRNA. Under hyperthyroid conditions, hypothalamic Klotho and CCK expressions were downregulated, suggesting an increased metabolic state and a hypothalamic response to regulate energy balance. AgRP, OX and CB1 were not affected by T 4 treatment. PTU had no effect on any of the parameters examined, suggesting it is not a sensitive thyroid inhibitor in fish. Overall, we show that unlike in mammals, hyperthyroid conditions in goldfish do not lead to an increased desire or need to consume food, furthering evidence for a weak link between the thyroid and appetite. [ABSTRACT FROM AUTHOR]

Abstract: Melanocortin receptors are considered promising candidates for the treatment of behavioral and metabolic disorders ranging from obesity to anorexia and cachexia. These experiments examined the response of mice to peripheral injections of two compounds. PG932 is a derivative of SHU9119 which is non-selective antagonist of melanocortin-3 and melanocortin-4 receptors (Mc3r and Mc4r). PG946 is a derivative of a hybrid of α- and β-MSH, and is a moderately selective Mc3r antagonist. SHU9119 increases food intake when administered intracerebroventricularly but is without effect when injected into the periphery. In contrast, PG932 was found to be highly effective at stimulating food intake when administered peripherally by intraperitoneal injection. The orexigenic effect of PG932 required functional Mc4r, suggesting that inhibition of this receptor is involved in the stimulation of food intake. PG946 did not significantly affect on feeding behavior. PG932 is thus a useful new compound for studies examining the regulation of appetite and energy balance, and may also prove useful for the treatment of cachectic conditions. [Copyright &y& Elsevier]

Abstract: PYY(3-36) is a gut regulatory peptide which has recently been found to reduce appetite. Variability of this effect across different experimental conditions has led to confusion and polarization of opinion on its potential as an anti-obesity treatment. This review summarizes recent progress in this area. The basic anorexigenic effect leading to weight loss in rodents has now been confirmed by several groups. Anorexia has also been confirmed in human studies although optimal route and dosing remain to be defined. Gastric bypass causes PYY levels to rise, which may in part mediate the weight loss occurring after this surgery, and levels have been found to be normal or low in obese people. The straightforward ARC model of mechanism, involving inhibition and activation, respectively, of NPY and POMC neurons, is giving way to a more complicated system involving vagal afferent signals. Conclusion: It works, but not how we thought it did. [Copyright &y& Elsevier]

Abstract: Employing immunohistochemistry techniques, we examined the c-fos expression in different hypothalamic areas, when plasma glucose levels were modified by the administration of insulin and 2-deoxyglucose (2-DG) respectively. Subsequently, the hypoglycemia produced by an injection of insulin significantly increased feeding concomitant to higher c-fos expression in the arcuate nucleus (ARC), paraventricular nucleus (PVN), dorsomedial hypothalamus (DMH) and lateral hypothalamus (LH), while no statistical changes in the ventromedial hypothalamus (VMH) were found. Also, the glucopenia induced by 2-DG administration produced similar stimulatory effects on appetite and the neuronal activity affecting all the hypothalamic areas studied, including the VMH. The peripheral blockade of the orexigenic hormone ghrelin with a specific antibody (AGA) significantly decreased food intake as induced from acute hypoglycemia and glucopenia. Curiously, the conjoint AGA and insulin or 2-DG administration produced a differential effect on the hypothalamic neurons analyzed, by increasing the number of c-fos positive neurons in the ARC, PVN and DMH, but not in the VMH and LH. This outcome suggests an interactive effect of the glucostatic pathways involving these two areas with the ghrelin signaling. [Copyright &y& Elsevier]

Abstract: In the current study we sought to determine whether hypothalamic IL-1β is regulated by melanocortin signaling and if melanocortin-induced changes in energy balance are dependent on IL-1β. A melanocortin agonist, MTII, increased hypothalamic IL-1β mRNA levels by two-fold, whereas a melanocortin antagonist, SHU9119, blunted lipopolysaccharide (LPS)-mediated increase of hypothalamic IL-1β content. Pharmacological or genetic disruption of IL-1 receptor signaling prevented MTII-mediated reductions in locomotor activity, but did not reduce MTII-induced anorexia. These data suggest a potential role for central melanocortins in mediating the decrease of ambulation characteristic of the ‘sickness’ response. [Copyright &y& Elsevier]

Abstract: A number of recent studies implicate the gut-brain peptide ghrelin as a putative “hunger signal”. Most of these studies, however, rely on either consummatory behavior (in humans or nonhuman animals) or self-report (in humans) to draw conclusions regarding the orexigenic properties of this peptide. The present study employs the deprivation intensity discrimination paradigm to assess the interoceptive sensory properties of ghrelin in rats. In this paradigm, one group of rats was placed in a training context and presented with sucrose pellets when 24h food deprived, but not when 1h food deprived (24+ group). A second group was trained using the opposite sucrose-deprivation level contingency (1+ group). Learning in this paradigm was demonstrated by animals approaching the food delivery location more frequently under their rewarded compared to their non-rewarded deprivation condition (prior to actual pellet delivery). After asymptotic performance of this discrimination was achieved, these animals (1h food deprived) were administered ghrelin or saline, either i.p. (3 or 6nmol) or i3vt (0.1 or 1nmol), placed in the training context, and appetitive responses were measured. Testing was conducted in extinction, eliminating confounding effects of food consumption. Results of these tests showed that 6nmol i.p. ghrelin and 0.1 and 1nmol i3vt ghrelin all generalized to a state of 24h food deprivation, indicating that exogenous ghrelin has sensory properties in common with the stimuli produced by 24h food deprivation. These results support the notion that endogenous ghrelin contributes to an interoceptive hunger cue, and that this may be a mechanism by which ghrelin influences food intake and appetitive behavior. [Copyright &y& Elsevier]

Abstract: The ingestion of foods is comprised of two distinct phases of behavior: appetitive and consummatory. While most food intake paradigms include both phases, the intraoral intake test emphasizes the stereotyped consummatory-phase by infusing a liquid food directly into the oral cavity. Several hypothalamic peptides have been shown to increase intake of chow in standard food intake paradigms and the current experiments sought to test whether these peptides would increase food intake in the intraoral intake paradigm. NPY, melanin-concentrating hormone (MCH) and orexin-A were infused into the third ventricle (i3vt) in a counterbalanced latin-square design just prior to rats getting 0.1M sucrose solution infused via indwelling intraoral catheters and compared it to intake on bottle tests with access to the same sucrose solution. On the first day, each peptide increased intraoral intake relative to saline in the between-subjects comparison. Moreover, intake of sucrose following i3vt saline increased as a function of training. By the final day of the experiment, rats receiving saline consumed as much sucrose as rats receiving NPY, MCH, or orexin-A. This finding was conceptually replicated in the second experiment in which rats drank sucrose freely from a bottle on the home cage. A third experiment directly assessed the role of previous exposure in the sucrose intake induced by NPY. Those results confirm that repeated exposure to sucrose increases baseline intake and attenuates the hyperphagic effect of NPY. These results are consistent with two conclusions: (1) NPY, MCH, and orexin-A increase both appetitive and consummatory-phase ingestive behaviors on initial exposures; (2) repeated training interacts with the effects of these orexigenic peptides. [Copyright &y& Elsevier]

Urocortin, a 40 amino acid peptide, is a corticotropin-releasing factor (CRF) related peptide, and can bind to all three types of CRF receptors (CRF type 1, type 2(a) and type 2(b) receptors) with higher affinities for these receptors than CRF. Immunoreactivity of urocortin is widely distributed in central nervous, digestive, cardiovascular, reproductive, immune and endocrine systems. Urocortin plays important roles in appetite-suppression, immunomodulation, steroidogenesis in the ovary, maintenance of the placental function, labor, and cardioprotection via CRF receptors. Although urocortin has potent adrenocorticotropin (ACTH) releasing activity in vitro, endogenous urocortin does not act on pituitary ACTH secretion in vivo. [Copyright &y& Elsevier]

Although a dynamic link between the two innate drives, appetite for food and the urge to reproduce, in vertebrate evolution has been known for a long time, a distinct neurochemical pathway mediating this integration has only recently been appreciated. Study of the precise anatomy of the neural track began in the early to mid 20th century after the sites of genesis of the two instincts were localized to the hypothalamus. This report narrates the birth and fruition to maturity of insights into the commonality of hypothalamic neuropeptide Y (NPY) signaling for the two instinctual drives along two distinct pathways. [Copyright &y& Elsevier]

We investigated the interaction of the orexigenic neuropeptide, hypocretin-1 (Hcrt-1, also known as orexin-A), with endogenous opioids (also orexigenic neuropeptides). Rats were injected with naltrexone (NTX, nonspecific opioid antagonist) i.p., i.c.v., in the lateral hypothalamus (LH), and in the accumbens shell (AcbSh), and naloxone methiodide (nonspecific opioid antagonist unable to cross the blood brain barrier) was injected i.p. Rats were then injected with Hcrt-1 in the LH. Food intake was measured for up to 4 h thereafter. Rats were also pretreated with NTX in the LH, with Hcrt-1 injected in the AcbSh. NTX suppressed Hcrt-1-induced feeding only when injected i.p., i.c.v., and in the AcbSh. These studies reveal the necessity for functional central opioidergic pathways involving the AcbSh, but not the LH in Hcrt-1-induced feeding. [Copyright &y& Elsevier]

The ability of sodium deficiency to stimulate vasopressin (VP) release was examined by determining if sodium deficiency sensitizes the animal to the behavioral disruption caused by intraventricular injections of VP. In sodium-replete rats, intraventricular injections of 50 ng VP on Day 1 had no effect on behavior, but this dose elicited abnormal behaviors (barrel rolls, hind-limb extensions) when administered on Day 2, indicating a sensitization phenomenon. In separate experiments, the first intraventricular injection of 50 ng VP in sodium-deficient but not in sodium-replete rats also elicited barrel rotations followed by hind-limb extension. Intraventricular injection of VP also disrupted motor behavior in sodium-replete rats that had multiple prior experiences with sodium deficiency but not in naive rats. These results show that sodium deficiency can mimic the effect of central injections of VP in sensitizing the brain to the behavioral effects of exogenous VP. This suggests that sodium deficiency induces the central release of VP. [Copyright &y& Elsevier]

Intracerebroventricular (ICV) injection of Agouti related protein (AgRP), an endogenous melanocortin 3 and 4 receptor (MC3/4-R) antagonist, produces a prolonged increase in food intake. To clarify the roles of the MC3-R and MC4-R in AgRP-induced hyperphagia, the feeding effect of AgRP (83–132) was compared with that of the selective MC4-R antagonist, JKC-363 (cyclic [Mpr11, D-Nal14, Cys18, Asp22-NH2]-beta-MSH11-22). Single ICV administration of AgRP (83–132) increased food intake for 48 h whilst ICV JKC-363 increased food intake for 8 h. An increase in body weight at 24 and 48 h was observed following AgRP (83–132) but not JKC-363 treatment. These data suggest that the sustained orexigenic action of AgRP (83–132) may not be through MC4-R antagonism. [Copyright &y& Elsevier]