The central anorexigenic mechanism of adrenocorticotropic hormone involves the caudal hypothalamus in chicks

Adrenocorticotropic hormone (ACTH), consisting of 39 amino acids, is most well-known for its involvement in an organism's response to stress. It also participates in satiety, as exogenous ACTH causes decreased food intake in rats. However, its anorexigenic mechanism is not well understood in any species and its effect on appetite is not reported in the avian class. Thus, the present study was designed to evaluate central ACTH's effect on food intake and to elucidate the mechanism mediating this response using broiler chicks. Chicks that received intracerebroventricular (ICV) injection of 1, 2, or 4 nmol of ACTH reduced food intake, under both ad libitum and 180 min fasted conditions. Water intake was also reduced in ACTH-injected chicks under both feeding conditions, but when measured without access to feed it was not affected. Blood glucose was not affected in either feeding condition. Following ACTH injection, c-Fos immunoreactivity was quantified in key appetite-associated hypothalamic nuclei including the ventromedial hypothalamus (VMH), dorsomedial hypothalamus, lateral hypothalamus (LH), arcuate nucleus (ARC) and the parvo- and magno-cellular portions of the paraventricular nucleus. ACTH-injected chicks had increased c-Fos immunoreactivity in the VMH, LH, and ARC. Hypothalamus was collected at 1 h post-injection, and real-time PCR performed to measure mRNA abundance of some appetite-associated factors. Neuropeptide Y, pro-opiomelanocortin, glutamate decarboxylase 1, melanocortin receptors 2–5, and urocortin 3 mRNA abundance was not affected by ACTH treatment. However, expression of corticotropin releasing factor (CRF), urotensin 2 (UT), agouti-related peptide (AgRP), and orexin (ORX), and melanocortin receptor 1 (MC1R) mRNA decreased in the hypothalamus of ACTH-injected chicks. In conclusion, ICV ACTH causes decreased food intake in chicks, and is associated with VMH, LH, and ARC activation, and a decrease in hypothalamic mRNA abundance of CRF, UT, AgRP, ORX and MC1R.     

Central neuropeptide FF reduces feed consumption and affects hypothalamic chemistry in chicks

Information on the physiological functions of neuropeptide FF; NPFF, a morphine modulating octapeptide in avians is lacking. Thus, we designed a study to investigate the effects of central NPFF with particular emphasis on appetite-related processes. Cobb-500 chicks were intracerebroventricularly (ICV) injected with 0, 4.16, 8.32 or 16.6nmol NPFF, and feed and water intake were quantified. Feed intake was linearly decreased as NPFF dose increased, and this effect decayed over time and was not significant by 120min post-injection. Water intake was not affected by ICV NPFF. In a second exp, we observed that naloxone completely reversed the NPFF-induced decrease in feed intake. The amount of time a visible marker took to travel through the total length of the alimentary canal linearly increased as NPFF dose increased. We measured neuronal activation in the lateral hypothalamus (LH), paraventricular nucleus (PVN) dorsomedial nucleus (DMN) and ventromedial hypothalamus (VMN) of the hypothalamus, and nucleus dorsomedialis posterior thalami (DMP) of the thalamus. The DMN, DMP, PVN and VMH were all activated by ICV NPFF while the LH was not affected. Finally, we determined that the anorexigenic effect of ICV NPFF is primarily behavior specific, since behaviors unrelated to ingestion were not increased the same duration of time as was consumatory pecking. We conclude that NPFF causes anorexigenic effects in chicks that are primarily behavior specific.     

Central and peripheral alytesin cause short-term anorexigenic effects in neonatal chicks

We studied the effects of alytesin, a natural analogue of bombesin, on appetite-related responses and behaviors in neonatal chicks. Chicks responded to both intracerebroventricular (ICV) and peripheral injections of alytesin with short-term reduced feed intake. ICV alytesin caused reduced short-term water intake when feed was present, but we determined this effect was secondary to feed intake since an effect on water intake was not detected in feed-restricted alytesin-treated chicks. The anorexigenic effect of both ICV and peripheral alytesin may be mediated at the hypothalamus, since all hypothalamic nuclei studied; regio lateralis hypothalami, nucleus dorsomedialis hypothalami, nucleus paraventricularis magnocellularis, nucleus perventricularis hypothalami, nucleus infundibuli hypothalami and the nucleus ventromedialis hypothalami, were activated as evident by increased c-Fos immunoreactivity. Central alytesin did not cause increased behaviors that were unrelated to ingestion and did not cause anxiety-related behavior patterns. Additionally, central alytesin did not affect pecking efficacy. We conclude that both ICV and peripheral alytesin injections induce anorexigenic effects in chicks, and the hypothalamus is involved. While the anorexigenic effects of alytesin and bombesin appear to be conserved across species, the two peptides may differ in other behavioral responses and central mechanisms of action.     

Xenin-a novel suppressor of food intake in rats

Peptides related to the amphibian octapeptide xenopsin are present in various locations in mammalians, such as the gastrointestinal mucosa or brain tissue. In the gastrointestinal tract, xenopsin-related peptides induce partially neurogenic contractions of the colon in humans. In brain, however, their function is not known. Structural similarities of xenopsin-related peptides with neurotensin, a known modulator of ingestive behavior, suggest a possible role in feeding regulation. Therefore, we examined the effect of xenin, a recently identified xenopsin-related pentacosa peptide, on feeding behavior of fasted rats. Male Wistar rats (n=12) were intracerebroventricularly (i.c.v.) injected with either saline (10 μl) or xenin at 0.5, 1.5, 5 or 15 μg dissolved in an identical volume of 10 μl, respectively. In further experiments, xenin 15 μg/0.5 μl or 0.5 μl saline were injected into the lateral hypothalamus (LH). After injections, food intake (g), percentage of time spent with feeding (%) and prandial water intake (ml) were subsequently recorded for 2 h. After i.c.v. injection of 15 μg of xenin 1-h food intake was significantly reduced by 42% and 2-h food intake was diminished by 25%, respectively, compared to saline injection (p<0.01). This reduction of food intake was paralleled by a significant decrease of time spent with feeding by 41% (after 1 h) or 23% (after 2 h). The xenin-induced suppression of feeding behavior was dose-dependent. Thus, the minimal effective dose of xenin was 1.5 μg, while the dose of 0.5 μg was ineffective. Prandial water intake was significantly reduced only by the highest dose of xenin. Following injection of 15 μg of xenin into the lateral hypothalamus food intake was not different from control experiments. These data demonstrate a potent feeding suppressive action of xenin following intracerebroventricularly injection but not injection into the lateral hypothalamus suggesting a possible role of xenin in the central control of feeding termination and satiety.     

Beta-melanocyte-stimulating hormone potently reduces appetite via the hypothalamus in chicks

The melanocortin system together with other appetite-related systems plays a significant role in appetite regulation. The appetite-related effects of one such melanocortin, β-melanocyte-stimulating hormone (MSH), are well documented in rodents; however, its effects in the avian class are not thoroughly understood. Thus, we designed a study to determine the effects of i.c.v. β-MSH injection on food and water intake, plasma corticosterone concentration, ingestive and non-ingestive behaviours, and hypothalamic neuronal activation using Cobb-500 chicks. Chicks responded to β-MSH-treatment with a reduction in food and water intake; however when water intake was measured independently of food intake, it was not affected. β-MSH-treated chicks also had increased plasma corticosterone concentrations and increased c-Fos reactivity in the periventricular, paraventricular and infundibular nuclei, and the ventromedial hypothalamus; however, the lateral hypothalamus was not affected. The effect on food intake is primary because behaviours that may be competitive with food intake were not increased in β-MSH-treated chicks. Based on these results, we conclude that β-MSH causes anorexigenic effects that are likely primarily mediated via stimulation of satiety-related hypothalamic nuclei in broiler-type chicks.     

Central action of xenin affects the expression of lipid metabolism-related genes and proteins in mouse white adipose tissue

Xenin is a gastrointestinal hormone that reduces food intake when administered centrally and it has been hypothesized that central action of xenin participates in the regulation of whole-body metabolism. The present study was performed to address this hypothesis by investigating the central effect of xenin on the expression of genes and proteins that are involved in the regulation of lipid metabolism in white adipose tissue (WAT). Male obese ob/ob mice received intracerebroventricular (i.c.v.) injections of xenin (5 μg) twice 12 h apart. Food intake and body weight change during a 24-h period after the first injection were measured. Epididymal WAT was collected at the end of the 24-h treatment period and levels of lipid metabolism-related genes and proteins were measured. Xenin treatment caused significant reductions in food intake and body weight compared to control vehicle treatment. Levels of fatty acid synthase (FASN) protein were significantly reduced by xenin treatment, while levels of adipose triglyceride lipase (Atgl) and beta-3 adrenergic receptor (Adrb3) mRNA and phosphorylated hormone sensitive lipase (Ser⁶⁶⁰-pHSL and Ser⁵⁶³-pHSL) were significantly increased by xenin treatment. These findings suggest that central action of xenin causes alterations in lipid metabolism in adipose tissue toward reduced lipogenesis and increased lipolysis, possibly contributing to xenin-induced body weight reduction. Thus, enhancing central action of xenin and its downstream targets may be possible targets for the treatment of obesity by reducing the amount of stored fat in adipose tissue.     

Substance P is associated with hypothalamic paraventricular nucleus activation that coincides with increased urotensin 2 mRNA in chicks

Exogenous administration of substance P (SP) exerts anorexigenic effects in both chicks and rats, but the central mechanism mediating this response is poorly understood. Therefore, this study was designed to elucidate mechanisms of SP-induced anorexia using chicks as models. Chicks that received intracerebroventricular (ICV) injections of SP dose-dependably reduced their food intake with no effect on water intake. Next, the diencephalon was isolated from SP-injected chicks and mRNA expression of neuropeptide Y (NPY), corticotropin releasing factor (CRF), urocortin 3 (UCN 3) and CRF receptors were measured but were not affected. When measured in the hypothalamus, mRNA abundance of these and NPY receptors, urotensin 2 (UTS2) and melanocortin receptor 4 (MCR4) were not affected by SP-injection. Quantification of c-Fos immunoreactivity in appetite-associated hypothalamic nuclei demonstrated that the paraventricular nucleus (PVN) was activated in SP-injected chicks. Finally, in the PVN isolated from SP-injected chicks, there was increased expression of UTS2 mRNA while CRF and UCN3 were not affected. Thus, the anorexigenic effects of SP appear to be mediated by PVN activation and may involve UTS2.     

Amygdala enterostatin induces c-Fos expression in regions of hypothalamus that innervate the PVN

Enterostatin selectively inhibits the intake of the dietary fat after both central and peripheral administration. Our previous studies have shown that a central site of action is the central nucleus of amygdala. Serotonergic agonists administered into the paraventricular nucleus (PVN) inhibit fat intake and serotonergic antagonists block the feeding suppression induced by amygdala enterostatin, suggesting that there are functional connections between the PVN and amygdala that affect the feeding response to enterostatin. Our purpose was to identify the anatomic and functional projections from the amygdala to the PVN and hypothalamic area that are responsive to enterostatin, by using a retrograde tracer fluorogold (FG) and c-Fos expression. Rats were injected with fluorogold unilaterally into the PVN and a chronic amygdala cannula was implanted ipsilaterally. After 10 days recovery, rats were injected with either enterostatin (0.1 nmol) or saline vehicle (0.1 microl) into the amygdala and sacrificed 2 h later by cardiac perfusion under anesthesia. The brains were subjected to dual immunohistochemistry to visualize both FG and c-Fos-positive cells. FG/c-Fos double-labeled cells were found in forebrain regions including the PVN, amygdala, lateral hypothalamus (LH), ventral medial hypothalamus (VMH) and arcuate nucleus (ARC). The data provides the first anatomical evidence that enterostatin activates amygdala neurons that have functional and anatomic projections directly to the PVN and also activates neurons in the arcuate, LH and VMH, which innervate the PVN.     

Central visfatin causes orexigenic effects in chicks

Intracerebroventricular injection of visfatin caused increased feed intake and pecking efficiency, but did not affect water intake in chicks. Visfatin-treated chicks had increased c-Fos immunoreactivity in the lateral hypothalamus, decreased reactivity in the ventromedial hypothalamus and the dorsomedial hypothalamus, infundibular nucleus, periventricular nucleus, paraventricular nucleus were not affected. A low dose of visfatin increased locomotion. We conclude that intracerebroventricular injection of visfatin causes orexigenic effects in chicks.     

Differential effects of enterostatin, galanin and opioids on high-fat diet consumption

Enterostatin, the activation peptide of pancreatic procolipase, suppresses high-fat diet consumption both centrally and peripherally. κ-opioid agonists are also known to stimulate fat intake. These experiments were conducted to determine if an opioidergic central pathway might mediate the effects of enterostatin and galanin on fat intake. Male Sprague-Dawley rats were adapted to a high-fat diet (56% energy) and were implanted with cannulae aimed at the lateral cerebral ventricle (LV) or third cerebral ventricle (3V). Injection of enterostatin (1 nmol, LV) suppressed high-fat diet consumption in fasted (20 h) rats. This inhibition of high-fat intake by enterostatin was attenuated by central injection of the specific κ-agonist U50488 (2.15, 21.5 and 215 nmol, LV) in a dose-dependent manner in fasted rats while only the highest dose of U50488 (215 nmol, LV) independently produced stimulation of high-fat diet consumption in sated rats. Galanin (0.1 nmol, 3V) induced consumption of high-fat diet in sated rats similar to that seen with U50488 and this stimulation was attenuated by peripheral injection of naloxone (1.0 mg/kg i.p.). We present a model which integrates the present data, as well as previous findings, in explaining a potential common opioid pathway modulating fat consumption.     

Inhibition of sexual behaviour and the luteinizing hormone surge by intracerebral progesterone implants in the female sheep

In female sheep, progesterone blocks the induction by oestradiol of both sexual behaviour and the pre-ovulatory surges of gonadotrophin releasing hormone (GnRH) and luteinising hormone (LH). However, the central sites of action of progesterone remain poorly defined, so we attempted to locate them by implanting progesterone intracerebrally in ovariectomised ewes treated with exogenous steroids to induce oestrous behaviour and the LH surge. Single bilateral implants or a double bilateral implants filled with progesterone or cholesterol were placed in the ventromedial hypothalamus (VMH) or the preoptic area (POA). Control ewes were not implanted. To determine the inhibitory capacity of the central progesterone implants, ewes received an injection (i.m.) of 8 μg or 16 μg of oestradiol. The single bilateral implants of progesterone failed to block oestrous behaviour and the LH surge induced by 8 μg of oestradiol. Double bilateral progesterone implants in the VMH blocked the sexual behaviour (P < 0.05) and the LH surge (P < 0.05), but implants in the POA blocked only sexual receptivity (P < 0.05). No changes were observed after central implantation of cholesterol. Our results support the hypothesis that progesterone acts centrally in the VMH and the POA to inhibit the induction of LH surge and sexual behaviour by oestradiol.     

Effects of Central and Peripheral Injection of Leptin on Food Intake and on Brain Fos Expression in the Otsuka Long-Evans Tokushima Fatty Rat with Hyperleptinaemia

Hyperleptinaemia is observed in obese animals and humans, suggesting that leptin resistance rather than leptin deficiency is a characteristic feature of obesity. This study was designed to determine whether peripherally or centrally administered leptin is effective on the short-term food intake and expression of Fos protein in the hypothalamus in the Otsuka Long-Evans Tokushima Fatty (OLETF) or Long-Evans Tokushima Otsuka (LETO) rat, as a control. The OLETF rat exhibits a polygenic syndrome of hyperphagia, obesity, hyperinsulinaemia, and hyperglycaemia. Male OLETF rats of 5, 8, and 14 weeks of age became heavier than LETO rats. Serum leptin concentrations were not significantly different between LETO and OLETF rats at the age of 5 weeks, but in 8- and 14-week-old OLETF rats were increased to 3.4 and 2.9 times those of LETO rats, respectively. The 8-week-old OLETF and LETO rats were given intraperitoneal (i.p.) injections with recombinant mouse leptin to measure the kinetics. There was a dramatic increase in plasma leptin concentration at 1 h, a decline by 3 h, and the concentrations 6 h after injection were similar to the basal levels. There were no significant difference between OLETF and LETO rats. In LETO rats at 5, 8 and 14 weeks of age, i.p. injection of leptin significantly decreased food intake. Whereas 5-week-old OLETF rats responded to leptin with a decrease in food intake, 8- and 14-week-old OLETF rats became resistant to peripherally administered leptin. In contrast, intracerebroventricular (i.c.v.) injections of leptin were very effective in inhibiting food intake in both OLETF and LETO rats at 14 weeks of age. Intraperitoneal injection of leptin in the LETO rats at each age increased the number of Fos-positive nuclei detected in the ventromedial hypothalamic (VMH), the dorsomedial hypothalamic (DMH) and arcuate nuclei, whereas there was no significant increase in the number of cells expressing c-fos protein in the hypothalamus of the 8- and 14 week-old OLETF rats with hyperleptinaemia. On the other hand, increased expression of c-fos protein in the VMH, DMH and arcuate nuclei following i.c.v. injection of leptin was observed in both OLETF and LETO rats at 5, 8 and 14 weeks of age. These data demonstrated that obese OLETF rats are peripherally leptin resistant, while they retain sensitivity to centrally administered leptin.     

Hypothalamic unit responses to alimentary perfusions in the anesthetised rat

Single unit discharges in the ventromedial hypothalamic nucleus (VMH) and lateral hypothalamic area (LH) were extracellularly recorded in urethane anesthetised female rats, while various solutions were perfused through the stomach or duodenum via implanted polythene tubes. Perfusates, which were maintained at 38°C, were 0.9% (w/v) NaCl, 2.5% NaCl, 5.25% glucose, 30% glucose, 5.0% casein hydrolysate, and liquid food. Only units which did not respond to somatosensory stimuli were tested. One hundred and twenty six units were recorded for periods of up to 3 hr, occasionally longer, in 57 animals. Of these, 74 were recorded during gastric perfusions and 52 during duodenal perfusions. Distension of the stomach elicited changes in firing rate in 16 LH and 8 VMH units. Both increases and decreases in firing rate in response to gastric distension were observed in both the LH and VMH. There was no evidence that nutrient or osmotic properties of the perfusates exerted any modifying influence on hypothalamic unit discharges. Distention of the duodenum by the perfusions elicited changes in firing rate in 12 LH and 6 VMH units. In this case all LH units decreased firing and all VMH units increased firing during distension of the lumen. In addition 2 VMH units appeared to increase their firing rate in association with glucose perfusions. The results are discussed in terms of the role of gastrointestinal feedback to the hypothalamus in food intake regulation.     

Effect of calcitonin gene-related peptide (CGRP) on avian appetite-related processes

Calcitonin gene-related peptide (CGRP) is released from the gastrointestinal tract following ingestion and causes satiety in mammals. Its effects on appetite in non-mammalian vertebrates are unreported. In Experiment 1, fasted chicks reduced food and water intake after central injection of CGRP. These effects were not associated with increased plasma corticosterone concentration. In Experiment 2, we showed that the effect on water intake was independent of food intake. In Experiment 3, central CGRP caused increased c-Fos immunoreactivity in the arcuate (ARC) nucleus, paraventricular nucleus (PVN), periventricular (PHN) and ventromedial (VMH) hypothalamic nuclei. The results of Experiment 4 demonstrate that intraperitoneal injection of CGRP also causes reduced food and water intake. c-Fos immunoreactivity was increased in the ARC, PHN, PVN and VMH in Experiment 5 after intraperitoneal injection of CGRP. Lastly in Experiment 6, we showed that central CGRP changes the type of pecks from feeding to exploratory, and reduces the number of escape attempts. The effect of CGRP appears to be primary on appetite in chicks. In conclusion, the mechanisms of CGRP induced satiety have some similarities and differences between avian and rodent models. The results presented here provide new insight into the evolution of vertebrate satiety regulatory mechanisms.     

Evidence for a different sensitivity to various central effects of interleukin-1 beta in mice.

Interleukin 1 (IL-1) induces a series of metabolic and endocrine effects. Activation of the hypothalamus-pituitary-adrenal axis, inhibition of food and water intake, elevation of serum interleukin-6 (IL-6) concentration and hypoglycemia are some of the effects induced by IL-1. The purpose of this study was to compare the sensitivity of these effects following central and peripheral administration of IL-1 beta. Different doses of IL-1 beta (0.1-1000 ng/mouse) were centrally (ICV) or peripherally (IP) injected to male mice two hours prior to sacrifice. The ICV administration was more efficacious than the IP injection in elevating serum corticosterone and IL-6 concentrations, whereas no difference was evident in the IL-1 beta-induced hypoglycemia. Central IL-1 beta administration was also more potent than IP injection in inhibiting overnight food and water intake. A dose-dependent effect was evident in all these cases. In summary, our data compare effects elicited by central or peripheral administration of different doses of IL-1 beta. This comparison suggests that the IL-1 beta stimulation of serum corticosterone and IL-6 and inhibition of food and water intake are events more centrally mediated than the IL-1 beta-induced hypoglycemia.     

Opioid-induced feeding: Localization of sensitive brain sites

These experiments were designed to identify brain sites at which opioids might act to influence ingestive behavior and to determine which opioid receptor types are involved. After food deprivation, rats were given microinjections of naloxone into several brain regions and food intake was measured. Injections into or near the paraventricular (PVN) or ventromedial (VMH) hypothalamic nuclei or the globus pallidus (GP) reduced food intake; injections into the striatum or lateral hypothalamus (LH) were ineffective. A second study examined the ingestive effects of roughly equimolar doses (1.43-1.75 nmol) of dynorphin A (DYN), beta-endorphin (beta-END), and D-Ala2,D-Leu5-enkephalin (DADLE) when injected into 4 different brain regions. Only DYN significantly increased food intake, and this effect was seen only with injections into the PVN and VMH. Beta-END stimulated water intake when injected into the PVN, VMH and GP but not the LH. Further studies indicated that with PVN injections, DYN was effective at a dose as low as 0.47 nmol, and that a higher dose of DADLE (4.39 nmol) did stimulate food intake. These studies support an important role for dynorphin and the kappa opioid receptor in the regulation of feeding and suggest that the opioid regulation of food and water intake can be differentiated both by sites of action and by effective agonists.     

Neuropeptide Y and food intake in fasted rats: effect of naloxone and site of action

Central administration of neuropeptide Y (NPY) induces food intake in freely feeding animals and this effect is mediated by hypothalamic sites. Little is known, however, about the effect of NPY on food intake and site of action in food-deprived animals. To examine this further, 24-h fasted rats received injections of saline or NPY into the lateral cerebral ventricle (10 micrograms/10 microliters; n = 8) or into the lateral (LH) or ventromedial hypothalamus (VMH) (1 microgram/0.5 microliters; n = 44). In addition, intracerebroventricular (i.c.v.) injections of NPY were carried out with or without i.c.v. naloxone (25 micrograms), a specific opioid receptor antagonist. During the first 40 min food intake was not different with or without NPY. After 60 and 120 min, food intake was 5.9 +/- 0.4 g and 8.3 +/- 0.6 g with i.c.v. saline which was significantly augmented by i.c.v. NPY to 8.7 +/- 0.9 g and 14.4 +/- 1.5 g, respectively (P less than 0.05). This increase in food consumption was due to a prolongation of feeding time. The opioid receptor antagonist naloxone significantly augmented latency to feed, both in the absence and presence of NPY (8.0 vs 1.7 min or 14.7 vs 2.8 min, respectively) and abolished the NPY-induced increase in food intake. Following intrahypothalamic injection of NPY, an increase in food intake (greater than 20%) was observed in 50% of the histologically identified LH and VMH sites, but only in 15% of the injection sites outside the LH/VMH.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ingested placenta blocks the effect of morphine on gut transit in Long-Evans rats

Opioids produce antinociception, and ingested placenta or amniotic fluid modifies that antinociception. More specifically, ingested placenta enhances the antinociception produced by selective activation of central kappa-opioid or delta-opioid receptors but attenuates that produced by activation of central mu-opioid receptors. Opioids also slow gut transit by acting on central or peripheral mu-opioid receptors. Therefore, we hypothesized that ingested placenta would reverse the slowing of gut transit that is produced by morphine, a preferential mu-opioid-receptor agonist. Rats were injected with morphine either centrally or systemically and fed placenta, after which gastrointestinal transit was evaluated. We report here that ingested placenta reversed the slowing of gut transit produced by centrally administered morphine but did not affect the slowing of gut transit produced by systemically administered morphine. These results suggest another likely consequence of placentophagia at parturition in mammals--reversal of opioid-mediated, pregnancy-based disruption of gastrointestinal function--as well as an important consideration in opioid-based treatments for pain in humans--enhancement of desirable effects with attenuation of adverse effects.     

Hypothalamic mechanisms associated with corticotropin-releasing factor-induced anorexia in chicks

Central administration of corticotropin-releasing factor (CRF), a 41-amino acid peptide, is associated with potent anorexigenic effects in rodents and chickens. However, the mechanism underlying this effect remains unclear. Hence, the objective of the current study was to elucidate the hypothalamic mechanisms that mediate CRF-induced anorexia in 4 day-old Cobb-500 chicks. After intracerebroventricular (ICV) injection of 0.02 nmol of CRF, CRF-injected chicks ate less than vehicle chicks while no effect on water intake was observed at 30 min post-injection. In subsequent experiments, the hypothalamus samples were processed at 60 min post-injection. The CRF-injected chicks had more c-Fos immunoreactive cells in the arcuate nucleus (ARC), dorsomedial nucleus (DMN), ventromedial hypothalamus (VMH), and paraventricular nucleus (PVN) of the hypothalamus than vehicle-treated chicks. CRF injection was associated with decreased whole hypothalamic mRNA abundance of neuropeptide Y receptor sub-type 1 (NPYR1). In the ARC, CRF-injected chicks expressed more CRF and CRF receptor sub-type 2 (CRFR2) mRNA but less agouti-related peptide (AgRP), NPY, and NPYR1 mRNA than vehicle-injected chicks. CRF-treated chicks expressed greater amounts of CRFR2 and mesotocin mRNA than vehicle chicks in the PVN and VMH, respectively. In the DMN, CRF injection was associated with reduced NPYR1 mRNA. In conclusion, the results provide insights into understanding CRF-induced hypothalamic actions and suggest that the anorexigenic effect of CRF involves increased CRFR2-mediated signaling in the ARC and PVN that overrides the effects of NPY and other orexigenic factors.