Endorphinergic and alpha-noradrenergic systems in the paraventricular nucleus: effects on eating behavior

Brain cannulated rats were injected with the opioid peptide beta-endorphin (beta-EP) directly into the hypothalamic paraventricular nucleus (PVN) where norepinephrine (NE) is most effective in stimulating eating behavior. Beta-Endorphin (1.0 nmole) reliably increased food intake in satiated animals, and this response was blocked by local administration of the selective opiate antagonist naloxone. The eating induced by beta-EP was positively correlated in magnitude with the NE response and, like NE, was antagonized by PVN injection of the alpha-noradrenergic blocker phentolamine. Naloxone had no effect on NE-induced eating, and the dopaminergic blocker fluphenazine failed to alter either beta-EP or NE eating. When injected simultaneously, at maximally effective doses, beta-EP and NE produced an eating response which was significantly larger than either of the responses elicited separately by beta-EP or NE and was essentially equal to the sum of these two responses. The evidence obtained in this study suggests that beta-EP and NE stimulate food ingestion through their action on PVN opiate and alpha-noradrenergic receptors, respectively, and that beta-EP's action is closely related to, and in part may be dependent upon, the PVN alpha-noradrenergic system for feeding control.     

Amylin decreases food intake in mice.

The isolation of amylin from pancreatic islets has stimulated interest in its potential role in the pathogenesis of type II diabetes mellitus and in its possible physiological roles. Amylin administered intraperitoneally decreased food intake in non-food-deprived and food-deprived diabetic and nondiabetic mice. Amylin also decreased feeding induced by insulin administration without significantly affecting blood glucose levels. Amylin also decreased food intake following intracerebroventricular administration. It is possible that amylin plays a physiological role in appetite regulation and may play a pathophysiological role in the altered appetites seen in some persons with type II diabetes mellitus.     

Alpha-melanocyte stimulating hormone plays an important role in the regulation of food intake by the central melanocortin system in chicks

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.     

Central gastrin inhibits feeding behavior and food passage in neonatal chicks.

The gastrin/cholecystokinin (CCK) family is recognized as the principal family of hormones involved in regulation of the gastrointestinal tract CCK is recognized as a satiety hormone in mammalian species, but it has been suggested that gastrin rather CCK may have an important role in controlling feeding behavior in the neonatal chick through a poorly developed blood brain barrier. So far, however, there is no direct evidence that central gastrin inhibits food intake in neonatal chicks. The aim of this study was to elucidate whether central administration of gastrin 1) inhibits feeding behavior and 2) alters food passage from the crop. The effects of central administration of gastrin on food intake were investigated in experiment 1. Birds (2-day-old) were food-deprived for 3 h and then gastrin or saline was injected intracerebroventricularly. Gastrin strongly inhibited food intake in a dose-dependent fashion for 2 h. Thereafter, the effects of central gastrin on feeding behavior and serum corticosterone concentration were examined in experiment 2. Following central administration of gastrin, food intake was depressed and pecking behavior was inhibited. Serum corticosterone concentration was not altered by central administration of gastrin. The influence of central gastrin on food passage from the crop was investigated in experiment 3. Central administration of gastrin clearly delayed food passage. In conclusion, central gastrin appears to have a strong effect for the satiety and gastrointestinal motility in the neonatal chick.     

The effects of centrally administered apelin-13 on food intake, water intake and pituitary hormone release in rats

Apelin is the recently identified endogenous ligand for the G-protein-coupled receptor, APJ. Preproapelin and APJ mRNA are found in hypothalamic regions known to be important in the regulation of food and water intake, and pituitary hormone release. The effects of intracerebroventricular (ICV) administration of pyroglutamylated apelin-13 on food and water intake and pituitary hormone release in rats were investigated. Apelin-13 had little effect on food intake, but dose-dependently increased drinking behaviour and water intake at 1 h. Apelin-13 (10 nmol) increased water intake by up to sixfold compared to saline. Compared to saline control, apelin-13 (10 nmol) significantly increased plasma ACTH and corticosterone and decreased plasma prolactin, LH and FSH at 30 min. In vitro, apelin-13 stimulated the release of CRH and AVP from hypothalamic explants, but had no effect on NPY release. These results suggest that apelin may play an important role in the hypothalamic regulation of water intake and endocrine axes.     

Peripheral and Central Administration of Xenin and Neurotensin Suppress Food Intake in Rodents

Xenin is a 25‐amino acid peptide highly homologous to neurotensin. Xenin and neurotensin are reported to have similar biological effects. Both reduce food intake when administered centrally to fasted rats. We aimed to clarify and compare the effects of these peptides on food intake and behavior. We confirm that intracerebroventricular (ICV) administration of xenin or neurotensin reduces food intake in fasted rats, and demonstrate that both reduce food intake in satiated rats during the dark phase. Xenin reduced food intake more potently than neurotensin following ICV administration. ICV injection of either peptide in the dark phase increased resting behavior. Xenin and neurotensin stimulated the release of corticotrophin‐releasing hormone (CRH) from ex vivo hypothalamic explants, and administration of α‐helical CRH attenuated their effects on food intake. Intraperitoneal (IP) administration of xenin or neurotensin acutely reduced food intake in fasted mice and ad libitum fed mice in the dark phase. However, chronic continuous or twice daily peripheral administration of xenin or neurotensin to mice had no significant effect on daily food intake or body weight. These studies confirm that ICV xenin or neurotensin can acutely reduce food intake and demonstrate that peripheral administration of xenin and neurotensin also reduces food intake. This may be partly mediated by changes in hypothalamic CRH release. The lack of chronic effects on body weight observed in our experiments suggests that xenin and neurotensin are unlikely to be useful as obesity therapies.     

Normal feeding behavior, body weight and leptin response require the neuropeptide Y Y2 receptor.

Neuropeptide Y (NPY), a 36-amino-acid peptide widely expressed in the brain is involved in many physiological responses, including hypothalamic control of food intake and cardiovascular homeostasis. NPY mediates its effects through binding to the Y1, Y2 and Y5 G-protein-coupled receptors. Little is known of the role of the Y2 receptor in mediating the different NPY effects. We inactivated the Y2 receptor subtype in mice and found that these mice developed increased body weight, food intake and fat deposition. The null mutant mice showed an attenuated response to leptin administration but a normal response to NPY-induced food intake and intact regulation of re-feeding and body weight after starvation. An absence of the Y2 receptor subtype also affected the basal control of heart rate, but did not influence blood pressure. These findings indicate an inhibitory role for the Y2 receptor subtype in the central regulation of body weight and control of food intake.     

Effects of neuropeptide Y antagonists on food intake in rats: differences with cold-adaptation

Hyperphagia followed both central neuropeptide Y (NPY) administration and the presumed increase of endogenous NPY activity after food deprivation. NPY induced greater hyperphagia in cold-adapted than non-adapted rats; fasting of comparable severity caused similar hyperphagia in the two groups. NPY-receptor-antagonist D-Tyr(27,36), D-Thr32-NPY(27,36) or functional NPY-antagonist D-myo-inositol-1,2,6-trisphosphate attenuated the hyperphagic effect of both NPY and fasting in non-adapted rats. However, while completely preventing the NPY-hyperphagia, they did not influence the fasting-induced hyperphagia in cold-adapted rats. With cold-adaptation the sensitivity to NPY and to its antagonists increases, but the hypothalamic NPY loses from its fundamental role in the regulation of food intake, and the hyperphagia seen in cold-adaptation may need some other explanation.     

Leptin and neuropeptide Y (NPY) modulate nitric oxide synthase: further evidence for a role of nitric oxide in feeding.

Recent studies have suggested a role for nitric oxide in the regulation of food intake. Neuropeptide Y (NPY) is one of the most potent orexigenic agents. Chronic administration of leptin decreases food intake. This study examined the effects of NPY and leptin on nitric oxide synthase (NOS) in the hypothalamus. Previously it has been demonstrated that obese (ob/ob) mice have elevated NOS levels in the hypothalamus. In this study we demonstrated that the administration of leptin (6 microg/day) subcutaneously (SC) for 3 days decreased body weight (P < 0.001) and food intake P < 0.001) in obese (ob/ob) mice as expected. In addition, leptin decreased NOS in the hypothalamus nu 37% (P < 0.01) and in brown adipose tissue by 69% (P < 0.01) but not in white adipose tissue. NPY was administered intracerebroventricularly to CD-1 mice at doses of 0.25 and 0.50 microg. Mice were sacrificed 15 min after injection and NOS was measured in their hypothalami. NPY at the lower dose increased NOS in the hypothalamus by 147%. These results, taken together, with previously published studies support the concept that nitric oxide may play a role as a mediator of the effects of NPY and leptin on food intake. The alterations of NOS in brown adipose tissue following leptin administration could result in changes in blood flow or metabolism in the brown fat.     

Intracerebroventricular administration of vasoactive intestinal peptide inhibits food intake

Vasoactive intestinal peptide (VIP) is a 28 amino acid peptide expressed throughout the peripheral and central nervous systems. VIP and the VIP receptor VPAC(2)R are expressed in hypothalamic nuclei involved in the regulation of energy homeostasis. VIP has been shown to be involved in the regulation of energy balance in a number of non-mammalian vertebrates. We therefore examined the effects of intracerebroventricular (ICV) administration of VIP on food intake, energy expenditure and activity in adult male Wistar rats. VIP administration caused a potent short lived decrease in food intake and an increase in activity and energy expenditure. The pathways potentially involved in the anorexigenic effects of VIP were investigated by measuring the release of neuropeptides involved in the regulation of food intake from hypothalamic explants treated with VIP. VIP significantly stimulated the release of the anorexigenic peptide alpha-melanocyte stimulating hormone (αMSH). These studies suggest that VIP may have an endogenous role in the hypothalamic control of energy homeostasis.     

CNS melanocortin system involvement in the regulation of food intake

Accumulating evidence indicates that the central melanocortin (MC) system plays a key role in the regulation of food intake and energy balance. This evidence includes findings that either spontaneous genetic mutations or targeted gene deletions that impair melanocortin signaling cause disrupted food intake and body-weight control. In addition, expression of the mRNA that encodes the endogenous agonists and antagonists for CNS melanocortin receptors is regulated by changes in energy balance and body-adiposity signals. Finally, administration of both natural and synthetic ligands to MC receptors produces changes in food intake. The data collectively suggest a critical role for melanocortin signaling in the control of energy balance.     

Effects of Insulin Administration in Diabetic Rats on Food and Drink Rhythmic Schedules

In normal rats food and water intakes are associated in terms of time and quantity and their diurnal rhythms are synchronized. Intake behavior in streptozotocin-induced diabetic rats (ID) with marked polyphagia and polydipsia and in diabetic rats with continuous insulin administration (IT) has been studied. The daily percentages of food and water intakes during the dark phase were lower in IT than in control rats (C), being even lower in ID rats. However, all three groups showed circadian rhythmicity in food intake, although with less amplitude in the ID and IT animals compared to the C ones. A loss of the normal circadian rhythm of water intake was observed in the ID rats and although the insulin administration recovered circadian rhythmicity, it did not restore the temporal relations between food and water intakes. These results may indicate that the circadian pattern of water intake is more influenced by insulin than food intake. The daily pattern of this hormone may play an important role in the circadian modulation of the homeostatic mechanisms integrating both intake behaviors.     

AMP-activated protein kinase plays a role in the control of food intake

AMP-activated protein kinase (AMPK) is the downstream component of a protein kinase cascade that acts as an intracellular energy sensor maintaining the energy balance within the cell. The finding that leptin and adiponectin activate AMPK to alter metabolic pathways in muscle and liver provides direct evidence for this role in peripheral tissues. The hypothalamus is a key regulator of food intake and energy balance, coordinating body adiposity and nutritional state in response to peripheral hormones, such as leptin, peptide YY-(3-36), and ghrelin. To date the hormonal regulation of AMPK in the hypothalamus, or its potential role in the control of food intake, have not been reported. Here we demonstrate that counter-regulatory hormones involved in appetite control regulate AMPK activity and that pharmacological activation of AMPK in the hypothalamus increases food intake. In vivo administration of leptin, which leads to a reduction in food intake, decreases hypothalamic AMPK activity. By contrast, injection of ghrelin in vivo, which increases food intake, stimulates AMPK activity in the hypothalamus. Consistent with the effect of ghrelin, injection of 5-amino-4-imidazole carboxamide riboside, a pharmacological activator of AMPK, into either the third cerebral ventricle or directly into the paraventricular nucleus of the hypothalamus significantly increased food intake. These results suggest that AMPK is regulated in the hypothalamus by hormones which regulate food intake. Furthermore, direct pharmacological activation of AMPK in the hypothalamus is sufficient to increase food intake. These findings demonstrate that AMPK plays a role in the regulation of feeding and identify AMPK as a novel target for anti-obesity drugs.     

Increase of beta-endorphin concentrations in the plasma and pituitary neuro-intermediate lobe of the rat on the afternoon of proestrus

Beta-endorphin (beta-EP) concentrations in the plasma and the anterior and neuro-intermediate lobes of the pituitary (AP and NIL) were quantitated by radioimmunoassay (RIA) and gel filtration chromatography in female rats at 1000, 1400, and 1900 h on the day of proestrus and diestrus day-1. There were no significant changes in beta-EP in the plasma, AP, or NIL on diestrus day-1. On proestrus, beta-EP in the plasma and NIL, but not the AP, increased significantly from 1000 to 1400 h and returned to basal levels by 1900 h. The time course of this increase of beta-EP in the NIL and plasma is consistent with the temporal sequence of the prolactin and gonadotropin surges on the afternoon of proestrus, suggesting that beta-EP in the NIL may be involved in the regulation of these neuroendocrine events.     

Neuromedin U has a physiological role in the regulation of food intake and partially mediates the effects of leptin

Intracerebroventricular (ICV) administration of Neuromedin U (NMU), a hypothalamic neuropeptide, or leptin, an adipostat hormone released from adipose tissue, reduces food intake and increases energy expenditure. Leptin stimulates the release of NMU in vitro, and NMU expression is reduced in models of low or absent leptin. We investigated the role of NMU in mediating leptin-induced satiety. ICV administration of anti-NMU immunoglobulin G (IgG) (5 nmol) to satiated rats significantly increased food intake 4 h after injection, an effect seen for 相似文献   

The role of endocannabinoids in the hypothalamic regulation of visceral function

The hypothalamus plays an important role in the regulation of several visceral processes, including food intake, thermoregulation and control of anterior pituitary secretion.Endogenous cannabinoids and CB(1) cannabinoid receptors have been found in the hypothalamus. In the present review, we would like to clarify the role of the endocannabinoid system in the regulation of the above-mentioned visceral functions.There is historical support for the role of marihuana (i.e. exogenous cannabinoids) in the regulation of appetite. Endocannabinoids also stimulate food intake. Furthermore, the specific CB(1) receptor antagonist SR141716 reduces food intake. Leptin treatment decreases endocannabinoid levels in normal rats and ob/ob mice. These findings provide evidence for the role of the hypothalamic endocannabinoid system in food intake and appetite regulation.Cannabinoids can change body temperature in a dose-dependent manner. High doses cause hypothermia while low doses cause hyperthermia. Cannabinoid administration decreases heat production. It seems that the effects of can- nabinoids on thermoregulation is exerted by altering some neurochemical mediator effects at both the presynaptic and postsynaptic level.THC and endocannabinoids have mainly inhibitory effects on the regulation of reproduction. Administration of anandamide (AEA) decreases serum luteinizing hormone (LH) and prolactin (PRL) levels. AEA causes a prolongation of pregnancy in rats and temporarily inhibits the postnatal development of the hypothalamo-pituitary axis in offspring. The action of AEA on the reproductory parameters occurs at both the hypothalamic and pituitary level. CB(1) receptors have also been found in the anterior pituitary. Further, LH levels in CB(1) receptor-inactivated mice were decreased compared with wild-type mice.Taken together, all these observations suggest that the endocannabinoid system is playing an important part in the regulation of the mentioned visceral functions and it provides the bases for further applications of cannabinoid receptor agonists and/or antagonists in visceral diseases regulated by the hypothalamus.     

Effect of disrupted episodic memory on food consumption: no impact of neuronal loss of endophilin A1 on food intake and energy balance

Food intake is generally assumed to reflect a regulatory tension between homeostatic and hedonic drivers. Information from individuals with memory dysfunction suggests that episodic memory may also play a significant role. We reasoned that if memory influences food intake, then disrupting a genetic factor that is important in episodic memory formation should affect food intake and energy balance. We performed spatial learning tests on neuronal specific endophilin A1 (EENA1) KO mice using the four-arm baited version of the radial arms maze (RAM). Energy regulation has also been evaluated. As anticipated neuronal EENA1 KO mice had impaired spatial memory. However, loss of endophilin A1 did not result in greater food intake, or altered energy absorption efficiency, relative to wild-type (WT) mice, when fed either low or high fat diets. Moreover, loss of EENA1 did not significantly affect other features of energy balance—physical activity and energy expenditure. No statistically significant changes were observed in the expression of hypothalamic neuropeptides related to food intake regulation, or circulating levels of leptin. We conclude that food intake and energy balance are largely governed by homeostatic and hedonic processes, and when these processes are intact memory probably plays a relatively minor role in food intake regulation.     

Central administration of neuropeptide Y induces wakefulness in rats

Neuropeptide Y (NPY) is a well-characterized neuromodulator in the central nervous system, primarily implicated in the regulation of feeding. NPY, orexins, and ghrelin form a hypothalamic food intake regulatory circuit. Orexin and ghrelin are also implicated in sleep-wake regulation. In the present experiments, we studied the sleep-modulating effects of central administration of NPY in rats. Rats received intracerebroventricular injection of physiological saline or three different doses of NPY (0.4, 2, and 10 microg in a volume of 4 microl) at light onset. Another group of rats received bilateral microinjection of saline or 2 microg NPY in the lateral hypothalamus in a volume of 0.2 microl. Sleep-wake activity and motor activity were recorded for 23 h. Food intake after the control and treatment injections was also measured on separate days. Intracerebroventricular and lateral hypothalamic administration of NPY suppressed non-rapid-eye-movement sleep and rapid-eye-movement sleep in rats during the first hour after the injection and also induced changes in electroencephalogram delta power spectra. NPY stimulated food intake in the first hour after both routes of administration. Data are consistent with the hypothesis that NPY has a role in the integration of feeding, metabolism, and sleep regulation.     

Effects of naltrexone and CCK on estrous behavior and food intake in Syrian hamsters

Food deprivation inhibits estrous behavior in several species of rodents, but little is known about the neurotransmitter systems mediating this phenomenon. We determined whether partial blockade of opioid receptors by continuous infusion of naltrexone and/or acute peripheral injection of cholecystokinin (CCK) administration would overcome the suppressive effects of food deprivation on estrous behavior in Syrian hamsters. Contrary to expectation, naltrexone produced a slight suppression of estrous behavior, and systemic CCK administration had no effect. This dose of naltrexone was sufficient to reduce in vivo binding of [(3)H]naloxone in the brain, and both compounds affected other parameters such as food intake and body weight gain. Thus, the doses of CCK and naltrexone that were used were physiologically effective. These findings suggest that neither peripheral CCK nor opioid systems are likely to play a major role in the suppression of hamster estrous behavior by food deprivation.     

下丘脑室旁核胃动素对消化功能影响的研究

目的:研究下丘脑室旁核注入胃动素及其拮抗剂对大鼠消化功能和体重增长的研究。方法:将剂量为0.005-5nmol的motilin和GM109注入大鼠下丘脑室旁核,1小时后可观察到大鼠摄食量显著增加并持续到两小时后。进食量的计算是通过预先称量好的鼠粮和应用药物20分钟、1小时、两小时后剩余数量比较而得出。实验持续一周。将实验组和对照组的进食量和体重进行比较。结果:室旁核注入胃动素5nmol的实验组和合并应用GM1090.005nmol的实验组在应用药物后1小时和2小时,可观察到摄食量显著增加(p<0.01),一周后体重也增加(p>0.05),然而摄食量的增加有显著性差异,体重的增加并无显著性差异。其他实验组也没有观察到显著性差异。结论:胃动素有调节消化运动,促进胃肠排空,促进食欲的作用。可能由于胃肠排空是频繁的,没有充裕的时间消化吸收,从而体重增加无显著性差异。