Role of leptin in the control of feeding of goldfish Carassius auratus: interactions with cholecystokinin,neuropeptide Y and orexin A,and modulation by fasting

To assess the role of leptin on food intake regulation in goldfish, we examined the effects of central (intracerebroventricular, ICV) and peripheral (intraperitoneal, IP) injections of recombinant murine leptin on feeding behavior. Centrally (100 ng/g) and peripherally (300 ng/g) injected leptin both caused a significant decrease in food intake, compared to the saline-treated controls. To test the hypothesis that leptin influenced orexigenic neuropeptide systems in goldfish, fish were co-injected with neuropeptide Y (NPY) or orexin A and leptin. Both NPY (5 ng/g) and orexin A (10 ng/g) significantly increased food intake. Fish co-injected ICV with NPY (5 ng/g) or orexin A (10 ng/g) and leptin (1 or 10 ng/g) had a food intake lower than that of fish treated with NPY or orexin A alone. NPY mRNA expression in goldfish brain was reduced 2 and 6 h following central injection of leptin. To test the hypothesis that the cholecystokinin (CCK) mediates the effects of leptin in goldfish, fish were simultaneously injected ICV with an ineffective dose of leptin (10 ng/g) and either ICV or IP with an ineffective doses of CCK (1 ng/g ICV or 25 ng/g IP). These fish had a food intake lower than vehicle-treated fish, suggesting that leptin potentiates the satiety actions of CCK. CCK hypothalamic mRNA expression was increased 2 h following central treatment with leptin. The CCK receptor antagonist proglumide blocked both central and peripheral CCK satiety effects. Blockade of CCK brain receptors by proglumide resulted in an inhibition of the leptin-induced decrease in food intake and an attenuation of the inhibiting action of leptin on both NPY- and orexin A-induced feeding. These data suggests that CCK has a role in mediating the effects of leptin on food intake. Fasting potentiated the actions of leptin and attenuated the effects of CCK. Whereas fasting had no effects on the brain mRNA expression of CCK, it increased the brain mRNA expression of NPY and decreased the expression of CART. These changes in neuropeptide expression were partially reversed when fish were treated ICV with leptin. These results provide strong evidence that, in goldfish, leptin influences food intake, in part by modulating the orexigenic effects of NPY and orexin and that its actions are mediated, at least in part, by CCK.     

Metabolic and Orexigenic Effects of Intracerebroventricular Neuropeptide Y are Attenuated by Food Deprivation

Administration of neuropeptide Y (NPY) into the hypothalamus or cerebral ventricles has been shown to increase food intake, the secretion of hormones such as insulin, glucagon and corticosterone and to alter the metabolism of carbohydrate and lipids. It has been suggested that metabolic effects of hypothalamic NPY may contribute to fat accretion in some types of obesity and to the metabolic and behavioural adaptation to food deprivation. However, it is currently unknown if different nutritional states alter the responses to hypothalamic NPY. Consequently, we have compared the effects of NPY injected into the third ventricle (ICV) in the fed and overnight-fasted state on ingestive behaviour, on insulin, glucagon and corticosterone secretion before, and following, an IV glucose bolus (IVGTT) and on blood glucose following an intra-arterial insulin bolus (ITT). Studies were performed on conscious, unrestrained adult female rats. In the fed state, 2 and 6  &mgr;g ICV NPY produced a potent orexigenic and dypsogenic effect. In the fasted state, the 2  &mgr;g dose had a dypsogenic effect, while only the 6  &mgr;g dose had a significant orexigenic effect. In the fed but not fasted state, 3  &mgr;g ICV NPY increased plasma glucagon and corticosterone levels and attenuated the decline in blood glucose during the ITT. By contrast, in both fed and fasted groups, 3  &mgr;g ICV NPY potentiated the insulin secretory response during the IVGTT.     

Neuropeptide Y facilitates activity-based-anorexia

The hypothesis that treatment with neuropeptide Y (NPY) can increase running activity and decrease food intake and body weight was tested. Female rats with a running wheel lost more weight than sedentary rats and ran progressively more as the availability of food was gradually reduced. When food was available for only 1h/day, the rats lost control over body weight. Correlatively, the level of NPY mRNA was increased in the hypothalamic arcuate nucleus. This phenomenon, activity-based-anorexia, was enhanced by intracerebroventricular infusion of NPY in rats which had food available during 2h/day. By contrast, NPY stimulated food intake but not wheel running in rats which had food available continuously. These findings are inconsistent with the prevailing theory of the role of the hypothalamus in the regulation of body weight according to which food intake is a homeostatic process controlled by "orexigenic" and "anorexigenic" neural networks. However, the finding that treatment with NPY, generally considered an "orexigen", can increase physical activity and decrease food intake and cause a loss of body weight is in line with the clinical observation that patients with anorexia nervosa are physically hyperactive and eat only little food despite having depleted body fat and up-regulated hypothalamic "orexigenic" peptides.     

Decreased NPY innervation of the hypothalamic nuclei in rats with cancer anorexia

Whether the decrease in food intake that occurs at the onset of anorexia in tumor bearing (TB) rats is related to a change in the hypothalamic neuropeptide Y (NPY) system was tested by comparing NPY expression in sham operated Fischer Control and anorectic TB rats. Coronal cryocut sections of their fixed brain were processed by the peroxidase-antiperoxidase method with NPY polyclonal antibodies. NPY-immunoreactive fibers were widely distributed throughout the forebrain, but were most prominent in the hypothalamic paraventricular, suprachiasmatic, arcuate and periventricular nuclei. NPY-immunoreactive neurons were visualized in Control and anorectic TB rats in the preoptic region, the arcuate nucleus, and occasionally in the lateral hypothalamus. Semiquantitative image analysis showed a significant decrease in the NPY immunostaining in some hypothalamic nuclei of the anorectic TB rats, most prominently in the supraoptic nucleus, the parvocellular portion of the paraventricular nucleus, and, to a lesser extent, the suprachiasmatic and arcuate nuclei. No changes in NPY innervation were seen in the ventromedial nucleus and the lateral hypothalamus. The data support the hypothesis of an altered hypothalamic NPY system at the onset of anorexia in TB rats and also reveal the hypothalamic nuclei through which NPY influences food intake.     

Some Acute Effects of Intracerebroventricular Neuropeptide Y on Insulin Secretion and Glucose Metabolism in the Rat

Acute administration of neuropeptide Y(NPY) into the hypothalamus and cerebral ventricles can stimulate insulin secretion in the absence of available food. However, the relationship of this effect to blood glucose and other hormones which regulate glucose metabolism remains unclear. The purpose of this study was to compare the effects of NPY injected into the third ventricle (ICV) on serum insulin, glucose, glucagon, corticosterone and non-esterified fatty acids. Studies were performed on conscious, unrestrained female rats, not given access to food. ICV NPY, 2 and 5  μg produced an increase in serum insulin and glucagon, while the 5  μg dose only increased plasma glucose transiently and increased non-esterified fatty acids for a longer period. Corticosterone was not affected by ICV NPY. The insulinaemic response to i.v. glucose, 0.5 g/kg was doubled by ICV NPY, 4  μg. The maximal insulin levels were 113±18 for ICV NPY versus 67±8  μU/ml for ICV saline-treated animals. The glycaemic response was not altered. The hypoglycaemic response to i.v. insulin, 0.15 U/kg was significantly attenuated by ICV NPY, 5  μg. We concluded that ICV NPY promotes insulin secretion in the absence of available food and may potentiate the insulinaemic response to hyperglycaemia. Furthermore, possibly through its effects on glucagon and non-esterified fatty acids, ICV NPY may decrease the ability of insulin to control glucose metabolism.     

Gonadotropin-inhibitory hormone-stimulation of food intake is mediated by hypothalamic effects in chicks

Gonadotropin-inhibitory hormone (GnIH), a 12 amino acid peptide, is expressed in the avian brain and inhibits luteinizing hormone secretion. Additionally, exogenous injection of GnIH causes increased food intake of chicks although the central mechanism mediating this response is poorly understood. Hence, the purpose of our study was to elucidate the central mechanism of the GnIH orexigenic response using 12 day post hatch layer-type chicks as models. Firstly, via mass spectrometry we deduced the chicken GnIH amino acid sequence: SIRPSAYLPLRFamide. Following this we used chicken GnIH to demonstrate that intracerebroventricular (ICV) injection of 2.6 and 7.8 nmol causes increased food intake up to 150 min following injection with no effect on water intake. The number of c-Fos immunoreactive cells was quantified in appetite-associated hypothalamic nuclei following ICV GnIH and only the lateral hypothalamic area (LHA) had an increase of c-Fos positive neurons. From whole hypothalamus samples following ICV GnIH injection abundance of several appetite-associated mRNA was quantified which demonstrated that mRNA for neuropeptide Y (NPY) was increased while mRNA for proopiomelanocortin (POMC) was decreased. This was not the case for mRNA abundance in isolated LHA where NPY and POMC were not affected but melanin-concentrating hormone (MCH) mRNA was increased. A comprehensive behavior analysis was conducted after ICV GnIH injection which demonstrated a variety of behaviors unrelated to appetite were affected. In sum, these results implicate activation of the LHA in the GnIH orexigenic response and NPY, POMC and MCH are likely also involved.     

Exogenous prolactin-releasing peptide's orexigenic effect is associated with hypothalamic neuropeptide Y in chicks

Exogenous administration of prolactin-releasing peptide (PrRP) exerts anorexigenic effects in rats while causing orexigenic effects in chicks. While the central mechanism mediating PrRP's effect on food intake in rodents is somewhat understood, in chicks information is lacking. Therefore, this study was designed to elucidate the hypothalamic mechanism of PrRP induction of hunger perception in chicks. Chicks that received intracerebroventricular (ICV) injections of PrRP dose-dependently increased their food intake with no effect on water intake or whole blood glucose concentration. The threshold of food intake stimulation was as low as 3 pmol, thus as compared to other neuropeptides PrRP is exceptionally potent. The mRNA abundance of several appetite-associated neuropeptide genes was quantified and hypothalamic neuropeptide Y (NPY) mRNA was increased in PrRP-injected chicks. Therefore, the orexigenic effects of PrRP may be associated with increased NPY-ergic tone. These results provide insight into the evolutionary aspects of appetite regulation during the course of divergent evolution of mammals and birds.     

Seasonal regulation of food intake and body weight in the male Siberian hamster: studies of hypothalamic orexin (hypocretin), neuropeptide Y (NPY) andpro-opiomelanocortin (POMC)

The aim of these experiments was to investigate the relationship between hypothalamic expression of orexin (also called hypocretin), neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) mRNA and seasonal cycles of body weight and food intake in the Siberian hamster. Adult males were transferred from long days of 16 h light and 8 h dark to short days of 8 h light and 16 h dark, a procedure known to induce major reductions in food intake and body weight in this species. After 8 weeks of exposure to short days, while body weight was declining, hypothalamic NPY mRNA levels as assessed by in situ hybridization were slightly lower (P < 0.05) than in age-matched controls exposed to long days. After 12 weeks with short days, when body weight would be expected to have reached its seasonal nadir, POMC mRNA levels were lower (P < 0.05) than in hamsters under long days. At no stage did orexin mRNA levels in hamsters under short days differ significantly from levels in those under long days. To investigate further the role of these peptide systems in seasonal changes in body weight and food intake, two provocative tests were carried out. Firstly, a 48-h fast induced a significant increase (P < 0.025) in hypothalamic NPY mRNA levels in both long- and short-day conditions, but did not change hypothalamic POMC or orexin mRNA levels. Secondly, systemic (intraperitoneal) treatment with recombinant murine leptin (5 mg/kg body weight) significantly decreased (P < 0.01) food intake over a 6-h post-treatment period in both long- and short-day conditions. However, this acute leptin treatment did not induce significant changes in hypothalamic orexin, NPY or POMC mRNA abundance. The increase in NPY expression in both long- and short-day conditions following food restriction and the suppression of food intake by leptin in both conditions suggests that acute homeostatic mechanisms operate in both long-day (obese) and short-day (nonobese) conditions. The lack of major changes in orexin, NPY and POMC in such different metabolic states suggest that other central systems must play a greater role in generating these states. Such findings are consistent with the 'sliding set-point' hypothesis, that is, seasonal cycles in food intake and fat metabolism are brought about by as yet unknown central mechanisms that chronically alter the level ('set point') around which homeostasis occurs, rather than resulting from changes in the potency of the acute feedback mechanisms themselves.     

Investigation of the melanocyte stimulating hormones on food intake. Lack Of evidence to support a role for the melanocortin-3-receptor

The melanocortin receptors, melanocortin-3-receptor (MC3-R) and melanocortin-4-receptor (MC4-R), are expressed in many discrete medial hypothalamic nuclei implicated in feeding regulation. The pro-opiomelanocortin product alpha-melanocyte stimulating hormone (alpha-MSH), an MC3/4-R agonist, decreases food intake following intracerebroventricular (ICV) injection in rats. MC4-R's involvement in feeding has been established although a function for the MC3-R is unclear. We investigated endogenous melanocortin ligand binding and activation at the MC3-R and MC4-R and their effects on feeding. We have shown that alpha-MSH, desacetyl-alpha-MSH and beta-MSH bound to the MC3-R and MC4-R with similar affinity and stimulated cAMP with similar potency in HEK 293 cells transfected with MC3-R and MC4-R. In contrast gamma(2)-MSH showed selectivity for the MC3-R over the MC4-R both in binding affinity and cAMP stimulation. alpha-MSH and beta-MSH injected ICV into fasted rats at doses of 1, 3 and 6 nmol resulted in a decrease in food intake, (2 h food intake: alpha-MSH 6 nmol, 1.7+/-0.3 g; beta-MSH 6 nmol, 1.5+/-0.3 g vs. saline 6.0+/-0.5 g, P<0.001). Desacetyl alpha-MSH did not reduce food intake at low doses but was significant at 25 nmol (2 h food intake: desacetyl-alpha-MSH 6.1+/-1.0 g vs. saline 9.5+/-1.4 g, P<0.05). In contrast, gamma(2)-MSH had no effect on food intake when administered ICV to fasted rats. We were unable to establish a role for the MC3-R in feeding regulation. Our evidence, however, strengthens the hypothesis that the melanocortin's effects on food intake are mediated via the MC4-R.     

Cyclic Feeding Behaviour and Changes in Hypothalamic Galanin and Neuropeptide Y Gene Expression Induced by Zinc Deficiency in the Rat

Dietary zinc-deficiency induces a striking reduction and a cyclic pattern of food intake in rodents. To elucidate the mechanisms for these effects, we studied the hypothalamic content, synthesis, and distribution of galanin (GAL) and neuropeptide Y (NPY) during zinc deficiency and refeeding in the rat. In Wistar rats, three weeks of zinc-deprivation consistently induced a reduction and a cyclic pattern of night-and day-time food intake, as well as of water intake. This was accompanied in zinc-deficient (ZD) rats, and to a lesser extent in pair-fed (PF) rats, by a decrease of hypothalamic GAL mRNA concentration (CTR: 100±8, ZD: 61±4, PF: 78±2 arbitrary densitometric units, ADU, P<0.01) and an increase of hypothalamic NPY (CTR: 100±11, ZD: 154±10, PF: 126±4 ADU, P<0.05), without peptide modification. The two neuropeptidergic systems were not affected by the cycles of feeding, with the exception of the NPY-immunoreactivity in the suprachiasmatic nuclei (geniculo-hypothalamic tract), that was inversely correlated to the food intake in both ZD and PF animals. In a second experiment, we showed that zinc-repletion for 4 days suppressed the behaviour induced by a two-week zinc-deprivation, and reversed the increase of NPY mRNA in ZD animals. We finally demonstrated that zinc-deficiency induced a similar behaviour in Zucker rats. However, in these rats whose synthesis of NPY is constitutively up-regulated, no change of NPY synthesis was observed in ZD rats, suggesting that the increase observed in Wistar is adaptative rather than instrumental to the abnormal food intake. In conclusion, we have further characterized the cyclic feeding behaviour of the zinc-deficient Wistar rats, and shown in these animals a decreased activity of the GAL system and an increased activity of the NPY system, likely corresponding to a compensatory response of the two neuropeptidergic systems, as observed in food-deprived animals. As spontaneous food intake of ZD rats does not increase, a resistance to NPY could also be present. These behavioural and neuropeptidergic changes were partially reversed by reintroduction of zinc in the diet. In Zucker rats, the same behaviour occurred despite an insensitivity of the NPY system to the zinc-deficiency. In addition, we describe a nutritional regulation of the NPY-immunoreactivity in the geniculo-hypothalamic tract, that could constitute the substrate of circadian rhythm modulation by timed feeding.     

Estradiol decreases the orexigenic effect of neuropeptide Y, but not agouti-related protein, in ovariectomized rats

Available data suggest that estradiol exerts an inhibitory effect on food intake by modulating the actions of multiple gut- and brain-derived peptides implicated in the control of food intake. For example, recent studies have shown that estradiol decreases the orexigenic effects of ghrelin and melanin-concentrating hormone. In the present study, we examined estradiol's ability to decrease the actions of two additional orexigenic peptides, neuropeptide Y (NPY) and agouti-related protein (AgRP). Food intake was monitored following lateral ventricular infusions of 5 microg NPY, 10 microg AgRP, or saline vehicle in ovariectomized rats treated with either 1 microg estradiol or sesame oil vehicle. NPY increased food intake for 2h in both oil- and estradiol-treated ovariectomized rats. During this interval, the orexigenic effect of NPY was significantly greater in oil-treated rats, relative to estradiol-treated rats. In contrast to the short-term action of NPY, a single injection of AgRP increased food intake for 3 days in oil- and estradiol-treated rats. Meal pattern analysis revealed that the orexigenic effect of AgRP is mediated by an increase in meal size, not meal number. Unlike that observed following NPY treatment, estradiol failed to modulate the magnitude by which AgRP increased food intake and meal size. We conclude that a physiological regimen of estradiol treatment decreases the orexigenic effect of NPY, but not AgRP, in ovariectomized rats.     

Hypothalamic paraventricular nucleus injections of urocortin alter food intake and respiratory quotient

Corticotropin releasing hormone (CRH) acts on the central nervous system to alter energy balance and influence both food intake and sympathetically-mediated thermogenesis. CRH is also reported to inhibit food intake in several models of hyperphagia including neuropeptide Y (NPY)-induced eating. The recently identified CRH-related peptide, urocortin (UCN), also binds with high affinity to CRH receptor subtypes and decreases food intake in food-deprived and non-deprived rats. The present experiment characterized further the feeding and metabolic effects of UCN by examining its impact after direct injections into the paraventricular nucleus (PVN) of the hypothalamus. In feeding tests (n=8), UCN (50-200 pmol) was injected into the PVN at the onset of the dark cycle and food intake was measured 1, 2 and 4 h postinjection. In separate rats (n=8), the metabolic effects of UCN were monitored using an open circuit calorimeter which measured oxygen consumption (V(O2)) and carbon dioxide production (V(CO2)). Respiratory quotient (RQ) was calculated as V(CO2)/V(O2). UCN suppressed feeding at all times studied and reliably decreased RQ within 30 min of infusion. Additional work examined the effect of UCN (50-100 pmol) pretreatment on the feeding and metabolic effects of NPY. NPY, injected at the start of the dark period, reliably increased 2 h food intake. This effect was blocked by PVN UCN administration. Similarly, UCN blocked the increase in RQ elicited by NPY alone. These results suggest that UCN-sensitive mechanisms within the PVN may modulate food intake and energy substrate utilization, possibly through an interaction with hypothalamic NPY.     

Central neuropeptide Y infusion and melanocortin 4 receptor antagonism inhibit thyrotropic function by divergent pathways

Weight loss inhibits thyrotropic function and reduces metabolic rate, thereby contributing to weight regain. Under negative energy balance there is an increase in the hypothalamic expression of both neuropeptide Y (NPY) and agouti related peptide (AgRP), the endogenous antagonist of melanocortin 4 (MC4) receptors. Both NPY and MC4 receptor antagonism reduce thyrotropic function centrally, but it is not known whether these pathways operate by similar or distinct mechanisms. We compared the time-course of effects of acute or chronic intracerebroventricular (ICV) administration of NPY (1.2 nmol acute bolus, or 3.5 nmol/day for 6 days) or the MC4 receptor antagonist HS014 (1.5 nmol bolus, or 4.8 nmol/day) on plasma concentrations of thyroid stimulating hormone (TSH) or free thyroxine (T4) in male rats pair-fed with vehicle-infused controls. These doses equipotently induced hyperphagia in acute studies, reduced latency to feed, and increased white adipose tissue mass after 6 days of infusion. Acute central NPY but not HS014 administration significantly reduced plasma TSH concentrations within 30–60 min and plasma free T4 levels within 90–120 min. These inhibitory effects were sustained for up to 5–6 days of continuous NPY infusion. HS014 induced a transient decrease in plasma free T4 levels that was observed only after 1–2 days of continuous ICV infusion. While both NPY and HS014 significantly increased corticosteronemia within an hour after ICV injection, the effect of NPY was significantly more pronounced and was sustained for up to 4 days of administration. Both NPY and HS014 significantly decreased the brown adipose tissue protein levels of uncoupling protein-3. We conclude that central NPY and MC4 antagonism decrease thyrotropic function via partially distinct mechanisms with different time courses, possibly involving glucocorticoid effects of NPY. MC4 receptor antagonism increases adiposity via pathways independent of increased food intake or changes in circulating concentrations of TSH, free T4 or corticosterone.     

Rapid and localized alterations of neuropeptide Y in discrete hypothalamic nuclei with feeding status

Neuropeptide Y (NPY) is believed to regulate the normal eating behavior and body weight in rats via central mechanisms. We have investigated whether NPY, which stimulates food intake, may in turn be modified by the nutritional state of the animals. Thus the impact of food deprivation (FD) (48 h) and subsequent refeeding on the levels of NPY in discrete hypothalamic areas was examined in this study. The results showed site specific change in only 3 of 7 hypothalamic sites. A 5-fold increment in NPY was reported in the paraventricular nucleus (PVN) and a 10-fold increase was observed in the arcuate nucleus-median eminence (ARC-ME). While subsequent refeeding for 6 h reversed the effect of FD in the ARC-ME, the levels of NPY in the PVN remained high in the refed rats. The perifornical lateral hypothalamus displayed a different pattern, namely, a significant increase in NPY content in refed as compared to satiated and deprived rats. The NPY levels in 4 other hypothalamic sites, namely, the dorsomedian, ventromedian, supraoptic and suprachiasmatic nuclei, and two extrahypothalamic sites, namely caudate nucleus and nucleus accumbens, showed total resistance to any change following deprivation and refeeding. These data emphasize the important and specific role of the paraventricular and arcuate nuclei in NPY's regulation of food intake and provide support for the idea that the variations of hypothalamic NPY after food deprivation reflect a specific physiological response of feeding regulatory system to alterations in the animal nutritional state and body weight.     

Specific hypothalamic neuropeptide Y variation with diet parameters in rats with food choice.

Neuropeptide Y (NPY) preferentially stimulates carbohydrate intake rather than fat intake but there is no information on the effects of food choice on the concentration of NPY in the brain. We measured brain NPY concentrations in male adult rats that had to choose between a high fat and a high carbohydrate diet or were fed a control diet for 2 weeks. In rats with food choice, energy intake increased (+17%). NPY levels increased in the parvocellular part (PVNp) of the PVN and decreased in the lateral hypothalamus and were significantly correlated with the carbohydrate-to-fat energy ratio but not with total energy intake. This suggests that hypothalamic NPY might be involved in food choice and that PVNp is important in the regulation of feeding behaviour by NPY.     

Dipeptidyl peptidase IV (DPP4)-deficiency attenuates diet-induced obesity in rats: possible implications for the hypothalamic neuropeptidergic system

The underlying mechanisms controlling food intake and satiety are thoroughly controlled, but seem to be insufficient under conditions of almost unlimited food supply. Hence, overweight and obesity are serious problems especially in industrialized countries. To assess the possible influence of CD26, exerting a dipeptidyl peptidase activity (DPP4) cleaving several energy homeostasis-relevant peptides, we investigated wild type and DPP4-deficient dark agouti rats in a model of diet-induced obesity and found a reduced weight gain in DPP4-deficient rats. When investigating the specific increase of whole body fat volume by MRI to assess the distribution pattern (subcutaneous vs. intraabdominal), there was an altered ratio under dietary conditions only in DPP4-deficient rats, which was due to lower intraabdominal fat amounts. Furthermore, we investigated the number of cells immunopositive for the leptin receptor (OB-R), the orexigenic leptin antagonist neuropeptide Y (NPY), as well as of the NPY receptors Y1, Y2, and Y5 within hypothalamic nuclei. Independent from the body weight, higher levels of NPY and all receptors were expressed in DPP4-deficent rats. Under obese conditions, hypothalamic Y2-levels were reduced in both strains. Concerning NPY and Y1, there were partly oppositional effects, with reduced hypothalamic Y1 levels only in wild types, and increased NPY levels only in DPP4-deficient rats. These effects might be responsible for unaltered food intake in DPP4-deficent rats compared to wild types, despite reduced weight gain. However, since the food intake remained unaffected, these effects suggest that DPP4 exerts its effects on intraabdominal fat also via peripheral actions.     

Effects of dietary folic acid supplementation on cerebrovascular endothelial dysfunction in rats with induced hyperhomocysteinemia

The gram-negative bacteria-derived endotoxin lipopolysaccharide (LPS) is known to play an important role in immune and neurological manifestations during bacterial infections. In mammals, peripheral or brain administration of LPS induces anorexia and is thought to exert its effects through activation of pro-inflammatory cytokines. In this study, we investigated the effects of peripheral (intraperitoneal, IP) and central (intracerebroventricular, ICV) injections of LPS on food intake of goldfish. Fish treated IP with 10, 25, 50, 100 or 250 ng/g LPS or ICV with 1, 10 and 100 ng/g LPS showed a significant dose-dependent decrease in food intake, compared to the saline-treated fish. We also examined the brain mRNA expression of several hypothalamic appetite-related neuropeptides in response to the administration of LPS. IP injections of LPS (100 ng/g) induced a decrease in NPY expression and an increase in CCK, CRF and CART expression. These results indicate that LPS is a potent anorexigenic factor in goldfish and that this endotoxin induces a reduction in appetite, at least in part, by influencing gene expression of appetite-related neuropeptides.     

Neuropeptide Y antibody attenuates 2-deoxy-

Obese individuals often suffer from depression. The olfactory bulbectomy (OBX) model is an animal model of depression that produces behavioral, physiological, and neurochemical alterations resembling clinical depression. The OBX model was employed to assess depression-related changes in food intake in obesity-prone, Osborne–Mendel (OM) rats and obesity-resistant, S5B/Pl rats. OBX increased food intake in OM rats beginning 7 days following surgery, however, OBX did not alter food intake in S5B/Pl rats at any time point. Fourteen days following surgery, OBX significantly increased locomotor activity (total lines crossed and rears) in the openfield test in OM and S5B/Pl rats. Fifteen days following surgery, prepro-neuropeptide Y (NPY) mRNA levels were significantly increased in the hypothalamus of bulbectomized OM rats and in the medial nucleus of the amygdala of bulbectomized OM and S5B/Pl rats. OBX decreased NPY Y2 receptor mRNA levels in the hypothalamus and medial nucleus of the amygdala in OM rats, while increasing NPY Y2 receptor mRNA levels in the medial nucleus of the amygdala of S5B/Pl rats. These data indicate that though both obesity-prone and obesity-resistant strains were susceptible to the locomotor effects of OBX, food intake and hypothalamic prepro-NPY mRNA were only increased in OM rats. Therefore, strain specific alterations in hypothalamic NPY may account for increased food intake in the obesity-prone rats following OBX, and suggests a potential mechanism to explain the comorbidity of obesity and depression.     

Olfactory bulbectomy increases food intake and hypothalamic neuropeptide Y in obesity-prone but not obesity-resistant rats

Obese individuals often suffer from depression. The olfactory bulbectomy (OBX) model is an animal model of depression that produces behavioral, physiological, and neurochemical alterations resembling clinical depression. The OBX model was employed to assess depression-related changes in food intake in obesity-prone, Osborne–Mendel (OM) rats and obesity-resistant, S5B/Pl rats. OBX increased food intake in OM rats beginning 7 days following surgery, however, OBX did not alter food intake in S5B/Pl rats at any time point. Fourteen days following surgery, OBX significantly increased locomotor activity (total lines crossed and rears) in the openfield test in OM and S5B/Pl rats. Fifteen days following surgery, prepro-neuropeptide Y (NPY) mRNA levels were significantly increased in the hypothalamus of bulbectomized OM rats and in the medial nucleus of the amygdala of bulbectomized OM and S5B/Pl rats. OBX decreased NPY Y2 receptor mRNA levels in the hypothalamus and medial nucleus of the amygdala in OM rats, while increasing NPY Y2 receptor mRNA levels in the medial nucleus of the amygdala of S5B/Pl rats. These data indicate that though both obesity-prone and obesity-resistant strains were susceptible to the locomotor effects of OBX, food intake and hypothalamic prepro-NPY mRNA were only increased in OM rats. Therefore, strain specific alterations in hypothalamic NPY may account for increased food intake in the obesity-prone rats following OBX, and suggests a potential mechanism to explain the comorbidity of obesity and depression.     

Mapping of hypothalamic sites involved in the effects of NPY on body temperature and food intake

The objective of the present study was to identify hypothalamic sites that might be implicated in the effects of neuropeptide Y (NPY) on both body temperature and food intake. For this purpose, the effects of direct microinjections of NPY in several doses (0.156–20 μg) into discrete hypothalamic nuclei on body temperature were examined in rats. To examine specificity of effects, food consumption of animals following injections was also measured. Results indicate that the influence of NPY on body temperature varies with the hypothalamic region where the peptide is administered. NPY had no effect on temperature after administration into the ventromedial (VMH) and the perifornical hypothalamus (PeF). However, a significant hypothermia was seen following administration into the preoptic (POA) and arcuate nucleus (Arc), and hyperthermia was seen after injection into the paraventricular nucleus (PVN). Finally, a biphasic effect was observed after injection into the lateral hypothalamus (LH): hyperthermia with relatively small doses and hypothermia with higher doses. Similar effects were obtained when administred into the third ventricle (3V) but in an inverted dose-related fashion: hypothermia at low and hyperthermia at higher doses. For feeding, NPY consistently increased food intake in all regions examined, with the strongest effect obtained after administration into the PeF. The present results clearly dissociate the effects of NPY on food intake and body temperature, and demonstrate that these effects are related to specific hypothalamic nuclei.