Postnatal intracerebroventricular exposure to neuropeptide Y causes weight loss in female adult rats

We investigated the effect of repetitive postnatal (2-7 days) intracerebroventricular administration of neuropeptide Y (NPY) on food intake and body weight gain in the 3- to 120-day-old Sprague-Dawley rats. NPY caused a 32% transient increase in body weight gain with elevated circulating insulin concentrations within 24 h. This early intervention led to the persistence of hyperinsulinemia and relative hyperleptinemia with euglycemia in the 120-day-old female alone. This perturbation was associated with 50% suppression in adult female hypothalamic NPY concentrations and a 50-85% decline in NPY immunoreactivity in the paraventricular and arcuate nuclei. This change was paralleled by a approximately 20% decline in food intake and body weight gain at 60 and 120 days. However, when exogenous NPY was stereotaxically reinjected into the paraventricular nucleus of the approximately 120-day-old adult females who were pretreated with NPY postnatally, an increase in food intake and body weight gain was noted, attesting to no disruption in the NPY end-organ responsivity. We conclude that postnatal intracerebroventricular NPY has long-lasting effects that predetermine the resultant adult phenotype in a sex-specific manner.     

Implantation of fibre encapsulated RIN 1056a cells transfected with NPY cDNA into the lateral ventricle of rats alters body weight

Neuropeptide Y (NPY) is a hypothalamic neuropeptide thought to play an important role in the regulation of food intake and energy expenditure. Our aim was to over-express bioactive NPY in the lateral ventricle by implanting cells transfected with NPY cDNA. Cells from the RIN 1056a clonal rat islet cell line were transfected with NPY cDNA. Radioimmunoassay, chromatography and receptor binding assays were used to ensure the secreted NPY was bioactive, before and after implantation. NPY cDNA transfected and untransfected control cells were encapsulated in PVDF hollow fibres to prevent tumour formation and implanted into the lateral ventricle of male Wistar rats. The effects on body weight and food intake were measured for 15 days. Animals implanted with NPY cDNA transfected RIN 1056a cells showed a greater rise in body weight than controls. This difference was statistically significant five days after implantation, and remained so until the end of the experiment. Cumulative food intake was also increased in rats implanted with NPY cDNA transfected RIN 1056a cells, but this difference failed to reach statistical significance. We have demonstrated that implantation of NPY over-expressing cells into the lateral hypothalamus of rats increases body weight gain.     

Diltiazem enhances food intake and gastrointestinal function in rats

The present study was to investigate the effects of diltiazem, a ghrelin receptor agonist, on food intake and gastrointestinal functions in rats. Rats were intragastrically administered with diltiazem solution (daily 16 mg/kg, 30 mg/kg or 80 mg/kg, 30 d), and the rats with saline as control. To detect the effects of diltiazem on food intake and body weight, the average daily food intake and body weight were recorded, and the serum metabolic hormones of plasma growth hormone (GH) and neuropeptide Y (NPY) were tested by radioimmunoassay. By means of the spectrophotometer and the modified Mett's method, the effects of diltiazem on rat's gastrointestinal function and pepsin activity were tested, respectively. In addition, the gastric juice's acidity of rats was detected by titration and the secretion amount was calculated. The results showed that the food intake and body weight were maximally promoted by diltiazem at the dose of 30 mg/kg daily (30 d). The average daily food intake and body weight were significantly increased, and the serum concentrations of GH and NPY were also remarkably increased in diltiazem-treated groups compared with those in control group. The results also showed that the gastric emptying rate, gastric acid secretion and the activity of pepsin were significantly increased in diltiazem-treated group compared with those in control group. These results suggest that diltiazem induces enhancement of eating, in the same time, it can also stimulate the gastrointestinal function and regulate growth of rat.     

Hyperphagia and obesity in OLETF rats lacking CCK-1 receptors

The brain-gut peptide cholecystokinin (CCK) inhibits food intake following peripheral or site directed central administration. Peripheral exogenous CCK inhibits food intake by reducing the size and duration of a meal. Antagonist studies have demonstrated that the actions of the exogenous peptide mimic those of endogenous CCK. Antagonist administration results in increased meal size and meal duration. The feeding inhibitory actions of CCK are mediated through interactions with CCK-1 receptors. The recent identification of the Otsuka-Long-Evans-Tokushima Fatty (OLETF) rat as a spontaneous CCK-1 receptor knockout model has allowed a more comprehensive evaluation of the feeding actions of CCK. OLETF rats become obese and develop non-insulin dependent diabetes mellitus (NIDDM). Consistent with the absence of CCK-1 receptors, OLETF rats do not respond to exogenous CCK. OLETF rats are hyperphagic and their increased food intake is characterized by a large increase in meal size with a decrease in meal frequency that is not sufficient to compensate for the meal size increase. Deficits in meal size control are evident in OLETF rats as young as 2 days of age. OLETF obesity is secondary to the increased food intake. Pair feeding to amounts consumed by intact control rats normalizes body weight, body fat and elevated insulin and glucose levels. Hypothalamic arcuate nucleus peptide mRNA expression in OLETF rats is appropriate to their obesity and is normalized by pair feeding. In contrast, pair fed and young pre-obese OLETF rats have greatly elevated dorsomedial hypothalamic (DMH) neuropeptide Y (NPY) mRNA expression. Elevated DMH NPY in OLETF rats appears to be a consequence of the absence of CCK-1 receptors. In intact rats NPY and CCK-1 receptors colocalize to neurons within the compact subregion of the DMH and local CCK administration reduces food intake and decreases DMH NPY mRNA expression. We have proposed that the absence of DMH CCK-1 receptors significantly contributes to the OLETF's inability to compensate for their meal size control deficit leading to their overall hyperphagia. Access to a running wheel and the resulting exercise normalizes food intake and body weight in OLETF rats. When given access to running wheels for 6 weeks shortly after weaning, OLETF rats do not gain weight to the same degree as sedentary OLETF rats and do not develop NIDDM. Exercise also prevents elevated levels of DMH NPY mRNA expression, suggesting that exercise exerts an alternative, non-CCK mediated, control on DMH NPY. The OLETF rat is a valuable model for characterizing actions of CCK in energy balance and has provided novel insights into interactions between exercise and food intake.     

Postnatal glucocorticoid exposure alters the adult phenotype

We examined the effect of six doses of dexamethasone (Dex) administered daily (2-7 days of age) to postnatal rats on body weight gain, food and water intake, peripheral hormonal/metabolic milieu, and hypothalamic neuropeptides that regulate food intake. We observed a Dex-induced acute (3 days of age) suppression of endogenous corticosterone and an increase in circulating leptin concentrations that were associated with a decrease in body weight in males and females. Followup during the suckling, postsuckling, and adult stages (7-120 days of age) revealed hypoleptinemia in males and females, and hypoinsulinemia, a relative increase in the glucose-to-insulin ratio, and a larger increase in skeletal muscle glucose transporter (GLUT 4) concentrations predominantly in the males, reflective of a catabolic state associated with a persistent decrease in body weight gain. The increase in the glucose-to-insulin ratio and hyperglycemia was associated with an increase in water intake. In addition, the changes in the hormonal/metabolic milieu were associated with an increase in hypothalamic neuropeptide Y content in males and females during the suckling phase, which persisted only in the 120-day-old female with a transient postnatal decline in alpha-melanocyte-stimulating hormone and corticotropin-releasing factor. This increase in neuropeptide Y (NPY) during the suckling phase in males and females was associated with a subsequent increase in adult food intake that outweighed the demands of body weight gain. In contrast to the adult hypothalamic findings, cerebral ventricular dilatation was more prominent in adult males. We conclude that postnatal Dex treatment causes permanent sex-specific changes in the adult phenotype, setting the stage for future development of diabetes (increased glucose:insulin ratio), obesity (increased NPY and food intake), and neurological impairment (loss of cerebral volume).     

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.     

Does neuropeptide Y contribute to the anorectic action of amylin?

Neuropeptide Y (NPY) is a potent feeding stimulant acting at the level of the hypothalamus. Amylin, a peptide co-released with insulin from pancreatic beta cells, inhibits feeding following peripheral or central administration. However, the mechanism by which amylin exerts its anorectic effect is controversial. This study investigated the acute effect of amylin on food intake induced by NPY, and the effect of chronic amylin administration on food intake and body weight in male Sprague Dawley rats previously implanted with intracerebroventricular (icv) cannulae. Rats received 1 nmol NPY, followed by amylin (0.05, 0.1, 0.5 nmol) or 2 microl saline. Increasing doses of amylin resulted in a dose-dependent inhibition of NPY-induced feeding by 31%, 74% and 99%, respectively (P < 0.05). To determine the chronic effects of i.c.v. amylin administration on feeding, rats received 0.5 nmol amylin or saline daily, 30 min before dark phase, over 6 days. Amylin significantly reduced food intake at 1, 4, 16 and 24 hours; after 6 days, amylin-treated rats showed a significant reduction in body weight, having lost 17.3 +/- 6.1 g, while control animals gained 7.7 +/- 5.1 g (P < 0.05). Brain NPY concentrations were not elevated, despite the reduced food intake, suggesting amylin may regulate NPY production or release. Thus, amylin potently inhibits NPY-induced feeding and attenuates normal 24 hour food intake, leading to weight loss.     

Sustained NPY Overexpression in the PVN Results in Obesity via Temporarily Increasing Food Intake

Increasing neuropeptide Y (NPY) signaling in the paraventricular nucleus (PVN) by recombinant adeno‐associated virus (rAAV)‐mediated overexpression of NPY in rats, results in hyperphagia and obesity in rats. To determine the importance of hyperphagia in the observed obesity phenotype, we pair‐fed a group of AAV‐NPY‐injected rats to AAV‐control‐injected rats and compared parameters of energy balance to ad libitum fed AAV‐NPY‐injected rats. For 3 weeks, AAV‐NPY‐injected rats, received the same amount of food as ad libitum‐fed rats injected with control rAAV They did not gain more body weight than these controls. When allowed access to food ad libitum, these AAV‐NPY‐injected rats increased food intake, which subsequently decreased when rats reached the same body weight as AAV‐NPY‐injected rats that were fed ad libitum for the entire study. These data indicate that overexpression of NPY in the PVN results in obesity by increasing food intake until a certain body weight is achieved.     

Regulation of hypothalamic NPY by diet and smoking

Appetite is regulated by a number of hypothalamic neuropeptides including neuropeptide Y (NPY), a powerful feeding stimulator that responds to feeding status, and drugs such as nicotine and cannabis. There is debate regarding the extent of the influence of obesity on hypothalamic NPY. We measured hypothalamic NPY in male Sprague-Dawley rats after short or long term exposure to cafeteria-style high fat diet (32% energy as fat) or laboratory chow (12% fat). Caloric intake and body weight were increased in the high fat diet group, and brown fat and white fat masses were significantly increased after 2 weeks. Hypothalamic NPY concentration was only significantly decreased after long term consumption of the high fat diet. Nicotine decreases food intake and body weight, with conflicting effects on hypothalamic NPY reported. Body weight, plasma hormones and brain NPY were investigated in male Balb/c mice exposed to cigarette smoke for 4 days, 4 and 12 weeks. Food intake was significantly decreased by smoke exposure (2.32+/-0.03g/24h versus 2.71+/-0.04g/24h in control mice (non-smoke exposed) at 12 weeks). Relative to control mice, smoke exposure led to greater weight loss, while pair-feeding the equivalent amount of chow caused an intermediate weight loss. Chronic smoke exposure, but not pair-feeding, was associated with decreased hypothalamic NPY concentration, suggesting an inhibitory effect of cigarette smoking on brain NPY levels. Thus, consumption of a high fat diet and smoke exposure reprogram hypothalamic NPY. Reduced NPY may contribute to the anorexic effect of smoke exposure.     

Chronic neuropeptide Y infusion during lactation suppresses pup growth and reduces the length of lactational infertility in rats

In lactating rats, food restriction potentiates the already high levels of hypothalamic neuropeptide Y (NPY). To investigate the role that high levels of NPY might play in the prolongation of lactational infertility that typically accompanies a food restricted lactation we investigated the effects of chronic central infusions of NPY in ad libitum-fed lactating females. First, we compared the effects of intracerebroventricular (icv) infusion of NPY from Days 12-19 postpartum at a dose of 14.4 microg/day with a similar treatment in nonlactating females. In subsequent experiments we examined the effects of NPY infusions into the lateral ventricle at doses of 6 or 20 mug/day or unilaterally into the medial preoptic area at a dose of 1 microg/day from either Days 12-19 or 7-21 postpartum. Effects on food intake; female body weight; and, where appropriate, litter weight and length of lactational diestrus were compared between NPY and vehicle-treated females. As expected NPY infusion produced a robust increase in body weight and food intake in nonlactating females that was accompanied by a suppression of cyclicity. By contrast NPY treatment in lactating rats resulted in a marked decrease in litter growth and an earlier termination of lactational diestrus.     

The hypothalamic paraventricular nucleus is not essential for orexigenic NPY or anorexigenic melanocortin action

Bilateral electrolytic lesions of the paraventricular nucleus of the hypothalamus (PVN) produce hyperphagia with excess weight gain. The orexigenic neuropeptide Y (NPY) system and the anorexigenic melanocortin system act in the PVN to regulate food intake, and participate in mediating the anorexic effects of leptin. We hypothesized that changes in the responsiveness of these systems may contribute to the hyperphagia observed in PVN-lesioned rats. Adult female Sprague-Dawley rats received either sham or electrolytic lesions in the PVN immediately followed by implantation of a guide cannula into the third cerebroventricle. Twenty-five days following surgery groups of sham and hyperphagic PVN-lesioned rats were injected intracerebroventricularly (i.c.v.) with either 118 pmole or 470 pmole of NPY and food intake was measured for 3 h. Food intake in response to NPY was nearly three-fold higher in PVN-lesioned rats as compared to sham rats. However, the response to 5 microg leptin i.c.v. was not different in lesioned versus sham rats. The effect of the melanocortin agonist MTII on food intake was tested in additional rats beginning either 7-14 days or 30-40 days following surgery. Doses of 0.1 nmole or 1.0 nmole of MTII were injected immediately before lights-off and food intake was measured at 2 h, 24 h and 48 h post-injection. Suppression of food intake in PVN-lesioned rats was not different from that in sham-lesioned rats. These data suggest that hyper-responsiveness to NPY may account in part for the hyperphagia observed in PVN-lesioned rats. Furthermore, based on the similarities of responses of PVN-lesioned and sham control rats to the anorexigenic agents MTII and leptin and the hypersensitivity of lesioned rats to NPY, we conclude that the PVN is not essential for NPY stimulation of food intake or for melanocortin suppression of food intake and that NPY and melanocortin receptors outside of the PVN are sufficient to produce these effects.     

Reduced feeding response to neuropeptide Y in senescent Fischer 344 rats

The anorexia of aging syndrome in humans is characterized by spontaneous body weight loss reflecting diminished food intake. We reported previously that old rats undergoing a similar phenomenon of progressive weight loss (i.e., senescent rats) also display altered feeding behavior, including reduced meal size and duration. Here, we tested the hypothesis that blunted responsiveness to neuropeptide Y (NPY), a feeding stimulant, occurs concurrently with senescence-associated anorexia/hypophagia. Young (8 mo old, n = 9) and old (24-30 mo old, n = 11) male Fischer 344 rats received intracerebroventricular NPY or artificial cerbrospinal fluid injections. In response to a maximum effective NPY dose (10 microg), the net increase in size of the first meal after injection was similar in old weight-stable (presenescent) and young rats (10.85 +/- 1.73 and 12.63 +/- 2.52 g/kg body wt (0.67), respectively). In contrast, senescent rats that had spontaneously lost approximately 10% of body weight had significantly lower net increases at their first post-NPY meal (1.33 +/- 0.33 g/kg body wt (0.67)) than before they began losing weight. Thus altered feeding responses to NPY occur in aging rats concomitantly with spontaneous decrements in food intake and body weight near the end of life.     

Neuropeptide Y effect on food intake in broiler and layer chicks

Broiler chicks eat more food than layer chicks. In this study, we examined the involvement of orexigenic peptide neuropeptide Y (NPY) in the difference in food intake between broiler and layer chicks (Gallus gallus). First, we compared the hypothalamic mRNA levels of NPY and its receptors (Y1 and Y5 receptors) between these strains at 1, 2, 4, and 8 days of age. Daily food intake was significantly higher in broiler chicks than layer chicks after 2 days of age. However, the hypothalamic NPY mRNA level was significantly lower in broiler chicks than layer chicks except at 8 days of age. In addition, the mRNA levels of NPY receptors were also significantly lower in broiler chicks than layer chicks at 2 and 4 days of age (Y1 receptor) or 2 days of age (Y5 receptor). These results suggest that the differences in the expressions of hypothalamic NPY and its receptors do not cause the increase in food intake in broiler chicks. To compare the orexigenic effect of NPY between broiler and layer chicks, we next examined the effects of central administration of NPY on food intake in these strains. In both strains, central administration of NPY significantly increased food intake at 2, 4 and 8 days of age. All our findings demonstrated that the increase in food intake in broiler chicks is not accompanied with the over-expression of NPY or its receptor.     

AAV mediated expression of anti-sense neuropeptide Y cRNA in the arcuate nucleus of rats results in decreased weight gain and food intake

Neuropeptide Y (NPY) is the most potent stimulant of feeding when administered by intracerebroventricular injection. Despite this, there is conflicting evidence as to its importance in the regulation of daily food intake and energy balance. It has been suggested that whilst it is important in the response to starvation it has little role in the regulation of daily food intake. To investigate the role of NPY in the regulation of food intake, anti-sense cRNA to NPY was expressed in the arcuate nucleus of adult male rats. The anti-sense NPY (AS-NPY) construct was initially tested in vitro and there was a decrease of approximately 50% in NPY release from anti-sense treated cells compared to controls (16.3 +/- 2.0 fmol/L [AS-NPY] vs 37.3 +/- 7.7 fmol/L [control], mean +/- SEM p < 0.05). NPY release from hypothalamic explants from anti-sense injected animals was decreased by over 50% compared to those from controls at both 15 and 20 days after AAV injection (15 days 42% +/- 6.5% [AS-NPY] vs 100% +/- 36% [control], 20 days 41% +/- 6% [AS-NPY] vs 100% +/- 27% [control] mean+/-SEM, p < 0.05). In a study lasting for 50 days, weight gain was significantly lower in anti-sense injected animals from day 16 (day 16: 6.25 +/- 1.10 g [AS-NPY] vs 9.42 +/- 0.65 g [control] mean +/- SEM, p < 0.05) and remained so until the end of the study when they had gained approximately 40% less weight than controls (day 50: 52.0 +/- 9.6 g [AS-NPY] vs 82.0 +/- 6.3 g [control] mean +/- SEM, p < 0.01). Cumulative food intake was significantly lower in the anti-sense injected animals from day 23 (day 23: 225.8 +/- 1.9 g [AS-NPY] vs 250.6 +/- 8.7 g [control], mean +/- SEM, p < 0.05) and remained so until the end of the study (day 50: 834.5 +/- 14.8 g [AS-NPY] vs 926.0 +/- 31.7 g [control], mean +/- SEM, p < 0.05). Similarly mean daily food intake was also reduced in the anti-sense injected animals (days 7-14: 24.9 +/- 0.4 g/day [AS-NPY] vs 27.2 +/- 0.4 g/day [control], mean +/- SEM, p < 0.01). These data are supportive of a role for NPY in the regulation of daily food intake as well as in response to starvation.     

Leptin sensitive neurons in the hypothalamus.

A major paradigm in the field of obesity research is the existence of an adipose tissue-brain endocrine axis for the regulation of body weight. Leptin, the peptide mediator of this axis, is secreted by adipose cells. It lowers food intake and body weight by acting in the hypothalamus, a region expressing an abundance of leptin receptors and a variety of neuropeptides that influence food intake and energy balance. Among the most promising candidates for leptin-sensitive cells in the hypothalamus are arcuate nucleus neurons that co-express the anabolic neuropeptides, neuropeptide Y (NPY) and agouti-related peptide (AGRP), and those that express proopiomelanocortin (POMC), the precursor of the catabolic peptide, alphaMSH. These cell types contain mRNA encoding leptin receptors and show changes in neuropeptide gene expression in response to changes in food intake and circulating leptin levels. Decreased leptin signaling in the arcuate nucleus is hypothesized to increase the expression of NPY and AGRP. Levels of leptin receptor mRNA and leptin binding are increased in the arcuate nucleus during fasting, principally in NPY/AGRP neurons. These findings suggest that changes in leptin receptor expression in the arcuate nucleus are inversely associated with changes in leptin signaling, and that the arcuate nucleus is an important target of leptin action in the brain.     

Leptin treatment during the neonatal period is associated with higher food intake and adult body weight in rats.

For this study, we have determined the effects of neonatal leptin treatment on the evolution of body weight. Experiment 1: pups were divided into two groups: LepF - injected with leptin (8 micro g/100 g of body weight) for the first 10 days of lactation and control (C) - receiving saline. Experiment 2: pups were divided into two groups: LepL - injected with the same leptin concentration of experiment one for the last 10 days of lactation, and C, which received saline. Body weight and food intake were monitored until age 150 days, after which leptin concentrations were measured by ELISA. The LepF group had a significant increase in body weight (p < 0.05) from day 98 onward, in food intake (p < 0.05) from day 74 onward, and higher serum leptin concentration compared to the control (108 %, p < 0.05). The LepL group had a significant increase in body weight (p < 0.05) from day 113 onward, in food intake from day 121 onward (p < 0.001), and higher serum leptin concentration compared to controls (6.9 %, p < 0.05). These results suggest that both periods of lactation constituted a critical window for body weight and food intake programming, but the effects are more marked when the leptin is injected within the first ten days.     

Electroacupuncture suppresses expression of gastric ghrelin and hypothalamic NPY in chronic food restricted rats

Electroacupuncture (EA) has been reported to reduce body weight in overweight subjects in clinical practice, as well as in rats and mice with diet-induced obesity. In the present study, this effect of EA was tested in lean rats subjected to long-term food restriction (FR, food was offered only 1 h/day). Two hertz EA administered once every other day produced a further reduction in body weight in FR rats. Exploration of the mechanism involved revealed significant downregulation of the orexigenic peptides: ghrelin in the stomach, and neuropeptide Y (NPY) but not Agouti-related peptide (AgRP) in the hypothalamus, which was in line with the reduction in food intake in rats receiving EA stimulation as compared with those receiving restraint only. Uncoupling protein 3 (UCP3), involved in accelerating energy expenditure, was not significantly altered. These results suggest that the EA-induced body weight reduction was due mainly to a decrease in food intake rather than an increase in energy expenditure. A reduction in the orexigenic peptides ghrelin and NPY may be involved in the underlying mechanism.     

Reduced feeding response to muscimol and neuropeptide Y in senescent F344 rats

Many mammals experience spontaneous declines in their food intake and body weight near the end of life, a stage we refer to as senescence. We have previously demonstrated that senescent rats have blunted food intake responses to intracerebroventricular injections of neuropeptide Y (NPY). In the present study, we tested the hypothesis that responsiveness to GABA, a putative potentiator of NPY's effect, is also diminished. Young and old male F344 rats received injections of NPY, muscimol, (MUS, a GABA-A receptor agonist), combinations of these two agents, and vehicle [artificial cerebrospinal fluid (aCSF)] into the hypothalamic paraventricular nucleus (PVN). Both young and old presenescent rats increased their food intake in response to NPY, MUS, and the combination of the two (in comparison to injections of aCSF). The combination treatment was generally more effective than either NPY or MUS alone. These data are consistent with suggestions that both NPY and GABA play a role in the regulation of feeding behavior. Senescent rats exhibited an attenuated NPY-induced food intake, no increase in response to MUS, and a response to NPY + MUS that was no larger than that of NPY alone. We conclude that PVN injections of GABA, as well as NPY, are less effective in stimulating feeding in senescent rats and suggest that alterations in their signaling pathways play a role in the involuntary feeding decrease seen near the end of life.     

Decreased orexigenic response to neuropeptide Y in rats with obstructive cholestasis

Neuropeptide Y (NPY) is a key factor in the neurochemical control of food intake, and obstructive cholestasis can be associated with disturbances in food intake. Our aim in this study was to determine whether obstructive cholestasis in the rat is associated with defective central responsiveness to NPY. Cholestasis was induced in rats by surgical bile duct resection. Rats with obstructive cholestasis exhibited a 20% reduction in food intake 2 days after laparotomy (compared with sham-resected controls) that had resolved by 4 days after surgery. Responsiveness to the orexigenic action of NPY was tested by measuring food intake after intracerebroventricular injection of NPY. In sham-resected rats, NPY infusion strikingly increased food intake, whereas bile duct-resected (BDR) rats showed a consistent significantly impaired feeding response to NPY at postlaparotomy days 2, 4, and 7. Separate experiments measured specific binding of [(3)H]NPY to hypothalamic receptors. Fos protein expression was measured in the hypothalamic paraventricular nucleus (PVN) as a marker of NPY-induced neuronal activation. The decreased orexigenic responsiveness to NPY was not caused by altered NPY binding at hypothalamic receptors or its ability to activate neurons in the PVN. Therefore, cholestatic rats demonstrate an attenuated NPY-induced orexigenic drive that occurs early after biliary obstruction, when cholestatic rats exhibit reduced food intake, and persists despite the return of food intake to normal levels and the presence of intact central NPY-related neuronal pathways.