NPY Y1 receptor is involved in ghrelin- and fasting-induced increases in foraging, food hoarding, and food intake

Fasting triggers a constellation of physiological and behavioral changes, including increases in peripherally produced ghrelin and centrally produced hypothalamic neuropeptide Y (NPY). Refeeding stimulates food intake in most species; however, hamsters primarily increase foraging and food hoarding with smaller increases in food intake. Fasting-induced increases in foraging and food hoarding in Siberian hamsters are mimicked by peripheral ghrelin, central NPY, and NPY Y1 receptor agonist injections. Because fasting stimulates ghrelin and subsequently NPY synthesis/release, it may be that fasting-induced increased hoarding is mediated by NPY Y1 receptor activation. Therefore, we asked: Can an Y1 receptor antagonist block fasting- or ghrelin-induced increases in foraging, food hoarding, and food intake? This was accomplished by injecting the NPY Y1 receptor antagonist 1229U91 intracerebroventricularly in hamsters fasted, fed, or given peripheral ghrelin injections and housed in a running wheel-based food delivery foraging system coupled with simulated-burrow housing. Three foraging conditions were used: 1) no running wheel access, free food, 2) running wheel access, free food, or 3) foraging requirement (10 revolutions/pellet) for food. Fasting was a more potent stimulator of foraging and food hoarding than ghrelin. Concurrent injections of 1229U91 completely blocked fasting- and ghrelin-induced increased foraging and food intake and attenuated, but did not always completely block, fasting- and ghrelin-induced increases in food hoarding. Collectively, these data suggest that the NPY Y1 receptor is important for the effects of ghrelin- and fasting-induced increases in foraging and food intake, but other NPY receptors and/or other neurochemical systems are involved in increases in food hoarding.     

Unchanged hypothalamic neuropeptide Y concentrations in hyperphagic, hypoglycemic rats: evidence for specific metabolic regulation of hypothalamic NPY

Hypothalamic concentrations of neuropeptide Y (NPY), a potent central appetite stimulant, increase dramatically in food-restricted and insulin-deficient diabetic rats. This suggest that NPY may drive hyperphagia in these conditions, which are characterized by weight loss and insulin deficiency. To test the hypothesis that insulin deficiency and weight loss are specific stimuli to hypothalamic NPY, we measured NPY concentrations in individual hypothalamic regions in rats with hyperphagia caused by insulin-induced hypoglycemia. Groups of 8 male Wistar rats were injected with ultralente insulin (20-60 U/kg) to induce either acute hypoglycemia (7 h after a single injection) or chronic hypoglycemia (8 days with daily injections). In hypoglycemic rats, plasma insulin concentrations were increased 6- to 7-fold compared with saline-injected controls; food intake was significantly increased with acute and chronic hypoglycemia and weight gain was significantly increased in the chronically hypoglycemic group. NPY concentrations were measured by radioimmunoassay in 8 hypothalamic regions microdissected from fresh brain slices. NPY concentrations were not increased in any region in either acute or chronic hypoglycemia. NPY therefore seems unlikely to mediate hyperphagia in hyperinsulinemia-induced hypoglycemia, supporting the hypothesis that weight loss is a specific stimulus to hypothalamic NPY and that insulin deficiency may be the metabolic signal responsible.     

Hypothalamic neuropeptide Y disturbances in the obese (cp/cp) JCR:LA corpulent rat.

Regional hypothalamic neuropeptide Y (NPY) concentrations were compared between cp/cp JCR:LA corpulent rats, which were grossly obese, hyperphagic, and hyperinsulinemic, and lean (+/+) controls. In freely fed cp/cp rats, NPY levels in the arcuate nucleus (ARC) were 31% higher than in lean rats (p less than 0.001). In lean rats, chronic food restriction significantly raised NPY levels by 22% in the ARC (p less than 0.05) and by 44% in the dorsomedial nucleus (DMH; p less than 0.05). By contrast, food-restricted cp/cp rats showed no change in the ARC, but NPY levels rose in the DMH (by 36%; p less than 0.05) and ventromedial nucleus (31%; p less than 0.05). Increased NPY levels in the ARC, the major site of hypothalamic NPY synthesis, suggests increased NPYergic activity in cp/cp rats; given the central actions of NPY, this could contribute to hyperphagia, obesity, and hyperinsulinemia in this syndrome. Abnormal NPY responses to food deprivation further suggest dysregulation of NPY in cp/cp rats.     

Hypothalamic neuropeptide Y receptor characteristics and NPY-induced feeding responses in lean and obese Zucker rats.

Increased hypothalamic neuropeptide Y levels have previously been demonstrated in several hypothalamic nuclei of the (fa/fa) Zucker rat. This study set out to characterise hypothalamic NPY receptors in both genotypres and to study the effect of exogenous NPY on feeding behavior in these rats. Spontaneous daytime food intake was raised in the obese rat (p less than 0.05). Total hypothalamic receptor density (Bmax) was reduced in the obese rat compared with the lean rat (by 56%, p less than 0.005), but affinity remained unaltered. The lowest dose of NPY tested (23.5 pmol) stimulated daytime feeding in lean rats after 1, 2 and 3 hours but was inaffective in the obese rat (p less than 0.05). At two higher doses (235 pmol and 2.35 nmol), NPY was equipotent in both genotypes over 1 and 2 hours but NPY-induced feeding was attenuated over 3 hours in the obese rat. These results suggest an overactive endogenous NPYergic system in the obese (fa/fa) rat which might contribute to hyperphagia and obesity in this strain.     

Diazoxide effects on hypothalamic and extra-hypothalamic NPY content in Zucker rats

To determine if the anorectic effects of the insulin antagonist diazoxide (DZ) are mediated by reduced central neuropeptide Y (NPY), female Zucker rats, given DZ (150 mg/kg/day) or placebo for about four weeks, were sacrificed following overnight fasting or free feeding. Several hypothalamic and extra-hypothalamic nuclei were extracted for NPY content. DZ reduced weight gain in obese rats and lowered glucose of lean and obese rats without affecting insulin. Contrary to the hypothesis, DZ increased NPY in hypothalamic nuclei of free fed lean and obese rats. DZ elevated hypothalamic NPY levels in fasted obese rats and had more diverse effects in extra-hypothalamic nuclei of lean rats.     

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.     

The regulation of hepatic stearoyl-coenzyme A desaturase in obese-hyperglycaemic (ob/ob) mice by food intake and the fatty acid composition of the diet.

1. The effects of food intake and the fatty acid composition of the diet on the hepatic stearoyl-CoA desaturase activity of obese-hyperglycaemic (ob/ob) mice were investigated. 2. Obese mice fed on a commercial mouse diet, ad libitum, had 6.5-fold more activity per liver cell than had lean mice. 3. On a diet containing 14% corn oil the activity was 65% less in obese mice and 62% less in lean mice compared with animals fed on the commercial diet. 4. Feeding with 14% saturated fat in the diet doubled the activity in lean mice compared with those on the commercial diet, but had no effect on the activity in obese mice. 5. Obese mice fed on the corn-oil diet contained a higher proportion of linoleic acid in the liver lipids than did lean mice fed on the commercial diet, but the acyl-CoA desaturase activity was 125% higher than in the lean mice. 6. Limiting the food intake of obese mice by pair-feeding with lean mice decreased their acyl-CoA desaturase activity when the animals were fed on the saturated-fat diet, but the activity remained 75% higher than in lean mice, whereas in obese mice pair-fed on the corn-oil diet the activity was the same as in lean mice. 7. During starvation the acyl-CoA desaturase activity in livers from obese mice decreased more slowly and proportionately less than in livers from lean mice. 8. It is concluded that increased substrate supply as a result of hyperphagia and not low concentration of linoleic acid is the main factor causing high acyl-CoA desaturase activity in obese mice.     

Unexpected regulation of hypothalamic neuropeptide Y by food deprivation and refeeding in the Zucker rat.

Neuropeptide Y strongly stimulates food intake when it is injected in the hypothalamic paraventricular (PVN) and ventromedian (VMN) nuclei. In Sprague-Dawley (SD) rats, NPY synthesis in the arcuate nucleus (ARC) is increased by food deprivation and is normalized by refeeding. We have previously shown that the obese hyperphagic Zucker rat is characterized by higher NPY concentrations in this nucleus. NPY might therefore play an important role in the development of hyperphagia. The aim of the present study was to determine if the regulation by the feeding state works in the obese Zucker rat. For this purpose, 10 weeks-old male lean (n = 30) and obese (n = 30) Zucker rats were either fed ad libitum, either food-deprived (FD) for 48 hours or food-deprived for 48 h and refed (RF) for 6 hours. NPY was measured in several microdissected brain areas involved in the regulation of feeding behavior. NPY concentrations in the ARC was about 50% greater in obese rats than in lean rats (p less than 0.02) whatever the feeding state. In the VMN, NPY concentrations were higher in the lean FD rats than in the obese FD rat (p less than 0.001). Food deprivation or refeeding did not modify NPY in the ARC, in the VMN or in the dorsomedian nucleus whatever the genotype considered. On the other hand, food deprivation induced a significant decrease in NPY concentrations in the PVN of lean rats. This decrease was localized in the parvocellular part of this nucleus (43.0 +/- 1.9 (FD) vs 54.2 +/- 2.1 (Ad lib) ng/mg protein; p less than 0.005). Ad lib levels were restored by 6 hours of refeeding. These variations were not observed in the obese rat. The regulation of NPY by the feeding state in the Zucker rat was therefore very different from that described in the SD rats. Strain or age of the animals used might explain these differences. High NPY levels and absence of regulation in obese Zucker rats could contribute to the abnormal feeding behavior of these rats.     

A role for NPY overexpression in the dorsomedial hypothalamus in hyperphagia and obesity of OLETF rats

Otsuka Long-Evans Tokushima Fatty (OLETF) rats lacking CCK-A receptors are hyperphagic, obese, and diabetic. We have previously demonstrated that these rats have a peripheral satiety deficit resulting in increased meal size. To examine the potential role of hypothalamic pathways in the hyperphagia and obesity of OLETF rats, we compared patterns of hypothalamic neuropeptide Y (NPY), proopiomelanocortin (POMC), and leptin receptor mRNA expression in ad libitum-fed Long-Evans Tokushima (LETO) and OLETF rats and food-restricted OLETF rats that were pair-fed to the intake of LETO controls. Pair feeding OLETF rats prevented their increased body weight and elevated levels of plasma insulin and leptin and normalized their elevated POMC and decreased NPY mRNA expression in the arcuate nucleus. In contrast, NPY expression was upregulated in the dorsomedial hypothalamus (DMH) in pair-fed OLETF rats. A similar DMH NPY overexpression was evident in 5-wk-old preobese OLETF rats. These findings suggest a role for DMH NPY upregulation in the etiology of OLETF hyperphagia and obesity.     

Triiodothyronine (T3) stimulates food intake via enhanced hypothalamic AMP-activated kinase activity

Thyroid hormone regulates food intake. We previously reported that rats with triiodothyronine (T3)-induced thyrotoxicosis display hyperphagia associated with suppressed circulating leptin levels, increased hypothalamic neuropeptide Y (NPY) mRNA and decreased hypothalamic pro-opiomelanocortin (POMC) mRNA. AMP-activated kinase (AMPK) is a serine/threonine protein kinase that is activated when cellular energy is depleted. We hypothesized that T3 causes an increase in hypothalamic AMPK activity, which in turn contributes to the development of T3-induced hyperphagia. Rats that were given s.c. injections of T3 (4.5 nmol/kg) had increased food intake 2 h later without alterations in NPY and POMC mRNA levels, but with increased hypothalamic phosphorylated AMPK (169%) and phosphorylated acetyl-CoA carboxylase (194%). To determine the more chronic effects of T3, rats were given 6 daily s.c. injection of T3 or the vehicle. Food intake was significantly increased. Multiple T3 injections increased hypothalamic phosphorylated AMPK (278%) and phosphorylated acetyl-CoA carboxylase (335%) compared to the controls. Intracerebroventricular administration of compound C, an AMPK inhibitor, blocked the food intake induced by a single or multiple injections of T3. Taken together, these results suggest that enhanced hypothalamic AMPK phosphorylation contributes to T3-induced hyperphagia. Hypothalamic AMPK plays an important role in the regulation of food intake and body weight.     

CRH and NPY are not decreased in hypophagic, protein-deprived rats

To test if elevated CRH and decreased NPY might account for pituitary-adrenal activity and hypophagia in dietary protein deprivation, rats received normal or protein-free diet, or were food-or weight-restricted to match effects of protein deprivation. Protein or food restriction increased plasma ACTH. However, hypothalamic CRH mRNA was unchanged by protein deficiency and significantly decreased by food restriction when protein intake was > 50% of normal. Arcuate nucleus NPY mRNA increased in rats given protein-free diet, correlating with leptin rather than decreased feeding. We conclude that CRH and NPY gene expression does not explain adrenocortical axis or feeding activity in protein-deprived rats.     

Differential Responses of Orexigenic Neuropeptides to Fasting in Offspring of Obese Mothers

Maternal obesity due to long‐term high‐fat diet (HFD) consumption leads to faster growth in offspring during suckling, and increased adiposity at 20 days of age. Decreased expression of the orexigenic neuropeptide Y (NPY) and increased anorexigenic proopiomelanocortin (POMC) mRNA expression were observed in the fed state. However, hunger is the major drive to eat and hypothalamic appetite regulators change in response to meals. Therefore, it is important to compare both satiated and fasting states. Female Sprague–Dawley rats (8 weeks old) were fed a cafeteria‐style HFD (15.33 kJ/g) or chow for 5 weeks before mating, with the same diet continuing throughout gestation and lactation. At postnatal day 20, male pups were killed either after overnight fasting or in the fed state. Pups from obese dams were hyperphagic during both pre‐ and postweaning periods. Pups from obese dams had higher hypothalamic mRNA expression of POMC and NPY Y1 receptor, but lower hypothalamic melanocortin‐4 receptor (MC4R) and its downstream target single‐minded gene 1 (Sim1), in the fed state. Overnight fasting reduced circulating glucose, insulin, and leptin and increased hypothalamic NPY Y1 receptor mRNA in pups from both lean and obese dams. Hypothalamic NPY and agouti‐related protein (AgRP) were only increased by fasting in pups from obese dams; reductions in MC4R and Sim1 were only seen in pups from lean dams. At weaning, the suppressed orexigenic signals in offspring from obese dams were normalized after overnight fasting, although anorexigenic signaling appeared impaired in these animals. This may contribute to their hyperphagia and faster growth.     

Insulin deficiency is a specific stimulus to hypothalamic neuropeptide Y: a comparison of the effects of insulin replacement and food restriction in streptozocin-diabetic rats.

Untreated insulin-deficient diabetes causes hyperphagia and neuroendocrine disturbances that may be partly mediated by increased hypothalamic activity of neuropeptide Y (NPY), a potent central appetite stimulant. The metabolic signal that stimulates hypothalamic NPY is unknown. This study aimed to determine whether insulin deficiency or hyperglycemia was responsible. Regional hypothalamic NPY concentrations were compared in streptozocin-diabetic (STZ-D) rats rendered nearly normoglycemic by either insulin replacement or food restriction. Untreated STZ-D rats were hyperphagic and showed significantly increased (p less than 0.01) hypothalamic NPY concentrations in the arcuate nucleus and lateral hypothalamic area. Once-daily ultralente insulin injections corrected hypoinsulinemia and hyperglycemia, abolished hyperphagia, and normalized NPY concentrations in all hypothalamic regions. By contrast, food restriction effectively lowered glycemia without raising insulin levels. In these underfed diabetic rats, NPY concentrations rose further and were significantly higher than nondiabetic and untreated diabetic levels in most hypothalamic regions. We conclude that insulin deficiency is a major stimulus to hypothalamic NPY in STZ-D, whereas hyperglycemia may exert an inhibitory influence. These findings support the hypothesis that hypothalamic NPY responds to specific metabolic cues and is involved in regulating energy balance and conserving body weight.     

Adaptive responses in hypothalamic neuropeptide Y in the face of prolonged high-fat feeding in the rat

While a dysregulation in neuropeptide Y (NPY) signaling has been described in rodent models of obesity, few studies have investigated the time-course of changes in NPY content and responsiveness during development of diet-induced obesity. Therefore we investigated the effect of differing lengths (2-17 weeks) of high-fat diet on hypothalamic NPY peptide content, release and NPY-induced hyperphagia. Male Sprague-Dawley rats (211 +/- 3 g) were fed either a high-fat diet (30% fat) or laboratory chow (5% fat). Animals were implanted with intracerebroventricular cannulae to investigate feeding responses to NPY (0.5 nmol, 1 nmol) after 4 or 12 weeks of diet. At the earlier stage of obesity, NPY-induced hyperphagia was not altered; however, animals maintained on the high-fat diet for the longer duration were hyper-responsive to NPY, compared to chow-fed control rats (p < 0.05). Overall, hypothalamic NPY peptide content tended to be decreased from 9 to 17 weeks of diet (p < 0.05). Total hypothalamic NPY content was negatively correlated with plasma leptin concentration (p < 0.05), suggesting the hypothalamic NPY system remains responsive to leptin's inhibitory signal. In addition, hypothalamic NPY overflow was significantly reduced in high-fat fed animals (p < 0.05). Together these results suggest a reduction in hypothalamic NPY activity in high-fat fed animals, perhaps in an attempt to restore energy balance.     

Effects of intracerebroventricular administration of the NPY-Y1 receptor antagonist, 1229U91, on hyperphagic and glycemic responses to acute and chronic intermediate insulin-induced hypoglycemia in female rats

Neuropeptide Y (NPY) Y1 receptors are implicated in CNS regulation of food intake, but their role in hypoglycemic hyperphagia remains unclear. The present studies utilized a pharmacological approach to investigate the hypothesis that NPY acts via Y1 receptor-dependent mechanisms to regulate feeding and blood glucose profiles during intermediate insulin-induced hypoglycemia. Groups of ovariectomized, estradiol benzoate-treated female rats were injected subcutaneously with one or four doses of neutral protamine Hagedorn insulin (NPH), on as many days, or with diluent alone. Before final treatments on day four, the animals were pretreated by intracerebroventricular (icv) delivery of the NPY Y1 receptor antagonist, 1229U91, or the vehicle, artificial cerebrospinal fluid (acsf). Food intake during acute hypoglycemia was significantly diminished between t_o and + 2 h in animals pretreated with the Y1 receptor antagonist versus vehicle. Administration of 1229U91 prior to the fourth of four NPH doses suppressed hypoglycemic hyperphagia over a relatively longer interval, e.g. 4 h, after t_o relative to the acute insulin group. Blood glucose levels after a single NPH injection were similar in acsf- and antagonist-pretreated rats at + 2, + 4, and + 6 h, but were lower at + 9 h in the latter group. Pretreatment with 1229U91 did not modify glucose profiles between + 2 and + 9 h after multiple dosing with NPH, but prevented recovery from hypoglycemia at + 12 h. The present results show that central NPY Y1 receptor antagonism inhibits hypoglycemic hyperphagia, and that this suppressive effect on feeding was of greater duration during recurring hypoglycemia. The data also show that Y1 receptor blockade decreases glycemic responses to both single and serial NPH dosing, albeit at different post-injection time points. The current studies support the view that NPY Y1 receptors function within central neural pathways that govern feeding and glycemic responses to intermediate-acting insulin, and that Y1 receptor-mediated stimulation of food intake may habituate in a positive manner to repetitive insulin-induced hypoglycemia. Further research is needed to evaluate the impact of chronic insulin-induced hypoglycemia on neuropeptide Y neurotransmission and Y1 receptor expression within regulatory circuitries that control food intake and glucostasis.     

The significance of hyperphagia and diet composition on the metabolism in ventromedial hypothalamic lesioned male rats

The metabolic consequences of ventromedial hypothalamic lesion were studied in a group of aged male rats which were obese and had decreased response to insulin. The effects of hyperphagia and ventromedial hypothalamic lesion per se were separated by comparing experimental animals fed isocalorically with controls and animals fed ad libitum. Ventromedial hypothalamic lesion as such led to increases in the glucose conversion to fatty acid and in lipoprotein lipase activity in adipose tissue. Protein catabolism as reflected by plasma urea levels, was enhanced. The lipoprotein lipase activity in heart tended to be lower after VMH lesion. These metabolic changes were amplified in the VMH lesioned rats fed ad libitum. The liver glycogen content was lowered by VMH lesion, but this effect was abolished by hyperphagia. In parallel experiments the influence of diet composition was studied by feeding similar groups with diet of high fat content. The glucose incorporation in fatty acids was in all groups markedly and similarly inhibited by the high fat diet. The increase in lipoprotein lipase activity in heart and adipose tissue of control rats with high fat intake could not be demonstrated in any of the groups with ventromedial hypothalamic lesion. The plasma urea level in the control group was not affected by the diet, but tended to increase in the ventromedial hypothalamic lesioned groups on high fat intake. These findings demonstrate that the well known metabolic effects of ventromedial hypothalamic lesions are also manifest in obese insulin resistant male rats. Furthermore, the responses to changes in diet composition are different from those of the control rats.     

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.     

Altered Hypothalamic Signaling and Responses to Food Deprivation in Rats Fed a Low‐Carbohydrate Diet

Objective: To model how consuming a low‐carbohydrate (LC) diet influences food intake and body weight. Research Methods and Procedures: Food intake and body weight were monitored in rats with access to chow (CH), LC‐high‐fat (HF), or HF diets. After 8 weeks, rats received intracerebroventricular injections of a melanocortin agonist (melanotan‐II) and antagonist (SHU9119), and feeding responses were measured. At sacrifice, plasma hormones and hypothalamic expression of mRNA for proopiomelanocortin (POMC), melanocortin‐4 receptor, neuropeptide Y (NPY), and agouti related protein (AgRP) were assessed. A second set of rats had access to diet (chow or LC‐HF) for 4 weeks followed by 24 h food deprivation on two occasions, after which food intake and hypothalamic POMC, NPY, and AgRP mRNA expression were measured. Results: HF rats consumed more food and gained more weight than rats on CH or LC‐HF diets. Despite similar intakes and weight gains, LC‐HF rats had increased adiposity relative to CH rats. LC‐HF rats were more sensitive to melanotan‐II and less sensitive to SHU9119. LC‐HF rats had increased plasma leptin and ghrelin levels and decreased insulin levels, and patterns of NPY and POMC mRNA expression were consistent with those of food‐deprived rats. LC‐HF rats did not show rebound hyperphagia after food deprivation, and levels NPY, POMC, and AgRP mRNA expression were not affected by deprivation. Discussion: Our results demonstrate that an LC diet influences multiple systems involved in the controls of food intake and body weight. These data also suggest that maintenance on an LC‐HF diet affects food intake by reducing compensatory responses to food deprivation.     

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.     

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.