Disruption in neuropeptide Y and leptin signaling in obese ventromedial hypothalamic-lesioned rats

Electrolytic lesions placed in the ventromedial hypothalamus (VMH) of rats induce instant hyperphagia and excessive weight gain. Since neuropeptide Y (NPY) is a potent hypothalamic orexigenic signal, and leptin secreted by adipocytes regulates NPY output, we tested the hypothesis that altered NPYergic-leptin signaling may underlie hyperphagia in VMH-lesioned rats. VMH-lesioned rats exhibiting hyperphagia and excessive weight gain in a time-related fashion were sacrificed on days 2, 7, and 21 post-surgery. Quite unexpectedly, NPY concentrations in the hypothalamic paraventricular nucleus (PVN), a major site of NPY release for stimulation of feeding, and in other sites, such as the dorsomedial nucleus, lateral hypothalamic area and median eminence-arcuate nucleus decreased, with the earliest diminution occurring on day 2 in the PVN only. In vitro basal and K⁺-evoked NPY release from the PVN of VMH-lesioned rats was significantly lower than that of controls. Analysis of hypothalamic NPY gene expression showed that although the daily decrease in NPY mRNA from 0800 to 2200 h occurred as in control rats, NPY mRNA concentrations were markedly reduced at these times in the hypothalami of VMH-lesioned rats. Leptin synthesis in adipocytes as indicated by leptin mRNA levels was also profoundly altered in VMH-lesioned rats. The daily pattern of increase in adipocyte leptin mRNA at 2200 h from 0800 h seen in controls was abolished, higher levels of leptin gene expression at 2200 h were maintained at 0800 h. The pattern of increase in serum leptin and insulin levels diverged in VMH-lesioned rats. Serum insulin concentration increased to maximal on day 2 and remained at that level on day 21-post-lesion; serum leptin levels on the other hand, increased slowly in a time-related fashion during this period. These results demonstrate that hyperphagia and excessive weight gain in VMH-lesioned rats are associated with an overall decrease in hypothalamic NPY and augmented leptin signaling to the hypothalamus. The divergent time course of increases in serum leptin and insulin levels suggest independent mechanisms responsible for their augmented secretion, and neither these hormones nor VMH lesions altered the daily rhythm in NPY gene expression. These observations underscore the existence of an independent mechanism controlling the daily rhythm in hypothalamic NPY gene expression and suggest that leptin feedback action requires an intact VMH.     

Ageing and the diurnal expression of mRNAs for vasoactive intestinal peptide and for the VPAC2 and PAC1 receptors in the suprachiasmatic nucleus of male rats

Ageing alters fundamental aspects of circadian rhythmicity in mammals; the effects include reduced rhythm amplitude and alterations in period length and in entrainment to the light/dark cycle. Such changes may reflect disruptions in cellular function within the suprachiasmatic nucleus (SCN), the site of the predominant circadian pacemaker. In the SCN, vasoactive intestinal peptide (VIP)-synthesizing neurones receive various inputs, including retinohypothalamic projections containing pituitary adenylate cyclase activating peptide (PACAP). SCN VIP cells establish connections with local neurones and send efferents beyond the nucleus. Considerable evidence implicates VIP and PACAP in circadian rhythm maintenance and/or entrainment to photic Zeitgebers. These actions involve members of a distinct family of receptors; mRNAs for two such receptors, VPAC2 and PAC1, are present in the SCN. This study used isotopic in situ hybridization to examine the effects of ageing on expression of mRNAs for VIP, VPAC2 and PAC1 in the SCN of male rats under a 12 : 12 h light/dark cycle. Analysis of film autoradiographs from young adult (2-3 months) or aged (19-20 months) rats, at eight time points across the light/dark cycle, showed loss of diurnal rhythmicity and reduced levels for VIP mRNA in the aged group. A diurnal rhythm of VPAC2 receptor mRNA was present in both groups, but its levels were reduced in the aged rats. There were no differences between the two groups for PAC1 receptor mRNA expression. The present results indicate that ageing reduces VIP and VPAC2 receptor mRNA and eliminates diurnal expression of VIP mRNA within the SCN of aged male rats.     

Rapid changes in hypothalamic neuropeptide Y produced by carbohydrate-rich meals that enhance corticosterone and glucose levels

Prior studies have demonstrated that chronic consumption over several weeks of a high-carbohydrate (65%) diet, compared to a moderate-carbohydrate (45%) or low-carbohydrate (15%) diet, potentiates the expression, synthesis and release of hypothalamic NPY. This effect occurs specifically in neurons of the arcuate nucleus (ARC) which project to the paraventricular nucleus (PVN). In the present experiments, tests involving acute manipulations were conducted to determine whether such diet-induced changes in NPY can occur rapidly, perhaps within 1-2 h, and whether these effects can be linked to specific changes in circulating glucoregulatory hormones or glucose itself., In adult, albino rats maintained on lab chow, the acute manipulations included the presentation of either a high-carbohydrate, moderate-carbohydrate or high-fat diet for 90 min at the onset of the natural feeding cycle. They also involved manipulations of glucose itself, either through the ingestion of a glucose (20%) solution in a drinking tube or intraperitoneal injection of a glucose solution (10%). After a high-carbohydrate meal compared to a moderate-carbohydrate or high-fat meal, NPY gene expression examined via in situ hybridization is found to be significantly enhanced in the ARC. The high-carbohydrate meal also potentiates NPY immunoreactivity in the ARC and PVN but has little effect on NPY in other hypothalamic areas examined and actually causes a reduction in the feeding-stimulatory peptide, galanin, specifically in the PVN. The meal-induced increase in NPY is associated with specific endocrine patterns, as revealed by measurements in serum collected from trunk blood or from rats implanted with a chronic jugular catheter. After a high-carbohydrate meal, levels of glucose, together with corticosterone and insulin, are significantly elevated, while non-esterified fatty acids are reduced. A possible effect of circulating glucose on hypothalamic NPY is further suggested by the finding that the consumption or a single injection of a glucose solution at the onset of the feeding cycle similarly elevates NPY mRNA and peptide immunoreactivity in the ARC and PVN. These results demonstrate that hypothalamic NPY can change rapidly in response to dietary carbohydrate. They also suggest that this effect may be related to changes in circulating CORT as well as to the availability or utilization of glucose.     

Activation of the central nervous system in obese Zucker rats during food deprivation.

This study was carried out to investigate the pattern of neuronal activations that occur in the obese fa/fa Zucker rat during food deprivation. The functional activation of neurons was estimated in lean and obese Zucker rats either fed ad libitum or food-deprived for 3, 6, 12, and 24 hours by assessing the expression of the immediate early gene c-fos. To identify the neurons instigating the activation of the hypothalamic-pituitary-adrenal axis in food-deprived obese rats, the retrograde tracer cholera toxin B subunit was injected in the parvocellular division of the paraventricular hypothalamic nucleus of obese rats and colocalized with c-fos mRNA during food deprivation. The expression of c-fos was barely detectable in food-deprived lean rats as well as in lean and obese animals fed ad libitum. However, 3 hours of food deprivation were sufficient to significantly induce c-fos in the paraventricular thalamic nucleus of obese rats. In addition, 6 and 12 hours of food deprivation resulted in the activation of regions that are similarly stimulated in "neurogenic" stresses. These regions include the parvocellular division of the paraventricular hypothalamic nucleus, the lateral septum, the basolateral amygdala, and some areas of the cortex. The highest number of neurons projecting to the parvocellular division of the paraventricular hypothalamic nucleus and revealing c-fos mRNA was, however, located in the paraventricular thalamic nucleus. In summary, the present results demonstrate in the obese fa/fa Zucker rats, that food deprivation leads to brain activations, which are in large part, similar to those induced by a "neurogenic" stress and that the paraventricular thalamic nucleus is involved in this response. These changes could contribute to the development of hyperphagia and obesity.     

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.     

Effects of monosodiuml-glutamate administration on neuropeptide Y-containing neurons in the rat hypothalamus

Immunocytochemical localization of neuropeptide Y (NPY) was performed in the hypothalamus of rats of which the arcuate nucleus had been destroyed with monosodiuml-glutamate in the neonatal period. The treatment produced a disappearance of most of the NPY cell bodies normally found in the arcuate nucleus. The concentration of fibers was decreased in the paraventricular nucleus, but not in the other hypothalamic nuclei. The treatment also induced the appearance of a large number of immunoreactive cell bodies in the paraventricular nucleus. These results strongly suggest that arcuate NPY neurons are projecting to the paraventricular nucleus and that the arcuate nucleus probably exerts some inhibitory tonic influence on NPY paraventricular neurons.     

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.     

Effects of monosodium L-glutamate administration on neuropeptide Y-containing neurons in the rat hypothalamus

Immunocytochemical localization of neuropeptide Y (NPY) was performed in the hypothalamus of rats of which the arcuate nucleus had been destroyed with monosodium L-glutamate in the neonatal period. The treatment produced a disappearance of most of the NPY cell bodies normally found in the arcuate nucleus. The concentration of fibers was decreased in the paraventricular nucleus, but not in the other hypothalamic nuclei. The treatment also induced the appearance of a large number of immunoreactive cell bodies in the paraventricular nucleus. These results strongly suggest that arcuate NPY neurons are projecting to the paraventricular nucleus and that the arcuate nucleus probably exerts some inhibitory tonic influence on NPY paraventricular neurons.     

Ageing and the diurnal expression of the mRNAs for vasopressin and for the V1a and V1b vasopressin receptors in the suprachiasmatic nucleus of male rats

Changes in the function of neuropeptide synthesizing cells within the suprachiasmatic nucleus (SCN), the site of the predominant circadian pacemaker, may underlie the disturbance of rhythms observed during ageing. Arginine vasopressin (AVP) is synthesized by nearly one-third of SCN neurones in the rat. This peptide has predominantly excitatory actions within the SCN mediated by V(1)-type receptors; the extent to which the V(1a) and/or V(1b) receptor subtypes are involved in SCN functions remains to be determined. The present study used isotopic in situ hybridization histochemistry to examine the effects of ageing on expression of mRNAs for AVP and V(1a) in the SCN and for V(1b) in the SCN and supraoptic nucleus (SON) of male rats kept under a 12 : 12 h light/dark cycle. Analysis of film autoradiographs from young adult (2-3-month-old; n = 40) or aged (19-20-month-old; n = 40) animals, at eight time points across the light/dark cycle, revealed an equivalent pattern and amplitude for the diurnal rhythm of AVP mRNA in the SCN of the young adult and aged groups. Both groups also displayed a significant diurnal rhythm in the expression of V(1a) receptor mRNA; however, the amplitude of this rhythm was reduced in the aged group, due to increased levels during the light phase and early part of night. Although the expression of V(1b) mRNA did not display a significant diurnal rhythm within the SCN or SON, persistently elevated levels for V(1b) mRNA were observed in the aged group at both sites.     

Evidence that hypothalamic neuropeptide Y gene expression and NPY levels in the paraventricular nucleus increase before the onset of hyperphagia in experimental diabetes

Neuropeptide Y (NPY) is the most potent endogenous orexigenic signal. Several lines of evidence indicate that the site of NPY action in transducing feeding signal may reside in the paraventricular nucleus (PVN) and neighboring sites in the hypothalamus. To test the hypothesis that an increase in NPY activity in the ARC-PVN pathway precedes the onset of diabetic hyperphagia, we evaluated NPY levels in seven hypothalamic nuclei and NPY gene expression in the hypothalamus at 48, 72 or 96 h after streptozotocin (STZ) treatment in rat. In STZ-treated diabetic rats, NPY gene expression in the hypothalamus and NPY levels only in the PVN significantly elevated at 48 h, while hyperphagia occurred sometimes after 48 h post-injection. These results show that augmentation in NPY neuronal activity in the ARC-PVN axis precedes the onset of increased food intake produced by STZ-induced insulinopenia. These findings affirm the hypothesis that increased NPY neurosecretion in the PVN may underlie the diabetes-induced hyperphagia.     

Intracerebroventricular injection of dibutyryl cyclic adenosine 3′,5′-monophosphate increases hypothalamic levels of neuropeptide Y

This investigation examined in vivo the relationship between the nucleotide cAMP and hypothalamic levels of two peptides, neuropeptide Y (NPY) and galanin (GAL), which are known to potentiate feeding behavior. In brain-cannulated rats, third ventricular injections of N⁶,2′-O-dibutyryl cyclic adenosine 3′,5′-monophosphate ((Bu)₂cAMP, 25 μg), compared to saline, caused a significant increase in NPY levels in the arcuate nucleus (ARC) and medial parvocellular portion of the paraventricular nucleus (mPVN), while having no impact in other hypothalamic areas. These site-specific changes in NPY occurred in the absence of any alteration in circulating levels of insulin, corticosterone, aldosterone or glucose, or of changes in hypothalamic levels of GAL. These findings implicate cAMP as having regulatory functions within specific hypothalamic NPY-synthesizing neurons, projecting from the ARC to the mPVN, that are believed to be involved in energy homeostasis.     

Impact of hypothalamic d-norfenfluramine and peripheral d-fenfluramine injection on macronutrient intake in the rat

Previous research with hypothalamic injection of serotonin (5-HT) has suggested that this monoamine may act within the medial hypothalamus to suppress carbohydrate intake in a selective, phasic and circadian-related fashion. To explore further the action of 5-HT in the brain, the present studies tested the serotonergic stimulants, d-norfenfluramine (DNF) and d-fenfluramine (DF), in freely feeding, brain-cannulated animals maintained on pure macronutrient diets (protein, carbohydrate and fat) and tested at different times of the diurnal cycle. The results show that administration of DNF into the paraventricular nucleus (PVN) potently influences appetite for a specific nutrient at a particular time of the light-dark cycle. Specifically, DNF injection at the onset of the nocturnal (active) period selectively and dose-dependently suppresses carbohydrate consumption, while leaving protein and fat intake unchanged. This drug, however, has no effect, even at high doses, on macronutrient intake in the middle and late h of the dark phase, strongly implicating a function for hypothalamic 5-HT in the control of carbohydrate ingestion at the beginning of the nocturnal cycle. The possibility that peripherally injected DF may act, in part, through this endogenous serotonergic system is supported by the additional finding that, at low doses of 0.06-0.5 mg/kg, DF preferentially modulates carbohydrate ingestion exclusively at the onset of the nocturnal period. However, at doses above 0.5 mg/kg, this compound produces a potent and general suppression of feeding of all macronutrients. In animals with brain cannulas aimed at different hypothalamic nuclei, the feeding-suppressive effect of DNF is found to be site specific; it is localized to the medial hypothalamic nuclei, including the ventromedial, suprachiasmatic and dorsomedial nuclei as well as the PVN. Serotonin in these nuclei may function to produce satiety specific for carbohydrate and, through the suprachiasmatic nucleus, control energy intake in a circadian-related manner.     

A second hypothalamic nucleus receiving retinal input in man: the paraventricular nucleus

A retinofugal projection to the suprachiasmatic nucleus of the hypothalamus has been described in man by means of a newly developed staining technique (PPD) for tracing degenerated fibers in the human brain. We applied the PPD method to the chiasmal/hypothalamic area of human autopsy brains from patients who had incurred prior optic nerve damage. We followed degenerated fibers from the optic nerve through the optic chiasm and the optic tract. At the optic chiasm/tract junction, some fibers were seen to diverge and to form an optic fascicle which traversed the lateral preoptic-anterior hypothalamic area towards the third ventricle. These degenerated fibers terminated in the paraventricular nucleus of the hypothalamus.

We suggest that there are at least two retinohypothalamic pathways in man. Some of the neuroendocrine imbalances in blind persons may be attributed to the disruption of the retinal input to the paraventricular and suprachiasmatic nuclei of the hypothalamus. These retinohypothalamic pathways may be the anatomical substrates for light/dark entrainment of human neuroendocrine and autonomic regulatory processes.     

Control of feeding and sexual behaviors by neuropeptide Y: physiological implications

Recent evidence suggests that a variety of hypothalamic neuropeptides may mediate interneuronal communication to coordinate diverse neuroendocrine and behavioral functions. In this work, we describe the effects of neuropeptide Y (NPY) on feeding and sexual behaviors. We observed that central administration of bolus NPY stimulated a robust, dose-related feeding response in satiated male and female rats. Continuous NPY receptor activation also evoked dose-related, intermittent feeding in a manner normally observed during nocturnal feeding. It appears that the paraventricular nucleus in the hypothalamus may be the primary site of NPY action because the anticipated reciprocal changes in NPY concentrations, in response to food deprivation followed by ad libitum food intake, occurred only in this site. Additional findings revealed that NPY-induced feeding may follow either substantial reduction or complete restraint of an inhibitory influence on feeding mediated by alpha 2-adrenoreceptor systems in satiated rats. Further, NPY was found to suppress male and female sexual behaviors. The suppressive effects on sexual behavior were apparent prior to or at the time of the onset of feeding after NPY administration. These observations may provide a neurochemical basis for clinical and animal studies on disorders of feeding associated with diminished reproductive functions.     

Postnatal light alters hypothalamic‐pituitary‐adrenal axis function and induces a depressive‐like phenotype in adult mice

The postnatal light environment that a mouse experiences during the critical first three postnatal weeks has long‐term effects on both its circadian rhythm output and clock gene expression. Furthermore, data from our lab suggest that postnatal light may also impact the hypothalamic‐pituitary‐adrenal (HPA) axis, which is a key regulator of stress. To test the effect of postnatal light exposure on adult stress responses and circadian rhythmicity, we raised mice under either 24‐h light – dark cycles (LD), constant light (LL) or constant dark (DD) during the first three postnatal weeks. After weaning we then exposed all animals to LD cycles (basal conditions), followed by LL (stressed conditions) environments. We examined brain neuropeptide and glucocorticoid receptor (GR) expression, plasma corticosterone concentration rhythm and body temperature rhythm, together with depression‐ and anxiety‐related behaviour. Results showed that LL‐ and DD‐raised mice exhibited decreased GR expression in the hippocampus, increased plasma corticosterone concentration at the onset of the dark phase and a depressive phenotype when exposed to LD cycles later in life. Furthermore, LL‐raised mice showed increased corticotrophin‐releasing hormone mRNA expression in the paraventricular nucleus of the hypothalamus. When exposed to LL as adults, LL‐raised mice showed a significant circadian rhythm of plasma corticosterone concentration, together with a shorter period and stronger circadian rhythm of body temperature compared to DD‐raised mice. Taken together, these data suggest that altered postnatal light environments have long‐term effects on the HPA axis and the circadian system, which can lead to altered stress responses and a depressive phenotype in adulthood.     

Elevated hypothalamic neuropeptide Y levels in rats with dorsomedial hindbrain lesions

Lesions centered on the area postrema (AP) and adjacent nucleus of the solitary tract (AP/mNTS-lesions) are reported to result in increased consumption of highly palatable diets. Recent studies suggest that neuropeptide Y (NPY) may cause a preference for carbohydrate-rich diets. Thus, it is possible that NPY may play a role in the enhanced intake of highly palatable diets by AP/mNTS-lesioned rats. In the studies reported here, we found that lesions centered on the AP result in increased levels of NPY-immunoreactivity in the paraventricular nucleus of the hypothalamus. Additionally, steady-state NPY mRNA in the basomedial hypothalamus including the arcuate nucleus was elevated. Enhanced NPY was not found throughout the hypothalamus however, as NPY-immunoreactivity was not elevated in the lateral hypothalamus or the tissue bordering the anteroventral third ventricle. These data suggest the possibility that elevated hypothalamic NPY, particularly in the arcuate and paraventricular nuclei, may contribute to the altered food intake and energy balance observed in rats with lesions centered on the AP.     

Neuropeptide Y in the arcuato-paraventricular pathway and diet selection in the vasopressin-deficient Brattleboro rat

Neuropeptide Y (NPY) is one of the most important brain peptides involved in feeding behavior. It influences both food choice and fluid homeostasis. The paraventricular and arcuate nuclei belong to the main pathway through which NPY stimulates carbohydrate intake. In this study, we measured NPY in various hypothalamic microdissected areas in Brattleboro di/di rats, a rat model of diabetes insipidus with specific dietary preferences. We confirmed that this rat is characterized by an increased fat intake (+10%; p < 0.001) and a decreased carbohydrate intake (−10%; p < 0.001) leading to a completely different dietary profile than that of di/+ controls. This profile was associated with a decrease in NPY in the paraventricular nucleus (−33%; p < 0.005) and in the ventromedial nucleus (−24%; p < 0.002). Intake of carbohydrate was negatively correlated with the gradient of NPY concentration between the arcuate and paraventricular nuclei. NPY could therefore contribute to the qualitative changes of feeding behavior in the Brattleboro rat through altered transport/release of the peptide and participate in the balance of neuropeptides that determines food choice in this strain of rat.     

Basic organization of projections from the oval and fusiform nuclei of the bed nuclei of the stria terminalis in adult rat brain.

The organization of axonal projections from the oval and fusiform nuclei of the bed nuclei of the stria terminalis (BST) was characterized with the Phaseolus vulgaris-leucoagglutinin (PHAL) anterograde tracing method in adult male rats. Within the BST, the oval nucleus (BSTov) projects very densely to the fusiform nucleus (BSTfu) and also innervates the caudal anterolateral area, anterodorsal area, rhomboid nucleus, and subcommissural zone. Outside the BST, its heaviest inputs are to the caudal substantia innominata and adjacent central amygdalar nucleus, retrorubral area, and lateral parabrachial nucleus. It generates moderate inputs to the caudal nucleus accumbens, parasubthalamic nucleus, and medial and ventrolateral divisions of the periaqueductal gray, and it sends a light input to the anterior parvicellular part of the hypothalamic paraventricular nucleus and nucleus of the solitary tract. The BSTfu displays a much more complex projection pattern. Within the BST, it densely innervates the anterodorsal area, dorsomedial nucleus, and caudal anterolateral area, and it moderately innervates the BSTov, subcommissural zone, and rhomboid nucleus. Outside the BST, the BSTfu provides dense inputs to the nucleus accumbens, caudal substantia innominata and central amygdalar nucleus, thalamic paraventricular nucleus, hypothalamic paraventricular and periventricular nuclei, hypothalamic dorsomedial nucleus, perifornical lateral hypothalamic area, and lateral tegmental nucleus. Moderately dense inputs are found in the parastrial, tuberal, dorsal raphé, and parabrachial nuclei and in the retrorubral area, ventrolateral division of the periaqueductal gray, and pontine central gray. Light projections end in the olfactory tubercle, lateral septal nucleus, posterior basolateral amygdalar nucleus, supramammillary nucleus, and nucleus of the solitary tract. These and other results suggest that the BSTov and BSTfu are basal telencephalic parts of a circuit that coordinates autonomic, neuroendocrine, and ingestive behavioral responses during stress.     

Enhanced inhibitory feeding response to alpha-melanocyte stimulating hormone in the diet-induced obese rat

A dysregulation in the hypothalamic neuropeptide systems involved in the control of appetite has previously been shown in models of diet-induced obesity. In the present study, male Sprague-Dawley rats were rendered obese by a highly palatable cafeteria-style diet over 20 weeks, while control rats had access to standard laboratory chow. Feeding responses to alpha-melanocyte stimulating hormone (alpha-MSH), an anorectic peptide and neuropeptide Y (NPY), a potent orexigenic agent were investigated in diet-induced obese and control animals. In addition, endogenous hypothalamic peptide levels were determined in these animals. Intracerebroventricular injections of either 4 nmol alpha-MSH or saline vehicle were given 10 min prior to the onset of the dark phase. Diet-induced obese rats had significantly enhanced nocturnal inhibitory feeding responses to alpha-MSH (P<0.05). The orexigenic feeding response induced by 1 nmol NPY was similar for both groups. At sacrifice, both alpha-MSH and NPY peptide content were selectively reduced in the paraventricular nucleus (PVN) of these animals (P<0.05). Although diet-induced obesity had no effect on responses to NPY, the significantly greater inhibition of nocturnal feeding by alpha-MSH and reduction in PVN alpha-MSH peptide level, suggests melanocortinergic signalling may be reduced in obesity which may account for the hyperphagia of these animals when presented with a palatable diet.