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Biomedical subjects

S F Leibowitz

Publications and source records attributed to S F Leibowitz.

At least 91 records · Page 5Linked to original sources
PubMed1989

Repeated hypothalamic stimulation with neuropeptide Y increases daily carbohydrate and fat intake and body weight gain in female rats.

Neuropeptide Y (NPY), repeatedly injected in the hypothalamic paraventricular nucleus (PVN), produces dramatic obesity and overeating in female rats maintained on a single nutritionally complete diet. In the present study, we investigated whether these effects could also be obtained in animals with a choice of three pure macronutrients: protein, carbohydrate, and fat. Female rats with indwelling PVN cannulas were injected with NPY (235 pmol) or its saline vehicle every 8 hr for 6 days. A third group was left undisturbed. Consumption of each macronutrient and body weight were measured every 24 hr for 6 days preinjection, 6 days during injections, and 21 days after the injections were terminated. Relative to vehicle or preinjection rates of body weight gain (approximately 1.5 g/day), NPY dramatically enhanced weight gain to a rate of 9.3 g/day and more than doubled total daily food intake. This augmentation was accounted for by increases in carbohydrate intake (+26.4 kcal/day) and fat intake (+48.5 kcal/day), with no significant potentiation of protein consumption. When the NPY injections were terminated, body weight and macronutrient intake returned to control levels within 1 or 2 weeks. These findings are consistent with a role for NPY in hypothalamic mechanisms of macronutrient intake and body weight regulation and suggest that disturbances in brain NPY may contribute to the development of eating and weight disorders.

Animals↗
PubMed1989

The effects of amphetamine and chlorpromazine on independent ingestion of milk in preweanling rats.

To assess the effects of catecholaminergic drugs on independent feeding during development, preweanling rats were administered amphetamine (AMPH) or chlorpromazine (CPZ) and were allowed to ingest milk through anteriorly located intra-oral cannulas. In 1-hr milk-deprived rat pups, AMPH stimulated milk intake at 3, 7 and 10 days of age and suppressed intake at 15 days. In 22-hr-deprived pups, AMPH had no effect at 3, 7 and 10 days, but reliably suppressed intake at 15 days. CPZ stimulated intake in 3-, 10- and 15-day-old milk-satiated pups. In 22-hr-deprived pups, CPZ had no effect at 3 and 10 days, but stimulated intake at 15 days. While AMPH produced pronounced nonappetitive behavioral activation in conjunction with enhanced intake in 1-hr-deprived pups, AMPH-induced activation occurred without enhanced intake in 22-hr-derived pups. Thus, there was a dissociation between AMPH's effect on milk intake and AMPH-induced nonappetitive behavioral activation. Collectively, the present results support the following conclusions. First, a catecholaminergic system(s) that enhances independent feeding is present very early in postnatal development of the rat. Second, level of food deprivation is an important state-dependent variable when assessing the effects of AMPH and CPZ on independent feeding in preweanling rats.

Age Factors↗
PubMed1989

Patterns of extracellular 5-hydroxyindoleacetic acid (5-HIAA) in the paraventricular hypothalamus (PVN): relation to circadian rhythm and deprivation-induced eating behavior.

Daily rhythms in extracellular levels of the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were examined in the region of the paraventricular nucleus (PVN), using intracerebral microdialysis combined with high performance liquid chromatography and electrochemical detection. Samples of PVN dialysate, from 11 rats on a 12/12 hr light/dark cycle, were collected and assayed for 5-HIAA every 2 hr for 3 days. During the first 2 days the rats were given free access to food. During the 3rd day they were deprived of food for a 24-hr period and then given food for 4 hr. The results showed that in freely-feeding rats, there was a 24-hr rhythm in the levels of 5-HIAA, with a marked transient peak just after the beginning of the dark portion of the light/dark cycle and stable levels at all other times. When the animals were food-deprived, PVN levels of this metabolite remained stable, and the early dark peak was abolished, suggesting that it might have been consequent to the eating behavior which normally occurred at this time. In the 4-hr refeeding period, there were no changes in 5-HIAA levels, despite the intense eating behavior which occurred during this time. These patterns of 5-HIAA in the PVN region, taken together with previous evidence, suggest that PVN serotonin metabolism may increase in association with feeding specifically in the early portion of the nocturnal eating period, when it may play a role in controlling food intake and macronutrient selection.

Animals↗
PubMed1989

PVN steroid implants: effect on feeding patterns and macronutrient selection.

The glucocorticoid corticosterone (CORT) plays a major role in feeding behavior, body weight regulation and metabolism. Recent work has demonstrated an interaction between circulating CORT and the alpha 2-noradrenergic feeding system of the hypothalamic paraventricular nucleus (PVN) and the existence of two different subtypes of glucocorticoid receptors in this nucleus. To examine the function of these specific PVN receptors, crystalline CORT and other steroid hormones were implanted directly into the PVN, and feeding patterns and macronutrient selection, of freely feeding adrenalectomized (ADX) and sham rats, were monitored at the beginning and end of the nocturnal feeding cycle. Results indicate that PVN CORT implants stimulate carbohydrate intake in ADX rats, at the onset of the dark cycle when the feeding-suppressive effects of ADX are strongest. Corticosterone was ineffective in sham rats and was also ineffective in potentiating food intake in ADX rats at the end of the dark phase. In contrast, implants of the mineralocorticoid aldosterone (ALDO) stimulated the ingestion of the fat diet, in both sham and ADX rats and during both the early and the late dark periods. Implants of ALDO also enhanced carbohydrate intake, but only in ADX rats and at dark onset. While the synthetic glucocorticoid, dexamethasone, had a small carbohydrate stimulatory effect similar to CORT, other steroids (deoxycorticosterone, progesterone and estrogen) were without effect. These results indicate a central site of action for the adrenal hormones in modulating nutrient intake. Based on a variety of evidence, it is suggested that the stimulatory effects of ALDO and CORT on macronutrient intake may be differentially mediated by Type 1 and Type 2 steroid receptor subtypes within the brain.

Aldosterone↗
PubMed1989

Nocturnal patterns of macronutrient intake in freely feeding and food-deprived rats.

Analyses of rats' feeding behavior at the start and the end of the nocturnal cycle have revealed dramatic alterations in macronutrient intake over time. At dark onset, rats displayed a preference for carbohydrate, with the first meal of the night consisting of approximately 60% of this nutrient. This carbohydrate intake was soon followed by a shift toward protein-predominant meals. Superimposed on this pattern of meal-to-meal shifts in nutrient selection appears to be an additional rhythm in which carbohydrate ingestion was favored at dark onset and protein and fat ingestion were favored during the late dark hours. Differential feeding patterns were also apparent following mild food deprivation. A 2-h period of deprivation at dark onset produced a strong compensatory feeding response, particularly of fat and carbohydrate. This pattern was not observed at the end of the dark, when little compensatory feeding was demonstrated. It is suggested that these feeding patterns may be related to the activity of certain hypothalamic neurotransmitters, e.g., norepinephrine and serotonin, known to be important in modulating temporal feeding patterns and nutrient intake.

Animals↗
PubMed1988

Feeding and macronutrient selection patterns in rats: adrenalectomy and chronic corticosterone replacement.

To analyze further the role of corticosterone (CORT) in the control of feeding behavior, we examined the impact of adrenalectomy (ADX) and chronic CORT implants on the food intake and macronutrient self-selection patterns of adult male rats at different periods of the diurnal cycle. Consistent with a separate study of acute CORT injection in ADX rats (Kumar and Leibowitz, 1988), the present findings indicate that ADX significantly attenuated the rats' daily (24 hr) ingestion of all three macronutrients, namely, protein, carbohydrate and fat. However, food intake in the dark cycle, specifically during the first few hours after dark onset, was significantly more affected (-70%) than feeding in the later dark and light periods (-25%). Moreover, during this early dark time when circulating CORT level normally peaks, ADX appeared to have its strongest suppressive effect on carbohydrate ingestion. Chronic subcutaneous CORT implants in the ADX animals reversed these effects of surgery and generally restored the rats' eating patterns to that of the cholesterol-implanted SHAM animals. These findings suggest that CORT exerts a decisive influence on caloric intake, on the diurnal pattern of feeding, and on appetite for specific macronutrients. The impact of CORT on carbohydrate intake is apparent specifically during the active eating period, particularly at dark onset when endogenous CORT levels normally peak and carbohydrate is exhibited as the preferred macronutrient.

Activity Cycles↗
PubMed1988

Glucose-dependent changes in alpha 2-noradrenergic receptors in hypothalamic nuclei.

Evidence indicates that hypothalamic norepinephrine (NE), acting via alpha 2-noradrenergic receptors, and also circulating glucose both have an important role in the control of normal feeding behavior in rats. In this report, we studied the relationship between glucose and the alpha 2-noradrenergic system, by manipulating blood glucose levels and analyzing changes in the binding of [3H]p-aminoclonidine [( 3H]PAC) to alpha 2-noradrenergic receptors in discrete hypothalamic areas. Brief periods (1-3 hr) of food deprivation, at the onset of the dark cycle, produced a significant decline in serum glucose levels and a simultaneous decrease in alpha 2-receptor binding sites, specifically in the hypothalamic paraventricular nucleus (PVN) as opposed to other hypothalamic areas. Restoration of circulating glucose levels, by refeeding for 0.5 hr after 2.5 hr food deprivation or by administration of glucose to 1 hr food-deprived rats, prevented this decline in serum glucose, as well as the reduction in PVN alpha 2-noradrenergic receptor density. In each of these experiments, a strong positive correlation between circulating glucose levels and PVN alpha 2-noradrenergic receptor sites was obtained. These findings suggest that blood glucose has direct impact upon alpha 2-noradrenergic receptor activity in the PVN and may affect feeding behavior, in part, through this neurochemical system.

Animals↗
PubMed1988

Clonidine hyperphagia: neuroanatomic substrates and specific function.

Recent studies have indicated that the alpha 2-noradrenergic agonist clonidine (CLON), when peripherally and centrally administered, potentiates feeding in satiated rats in a manner similar to that observed following injection of norepinephrine (NE) into the hypothalamic paraventricular nucleus (PVN). The present experiments examined the effects of CLON on meal patterns and macronutrient selection and compared these findings to earlier NE-stimulated feeding studies. Administration of CLON (25 nmoles), directly into the PVN (n = 5), similar to PVN injected NE, produced an increase in meal size (190%) and feeding duration (164%), with no change in meal frequency. Additional tests were conducted in rats with PVN electrolytic or 6-hydroxydopamine lesions. In Sham rats (n = 16) peripheral CLON (0.05 mg/kg), like NE, produced an increase in food intake and particularly potentiated carbohydrate ingestion. Discrete electrolytic lesions of the PVN (n = 5) abolished this CLON-induced feeding and carbohydrate preference, suggesting that the PVN may be a primary site for CLON-stimulated hyperphagia. Neurotoxin lesions of the PVN (n = 17), which reduced PVN NE levels by 75%, failed to alter peripheral CLON-induced feeding. This and other evidence indicates that this agonist may be acting via postsynaptic alpha 2 receptors in the PVN to potentiate carbohydrate intake, rather than via presynaptic release of NE from nerve endings in the PVN.

Animals↗
PubMed1988

Multiple brain sites sensitive to feeding stimulation by opioid agonists: a cannula-mapping study.

Evidence suggests that brain opioid receptors of the mu, delta and kappa subtypes may be involved in the control of feeding behavior. However, limited information is available regarding the specific anatomical location of these feeding relevant opioid receptors. To address this problem, we microinjected three opioid agonists, morphine, (D-Ala2)-Met-enkephalinamide (DALA) or MR 2034, into one of 15 different brain areas and measured the subsequent feeding responses of satiated rats. Morphine (25 nmol) and DALA (6.8 nmol) both elicited strong feeding responses from the same five brain areas, namely, the paraventricular, dorsomedial and lateral hypothalamus, as well as from sites within the septum and amygdala. No other brain sites yielded significant responses to these opioid receptor agonists. In contrast to this anatomically specific pattern of effects, the opioid agonist MR 2034 (8.6 nmol) produced a feeding response which was generally smaller in magnitude and had little anatomical specificity. These findings suggest that opioid receptor systems for stimulating feeding exist in multiple discrete brain areas. Of the regions tested, specific sites within the hypothalamus, septum and amygdala are distinguished as being most sensitive to feeding stimulation by morphine and DALA.

Animals↗
PubMed1988

Neuropeptide Y, epinephrine and norepinephrine in the paraventricular nucleus: stimulation of feeding and the release of corticosterone, vasopressin and glucose.

The paraventricular nucleus (PVN) is known to have an important function in mediating a variety of behavioral and endocrine responses. In the present study, the responsiveness of the PVN to the effects of the coexisting neurotransmitters, neuropeptide Y (NPY), epinephrine (EPI) and norepinephrine (NE), was examined. Albino rats were each chronically implanted with a swivel brain-cannula that permits chemicals to be infused without disturbing the animals' ongoing behavior. When infused into the PVN, each of these neurotransmitters elicited a reliable feeding response during the first hour after injection. The response to EPI was significantly stronger than that of NE and NPY, while the latency to eat after injection was considerably longer for NPY as compared to the catecholamines. In tests with food absent, each of these substances also increased blood levels of corticosterone (EPI greater than NE = NPY) and vasopressin (NPY greater than EPI greater than NE) and revealed a significant positive correlation between circulating levels of these two hormones. In addition, EPI and NE, in contrast to NPY, caused a simultaneous rise in blood glucose, producing levels that were positively correlated with the hormones. No relationship, however, was detected between these endocrine changes and the rats' feeding-stimulatory responses. Together with other evidence, these results suggest that adrenergic as well as noradrenergic innervation to the PVN has a key role in the behavioral and endocrine systems of this nucleus and, moreover, that NPY generally mimics the effects of these catecholamines in the PVN.

Animals↗
PubMed1988

Hypothalamic paraventricular nucleus: interaction between alpha 2-noradrenergic system and circulating hormones and nutrients in relation to energy balance.

Extensive evidence suggests that norepinephrine (NE) in the brain is active in the control of eating behavior. Central injection studies demonstrate a stimulatory effect of NE on food intake, a response which is mediated by alpha 2-noradrenergic receptors located in the medial hypothalamus, in particular the paraventricular nucleus (PVN). Activation of these PVN receptors stimulates ingestion specifically of carbohydrate-rich foods, and this response is believed to reflect the role of endogenous NE in controlling natural appetite for this macronutrient. This alpha 2-noradrenergic system in the PVN appears to be physiologically activated at the onset of the animals' active cycle, when there is a natural peak in preference for carbohydrate. At this time, the adrenal hormone corticosterone, which is known to play a major role in carbohydrate metabolism, is found to interact positively with NE in the potentiation of carbohydrate ingestion. Circulating glucose also influences the activity of PVN alpha 2-noradrenergic receptors at this time, and, moreover, alpha-noradrenergic stimulation of the PVN produces an increase in circulating levels of both corticosterone and glucose. This and other evidence has led to the hypothesis that NE in the PVN, through the activation of glucocorticoid- and glucose-sensitive alpha 2-receptor sites, is physiologically active in energy homeostasis, most particularly at the onset of the animal's active cycle. Specifically, this neurotransmitter in the PVN evokes a state of energy conservation. This state involves adjustments in carbohydrate ingestion as well as metabolism, that allow animals to maintain energy reserves by anticipating or responding to a depletion.

Animals↗
PubMed1988

Impact of acute corticosterone administration on feeding and macronutrient self-selection patterns.

Food intake, body weight, and meal patterns in rats are known to be specifically influenced by circulating corticosterone (CORT). The present study examined, in Sprague-Dawley rats, the role of CORT in the regulation of caloric intake and choice of macronutrients during specific periods of the light-dark cycle. Adrenalectomy (ADX) significantly attenuated the ingestion of all three macronutrients, namely, protein, carbohydrate, and fat, in different test periods of the light-dark cycle. This deficit was significantly stronger just before or during the early dark hours, compared with the light period, and it was immediately CORT reversible. During this same early dark period, the stimulatory effect of CORT (0.5 or 2.0 mg/kg sc) on total food intake in ADX animals was also significantly stronger than during the light period. At this time, the CORT-injected ADX animals consumed an even greater amount of total food intake than did the vehicle-injected sham-operated animals and showed a significant preference for carbohydrate, as opposed to no change or a decline in preference for protein or fat. These findings, in light of other evidence, suggest that CORT ensures and stabilizes the ingestion of all three macronutrients but, in particular, stimulates carbohydrate ingestion during the important feeding period at the dark onset when CORT levels normally peak. It is proposed that CORT may provide a critical signal, in conjunction with hypothalamic neurotransmitter systems, in the behavioral and metabolic regulation of body energy balance.

Adrenalectomy↗
PubMed1988

[Central neurotransmitters and control of specific appetite for the macronutrients].

Studies of brain monoamines and neuropeptides have provided extensive evidence in support of their role in the control of food intake, meal patterns and appetite for specific macronutrients. In this process, the medial and lateral portions of the hypothalamus have a critical responsibility in balancing signals for hunger and satiety. Via its rich and biologically active neurotransmitter substances, the hypothalamus monitors and integrates the complex sensory and metabolic input concerning the nutritional status of the organism and transduces this information into appropriate quantitative and qualitative adjustments in food intake. The specific neurotransmitters for which there is the most extensive evidence for a physiological function include the eating-stimulatory substances norepinephrine, opioid peptides, pancreatic polypeptides, galanin and gamma-aminobutyric acid; and the eating-inhibitory substances dopamine, epinephrine, serotonin and several gut-brain peptides. From biochemical, pharmacological and anatomical studies, hypotheses have been generated to explain the role of these various monoamines and neuropeptides in controlling total energy intake, in determining the amount and pattern of macronutrient selection, and in maintaining normal energy and nutrient stores under dynamic conditions within the external environment.

Animals↗
PubMed1988

Hypothalamic serotonin: pharmacological, biochemical, and behavioral analyses of its feeding-suppressive action.

Studies of the neuropharmacology of eating behavior demonstrate that monoaminergic neurotransmitters in the brain have an active and important role in the control of food ingestion, in animals and also possibly in humans. The anatomical focus of the animal studies has been the hypothalamus, which appears to play a key role in this process. This structure receives and integrates input from metabolic, hormonal, neurogenic, thermal, and cortical factors, which reflect the nutritional status of the organism, and then it translates this information into signals for inducing appropriate adjustments in food consumption. While this review focuses on the indoleamine, serotonin, with respect to its effects after peripheral and central administration, attention is also given to the catecholamines, which are believed to interact with serotonin in the complex process of controlling eating patterns and appetite for specific macronutrients.

Animals↗
PubMed1987

Serotonin and 5-hydroxyindoleacetic acid levels in discrete hypothalamic areas of the rat brain: relation to circulating corticosterone.

We examined the influence of adrenalectomy (ADX), and chronic corticosterone (CORT) replacement, on serotonin (5-HT) and 5-hydroxyindolacetic acid (5-HIAA) levels in discrete hypothalamic areas of the rat brain. A significant decrease in 5-HT (-25%) and 5-HIAA (-28%) content was observed in the paraventricular nucleus (PVN) 7 days following ADX. A similar decrease in 5-HT levels (-27%) was observed in the preoptic area (POM) following ADX. In contrast, 5-HT and 5-HIAA levels in the supraoptic nucleus (SON) were significantly elevated by 82% and 54%, respectively. Replacement therapy with subcutaneous CORT implants (200 mg) was effective in preventing these effects of ADX in some cases. These findings suggest that the pituitary-adrenal endocrine system may influence various physiological and behavioral functions via its action on serotonergic neurons within specific hypothalamic sites.

Adrenalectomy↗
PubMed1987

Alterations in catecholamine levels and turnover in discrete brain areas after food deprivation.

The present study determined the levels and turnover of norepinephrine (NE), epinephrine (EPI) and dopamine (DA) in discrete brain areas of rats after 48 hr food deprivation. The steady-state levels of NE, EPI and DA in saline-treated food-deprived rats, relative to satiated rats, remained basically unchanged. However, 48 hr deprivation caused a site-selective potentiation, specifically in the hypothalamic paraventricular nucleus, in the depletion of NE after alpha-methyl-p-tyrosine injection (IP, 200 mg/kg), indicating an increase in NE turnover. While changes in EPI turnover could not be demonstrated, an apparent increase in DA turnover was detected in the perifornical lateral hypothalamus and anterior hypothalamic nucleus after deprivation, while decreased DA turnover was seen in the hypothalamic dorsomedial nucleus and caudate nucleus. These results may reflect specific functions of hypothalamic catecholamines in control of food intake.

Animals↗
PubMed1987

Effects of chronic paraventricular nucleus infusion of clonidine and alpha-methyl-para-tyrosine on macronutrient intake.

Earlier studies have demonstrated that acute injections of norepinephrine (NE) and clonidine (CLON) into the paraventricular nucleus (PVN) elicit feeding in satiated rats. This study examined the effects of chronic PVN infusion of alpha-methyl-paratyrosine (alpha-MpT), a catecholamine synthesis inhibitor, on intake of a mixed milk-mash diet and on the ingestion of pure macronutrients, protein, carbohydrate and fat. The impact of chronic CLON administration on intake of these macronutrient preparations was also investigated. Over a 14-day period, chronic infusion of alpha-MpT (50 nmoles/30 sec/0.5 microliter) resulted in a reduction of total daily food intake in rats maintained on a milk-mash diet. Chronic administration of CLON (3 nmoles/30 sec/0.5 microliters) was observed to produce a specific increase in ingestion of the carbohydrate, along with a suppression in the intakes of the protein and fat. These results are similar to those previously demonstrated for NE. In contrast, chronic infusion of alpha-MpT into the PVN caused a specific reduction of carbohydrate consumption and an enhancement of protein ingestion, with fat intake unaffected. This evidence suggests that the alpha 2-noradrenergic system of the PVN plays an important role in the daily regulation of macronutrient intake, specifically of carbohydrate.

Animals↗