PubMed Health⌕ Search

Biomedical subjects

S F Leibowitz

Publications and source records attributed to S F Leibowitz.

At least 19 recordsLinked to original sources
PubMed1994

Hypothalamic neuropeptide Y, its gene expression and receptor activity: relation to circulating corticosterone in adrenalectomized rats.

Previous evidence has suggested a possible relationship between the adrenal steroid, corticosterone (CORT) and neuropeptide Y (NPY) in the brain. To provide a more systematic analysis of this interaction, the present study employed a variety of techniques, including in situ hybridization to measure NPY gene expression, radioimmunoassay to examine peptide levels and radioligand [125I]peptide YY (PYY) binding for analysis of peptide receptors. The results show that adrenalectomy (ADX), which caused a decline in CORT to levels < 0.3 micrograms %, has generally little impact on the hypothalamic NPY projection system under normal, basal conditions. This includes peptide gene expression or content in the area of its cell bodies (arcuate nucleus, ARC), in addition to peptide binding at its receptor sites. While it also includes peptide content at most hypothalamic terminal sites, there are three notable exceptions, namely, the medial paraventricular (PVN) and dorsomedial nuclei and medial preoptic area, where NPY nerve terminals and glucocorticoid receptors are particularly dense and the decline in CORT through ADX markedly reduces NPY content. In contrast, evidence obtained from CORT replacement in ADX rats shows that this steroid has profound impact on all components of the hypothalamic NPY system. This peptide-steroid interaction is apparent at the level of the cell body (ARC), as well as at the nerve terminal or receptor site (PVN and ARC), where CORT levels > 10 micrograms % strongly potentiate NPY gene expression, peptide content and radioligand binding. These and other findings suggest that this CORT-NPY interaction in the hypothalamus occurs physiologically under conditions, e.g., at the onset of the active feeding cycle, when circulating CORT normally rises.

Adrenalectomy↗
PubMed1994

Specificity of hypothalamic peptides in the control of behavioral and physiological processes.

This review summarizes two model systems for understanding how brain neurochemicals, in conjunction with peripheral endocrine and metabolic processes, may be active in controlling very different functions in relation to energy and nutrient balance. As proposed, these systems are unquestionably oversimplified; however, they generate testable hypotheses for future investigations that will help to advance and revise these working models, as well as those of other peptide systems in the brain. Under normal conditions, these peptide systems are behaviorally and endocrinologically specific, and they are activated at very different periods of the daily cycle and at different stages of development. However, under pathologic conditions, their specificity and rhythmicity may be greatly disturbed. This occurs in states involving hypercortisolemia along with hyperinsulinemia or insulin deficiency, when these peptide systems become chronically activated. To determine whether this increased activity actually contributes to conditions of hyperphagia and obesity, and, thus, whether a reversal of this neurochemical activity may help in the treatment of these conditions, critical studies with various pharmacological manipulations are required. Of equal importance are investigations examining the development of these pathologic conditions, from birth to maturity, and their associated disturbances in neurochemical and endocrine processes. A thorough understanding of gene expression in localized brain areas and the contribution of various transcription factors to this process should allow the identification and development of methods that are useful in the treatment, as well as prevention, of disturbed patterns of nutrient intake, fat deposition, and body weight gain.

Animals↗
PubMed1994

Galanin-containing neurons in the paraventricular nucleus: a neurochemical marker for fat ingestion and body weight gain.

The physiological function of the peptide galanin (Gal) remains to be established. It is known to exist in high concentrations within the hypothalamus and to modulate the secretion of specific hormones, as well as to potentiate food consumption. Our study provides evidence for an essential function of neuronal Gal, within a specific hypothalamic area, in stimulating the behavioral process of fat ingestion and body weight gain. Through analyses of peptide levels via RIA and of gene expression via in situ hybridization, a close positive association is established between Gal in the paraventricular nucleus (PVN), particularly its midlateral region, and fat ingestion. No such relationship is detected for Gal in other brain areas or between PVN Gal and ingestion of carbohydrate or protein, supporting the behavioral and anatomical specificity of this relationship. Through PVN injection studies with antisense oligonucleotides to Gal mRNA, a dramatic decline in fat ingestion and body weight suggests that endogenous Gal contributes to the natural appetite for fat. Thus, Gal in the PVN is identified as a neurochemical marker for fat ingestion and, consequently, body weight gain.

Analysis of Variance↗
PubMed1994

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 micrograms), 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.

Aldosterone↗
PubMed1994

Hypothalamic galanin-like immunoreactivity and its gene expression in relation to circulating corticosterone.

The neuropeptide galanin (GAL), which exists in dense concentrations within the hypothalamus, has physiological actions which are neuroendocrine in nature. In light of evidence showing GAL to alter the release of the adrenal steroid, corticosterone (CORT), a possible effect of this steroid on GAL gene expression and peptide production in discrete hypothalamic and brainstem sites was investigated. Using radioimmunoassay and in situ hybridization techniques, this peptide was examined in rats that had received SHAM surgery, adrenalectomy (ADX) and ADX+CORT replacement. The results showed a clear, site-specific change in GAL in relation to circulating CORT. A loss of CORT after ADX caused a dramatic decline in GAL peptide and mRNA levels in the arcuate nucleus and peptide levels in the median eminence, with no change occurring in other hypothalamic areas. In the brainstem, a similar change was detected in the dorsal raphe nucleus but not the locus coeruleus. The GAL peptide and mRNA levels in these specific brain areas of ADX rats was restored by CORT replacement, which had no impact on GAL in other brain sites. These findings demonstrate that CORT's impact on brain GAL is highly site specific, possibly determined by local concentrations of steroid receptors.

Adrenal Glands↗
PubMed1994

Diurnal rhythm of galanin-like immunoreactivity in the paraventricular and suprachiasmatic nuclei and other hypothalamic areas.

The peptide galanin (GAL), when injected into the rat hypothalamus, is known to stimulate feeding behavior and affect the secretion of various hormones, including insulin and the adrenal steroid, corticosterone. To determine whether endogenous peptide levels shift in relation to natural rhythms of feeding and circulating hormone levels, rats were sacrificed at different times of the light/dark cycle, and their GAL levels were measured, via radioimmunoassay, in medial hypothalamic dissections and micropunched hypothalamic areas. The results suggest the existence of two distinct diurnal rhythms for hypothalamic GAL. One rhythm, detected exclusively in the area of the SCN, is characterized by bimodal peaks of GAL, threefold higher than basal peptide levels, around the onset of the dark and light periods. The second rhythm shows a single peak of GAL towards the middle of the nocturnal feeding cycle, specifically between the third and sixth hour. This latter rhythm is evident in the dorsal region of the medial hypothalamus, localized specifically to the lateral portion of the PVN. Moreover, it is inversely related to circulating insulin but unrelated to the adrenal steroids, suggesting a possible association between this pancreatic hormone and GAL in the PVN.

Aldosterone↗
PubMed1994

Adrenal steroid receptors: interactions with brain neuropeptide systems in relation to nutrient intake and metabolism.

The glucocorticoid, corticosterone (CORT), is believed to have an important function in modulating nutrient ingestion and metabolism. Recent evidence described in this review suggests that the effects of this adrenal hormone are mediated through two steroid receptor subtypes, the type I mineralocorticoid receptor and the type II glucocorticoid receptor. These receptors, which have different affinities for CORT, respond to different levels of circulating hormone. They mediate distinct effects of the steroid, which can be distinguished by the specific nutrient ingested and by the particular period of the circadian cycle. Under normal physiological conditions, the type I receptor is tonically activated, either by low basal levels of circulating CORT (0.5-2 microgram %) normally available across the circadian cycle or possibly by the mineralocorticoid aldosterone. This type I activation is required for the maintenance of fat ingestion and fat deposition that occurs during most meals of the feeding cycle. In contrast, the type II receptor is phasically activated by moderate levels of CORT (2-10 micrograms %) normally reached during the circadian peak. Activation of this receptor is required for the natural surge in carbohydrate ingestion and metabolism that is essential at the onset of the active feeding cycle when the body's glycogen stores are at their nadir, and gluconeogenesis is needed to maintain blood glucose levels. This receptor is also activated during periods of increased energy requirements, such as, after exercise and food restriction, when CORT levels rise further (> 10 micrograms %) and when its catabolic effects on fat and protein stores predominate to provide additional substrates for glucose homeostasis. These functions of CORT on fat and carbohydrate balance are mediated, in part, by type I and type II receptors located within the hypothalamic paraventricular nucleus, which is known to have key functions in controlling nutrient intake and metabolism, as well as circulating CORT levels. Moreover, the type II receptors within this nucleus, in addition to the arcuate nucleus, may interact positively with the peptide, neuropeptide Y, and the catecholamine, norepinephrine, both of which act to enhance natural carbohydrate feeding and CORT release at the onset of the natural feeding cycle. Thus, under normal conditions, endogenous CORT has a primary function in controlling nutrient ingestion and metabolism over the natural circadian cycle, through the coordinated action of the type I and type II steroid receptor systems. Through this action, CORT has impact on total caloric intake and body weight gain over the long term.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenal Cortex Hormones↗
PubMed1993

Changes in extracellular PVN monoamines and macronutrient intake after idazoxan or fluoxetine injection.

Norepinephrine (NE) and serotonin (5-HT) in the paraventricular nucleus (PVN) have opposite effects on feeding, with NE stimulating carbohydrate intake through alpha 2 noradrenergic receptors and 5-HT inhibiting carbohydrate intake. This study examined the action of drugs that affect brain monoaminergic systems, in terms of their impact on nutrient intake and on PVN monoamines measured using microdialysis. The drugs studied were idazoxan, a blocker of alpha 2 receptors, or fluoxetine, a 5-HT reuptake blocker. In rats maintained on pure macronutrient diets, idazoxan (1 mg/kg) and fluoxetine (10 mg/kg), 120 min after injection both reduced total food intake, and specifically carbohydrate intake. In dialysis experiments, successive 20-min dialysate samples were taken, three samples before and seven samples after intraperitoneal injection of idazoxan (5 and 20 mg/kg), fluoxetine (10 mg/kg), or vehicle. Idazoxan increased NE, homovanillic acid, and dihydroxyphenylacetic acid in the PVN. Fluoxetine induced a significant increment of 5-HT in PVN, while producing a smaller increase in NE, dopamine, and homovanillic acid. These results support the conclusion that the impact of these drugs on macronutrient intake may be a consequence of their action on endogenous monoamine systems in the PVN. Thus, in this nucleus, the blockade of alpha 2-noradrenergic receptors, like stimulation of 5-HT receptors, attenuates normal ingestion of carbohydrate.

Adrenergic alpha-Antagonists↗
PubMed1993

Glucocorticoid receptors in PVN: interactions with NE, NPY, and Gal in relation to feeding.

Norepinephrine (NE) and neuropeptide Y (NPY) potentiate carbohydrate ingestion after injection into the paraventricular nucleus (PVN), whereas injection of galanin (Gal) potentiates fat intake. The present study examines the relation between these neurochemically induced feeding behaviors and the adrenal steroids acting locally within the PVN. Results demonstrate that PVN NE- and NPY-induced carbohydrate intake is abolished by adrenalectomy surgery (ADX) and by local PVN implants of the type II receptor antagonist RU-486. Carbohydrate intake in response to PVN NE or NPY injection is unaffected by the type I antagonist RU-28318. In contrast, the stimulatory effect of PVN Gal injection on fat intake is unchanged by surgical ADX or by PVN administration of RU-486 or RU-28318, suggesting that the stimulatory action of Gal on fat ingestion occurs independently of corticosterone (Cort) and of PVN type I or type II steroid receptors. It is concluded that endogenous Cort has a permissive effect on the carbohydrate feeding responses elicited by NE and NPY in the PVN and that this interaction is mediated by type II glucocorticoid receptors within this nucleus.

Adrenalectomy↗
PubMed1992

Impact of a galanin antagonist on exogenous galanin and natural patterns of fat ingestion.

The peptide galanin (GAL) has a potent stimulatory effect on fat ingestion after administration into the hypothalamic paraventricular nucleus (PVN). This study examined a newly synthesized GAL antagonist, M40, in two separate experiments involving: (1) PVN injections of M40 alone in freely feeding animals, to investigate the importance of endogenous GAL receptor activity in determining natural patterns of fat ingestion, and (2) PVN injections of M40 in combination with exogenous GAL, to determine whether endogenous GAL receptors mediate this peptide-induced response. The results demonstrate that PVN injection of M40 by itself dose-dependently (2-108 pmol) reduces spontaneous ingestion of the fat diet. This phenomenon is robust, behaviorally specific and opposite to that induced by GAL itself. Moreover, the stimulatory effect of PVN-injected GAL on fat ingestion can be blocked by prior PVN administration of M40 at relatively low doses (2-6 pmol), indicating that M40 is a potent antagonist of GAL receptors in the hypothalamus. Together, these results provide the first evidence for the existence of endogenous GAL receptors in mediating the action of exogenous GAL in the hypothalamus. They also constitute a crucial step in demonstrating a physiological function of these PVN GAL receptors in controlling natural patterns of fat ingestion.

Animals↗
PubMed1992

The pharmaco-ontogeny of the perifornical lateral hypothalamic beta 2-adrenergic and dopaminergic receptor systems mediating epinephrine- and dopamine-induced suppression of feeding in the rat.

The functional ontogeny of beta 2-adrenergic and dopaminergic receptors in the perifornical lateral hypothalamus (PLH) that mediate adrenergic and dopaminergic suppression of feeding in rats was investigated. Rat pups, ranging in age from 2 to 15 days, were removed from their mothers and implanted with a brain cannula directed unilaterally at the PLH or a more rostral site lateral to the anterior nucleus of the hypothalamus. On the next day, following a 22-h period of food and water deprivation, each pup was implanted with an intra-oral cannula for oral infusion of milk that could be swallowed or rejected. Subsequently, each pup received an intracerebral injection of saline, or a single dose of epinephrine (EPI, 0.1-30.0 nmol), the beta 2-adrenergic receptor agonist salbutamol (1.0-30.0 nmol) or the dopaminergic receptor agonist apomorphine (1.0-30.0 nmol). Milk intake was then assessed following a 1-h period of infusion. The results showed significant dose-dependent suppression of milk intake in pups as young as 2 days of age in response to PLH injection of EPI, salbutamol and apomorphine. In contrast to its effectiveness in the PLH at 2 days of age, EPI failed to suppress milk intake at this age following injection into a more rostral site lateral to the anterior nucleus of the hypothalamus. Together, these findings suggest that both beta 2-adrenergic and dopaminergic receptors, mediating adrenergic and dopaminergic suppression of feeding, are functionally mature very early in the postnatal development of the rat. Moreover, consistent with evidence in adult rats, these catecholaminergic receptors in young pups appear to be located in the region of the PLH.

Aging↗
PubMed1992

The pharmaco-ontogeny of the paraventricular alpha 2-noradrenergic receptor system mediating norepinephrine-induced feeding in the rat.

The present study was undertaken to assess the functional ontogeny of alpha 2-noradrenergic receptors in the hypothalamic paraventricular nucleus (PVN) that mediate noradrenergic stimulation of feeding in the rat. Rat pups, ranging in age from 2 to 15 days, were removed from their mothers and implanted with a brain cannula directed unilaterally at the PVN or third ventricle. On the following day, each pup was implanted with an intra-oral cannula for oral infusion of milk or water that could be swallowed or rejected. Following a 1-h period of satiation, each pup received an intracerebral injection of saline, or a single dose of norepinephrine (NE, 0.01-100.0 nmol) or the alpha 2-noradrenergic receptor agonist clonidine (0.01-1.0 nmol). Milk or water intake was then assessed following a 1-h period of infusion. Injection of NE into the PVN and third ventricle significantly enhanced milk intake at 2 days of age. NE was 10-fold more potent in the PVN than in the ventricle. While paraventricular injections of NE stimulated milk and water intake equally at 2 days of age, NE produced a greater stimulation of milk than water intake at 15 days of age. Like NE, clonidine significantly enhanced milk intake at 2 days of age following injection into the PVN. Collectively, these findings suggest that alpha 2-noradrenergic receptors, mediating noradrenergic stimulation of feeding, are functionally mature very early in the postnatal development of the rat. Moreover, consistent with evidence in the adult rat, these findings indicate that alpha 2-noradrenergic receptors relevant to feeding are located in the vicinity of the PVN.

Animals↗
PubMed1992

Differential effects of galanin and neuropeptide Y on extracellular norepinephrine levels in the paraventricular hypothalamic nucleus of the rat: a microdialysis study.

Evidence suggests that the peptides galanin (GAL) and neuropeptide Y (NPY) interact with the amine norepinephrine (NE) in the hypothalamic paraventricular nucleus (PVN) to stimulate feeding behavior. To directly investigate the nature of these interactions, extracellular levels of PVN NE were monitored in freely-moving rats using the microdialysis/HPLC technique. Following PVN administration of GAL (0.3 nmol), NPY (78 pmol) or Ringer's solution, local NE levels were measured at 20-min intervals for 2 hrs postinjection, under two feeding conditions, namely, in the presence or absence of food. The results demonstrate different effects of these peptides on endogenous NE levels. Following GAL administration, PVN NE levels were enhanced by 80 to 90%, up to 40 min postinjection, independent of food availability. In contrast, following NPY injection, NE levels were significantly reduced 20 min postinjection with food absent, and when food was available, NE levels tended to be enhanced. These results, consistent with pharmacological and biochemical studies, reveal different patterns of peptide-amine interactions in the PVN.

Animals↗
PubMed1992

Effects of adrenal steroid agonists on food intake and macronutrient selection.

These experiments tested the effects of subcutaneous (SC) and paraventricular nucleus (PVN) administration of the steroid receptor agonists, corticosterone (CORT), aldosterone (ALDO), RU28362, and dexamethasone (DEX), on food intake and macronutrient selection during the first h of the dark feeding period in the rat. Results indicate that CORT and the selective type II receptor agonist RU28362 specifically stimulate carbohydrate ingestion after SC or PVN administration, while DEX has no effect on feeding. This selective effect of SC CORT on carbohydrate ingestion is dose dependent, seen at doses ranging from 0.125 to 2.0 mg/kg. Moreover, the stimulatory effects of CORT and RU28362 on carbohydrate intake are observed in ADX rats but not in sham rats. This is in contrast to SC and PVN administration of the type I receptor agonist ALDO, which specifically enhances fat ingestion in both sham and ADX rats. These results, with both peripheral and central steroid administration, reveal selective effects of type I and type II receptor stimulation on fat and carbohydrate intake, respectively.

Adrenalectomy↗
PubMed1992

Effect of food deprivation and refeeding on the concentration of vasopressin and oxytocin in discrete hypothalamic sites.

Recent evidence has implicated hypothalamic peptides, such as arginine vasopressin (AVP) and oxytocin (OT) in the control of feeding behavior. In this study, we investigated the impact of food deprivation (48 h) and subsequent refeeding (6 h) on the concentration of AVP and OT in discrete hypothalamic areas, as well as in the neurohypophysis. We also estimated in these rats certain peripheral measures, including hydroelectrolytic parameters, plasma and urine AVP, and plasma corticosterone. The results of this study revealed that food deprivation for 48 h produced little change in OT concentration in the various hypothalamic nuclei studied, including the paraventricular and supraoptic nuclei, with the exception of the median eminence (ME), where a significant decline (-36%; p < 0.05) was detected. This effect was not significantly reversed by 6 h of refeeding. With respect to AVP concentration, food deprivation caused a reliable decline exclusively in the parvocellular subdivision of the paraventricular nucleus (pPVN; -45%; p < 0.01) and in the supraoptic nucleus (SON; -45%; p < 0.01). No change in AVP was detected in the ME or in most other hypothalamic nuclei examined. Refeeding for 6 h actually potentiated the effect of food deprivation, decreasing further from baseline the content of AVP in the pPVN and SON. The only other hypothalamic area to exhibit a change in AVP content was the ventromedial nucleus, where AVP level increased (p < 0.001) after deprivation and declined to normal after 6 h of refeeding. The content of AVP and OT in the neurohypophysis was unaffected by food deprivation and subsequent refeeding.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Neurochemical-neuroendocrine systems in the brain controlling macronutrient intake and metabolism.

Appetite, energy balance and body weight gain are modulated by diverse neurochemical and neuroendocrine signals from different organs in the body and diverse regions in the brain. The hypothalamus plays an important integrative function in this process, acting through a variety of systems that involve a close interaction between nutrients, amines, neuropeptides and hormones. These systems underlie normal nutrient intake and metabolism and are thought to be responsible for shifts in feeding behavior across the circadian cycle and fluctuations relating to gender and age in both rats and humans. Moreover, alterations in these normal neurochemical-neuroendocrine systems may be associated with abnormal eating patterns, such as anorexia nervosa, bulimia and obesity. Understanding the systems that control eating behavior might provide a foundation for the treatment and possible prevention of such disorders.

Animals↗
PubMed1992

Blockade of natural and neuropeptide Y-induced carbohydrate feeding by a receptor antagonist PYX-2.

Neuropeptide Y (NPY injected into the paraventricular nucleus (PVN) of rats has a potent stimulatory effect specifically on carbohydrate intake. This study examined the behavioral effects of a newly synthesized NPY antagonist, PYX-2. After PVN injection of PYX-2 (50-900 pmoles) alone, a strong dose-dependent reduction in spontaneous carbohydrate intake at the onset of the dark cycle was observed in freely-feeding rats. Moreover, at even lower doses (12.5 and 25.0 pmoles), PYX-2 also blocked the stimulatory action of PVN NPY (100 pmoles) on carbohydrate ingestion. These results provide the first evidence for the existence of endogenous NPY receptors in mediating the action of exogenous NPY in the hypothalamus. They also constitute a crucial step in demonstrating a physiological function of these PVN NPY receptors specifically in controlling carbohydrate ingestion at the onset of the natural feeding cycle.

Anesthesia↗