Biomedical subjects
N Geary
Publications and source records attributed to N Geary.
Cyclic estradiol treatment normalizes body weight and test meal size in ovariectomized rats.
We tested whether cyclic estradiol treatment, like continuous estradiol treatment, is sufficient to normalize meal size and body weight in ovariectomized rats. In Experiment 1, adult Long-Evans rats were ovariectomized and subcutaneously injected with 0, 0.2, or 2.0 microg estradiol benzoate (EB) in sesame oil each Tuesday and Wednesday. Oil-treated ovariectomized rats gained more weight during 4 weeks of ad lib feeding (48 +/- 5 g) than intact rats (16 +/- 1 g, p < 0.01). Cyclic treatment with 2.0 microg EB normalized weight gain (11 +/- 2 g). During the next week, plasma samples were assayed for estradiol. Cyclic treatment with 2.0 microg EB produced excursions of plasma estradiol that appeared similar to those of intact, cycling rats: estradiol level reached 190 +/- 60 pmol/L after the second EB injection before decreasing to undetectable levels (<30 pmol/L) by cycle end. In Experiment 2, test meal sizes after overnight food deprivation were measured. Cyclic treatment with 2.0 microg EB produced both tonic (i.e., at cycle onset, meal size was smaller in estradiol-treated than oil-treated rats) and phasic (i.e., meal size was smaller late in the EB-treatment cycle than early in it) decreases in meal size. Thus, a weekly cyclic regimen of estradiol treatment that produces changes in plasma estradiol concentration similar to those in intact cycling rats is sufficient to produce the body weight and meal size patterns that characterize normal hypothalamic-pituitary-gonadal function.
Cyclic estradiol treatment phasically potentiates endogenous cholecystokinin's satiating action in ovariectomized rats.
The influence of ovarian cycling and of exogenous estradiol on the cholecystokinin (CCK) satiety-signalling system was investigated in intact and ovariectomized Long-Evans rats, respectively. Intraperitoneal injection of 1 mg/kg devazepide, the most potent and selective CCK(A) receptor antagonist, increased test meal size during estrus, but not during diestrus, confirming the influence of hypothalamic-pituitary-gonadal function on CCK satiety in intact rats. Devazepide was then tested in ovariectomized rats that received chronic cyclic estradiol (2 microg estradiol benzoate on Tuesday and Wednesday each week) or oil treatment. Devazepide did not increase meal size in estradiol-treated rats on Tuesday, prior to estradiol treatment, compared to oil-treated rats, but did selectively increase meal size on Friday, late in the estradiol replacement cycle, compared to Tuesday, early in the cycle. These results suggest that a phasic potentiation of the endogenous CCK satiety-signalling system is part of the mechanism for the decrease in meal size in female rats during estrus.
Endogenous cholecystokinin's satiating action increases during estrus in female rats.
Food intake and meal size are reduced in female Long-Evans rats during estrus. To investigate the contribution of the satiating action of endogenous cholecystokinin (CCK) to this, rats were injected with 1 mg/kg of the potent, selective CCK(A) receptor antagonist, devazepide, during diestrus, when meal size is maximal, and during estrus, when it is minimal. Devazepide increased spontaneous food intake and meal size during estrus, but not during diestrus. Meal frequency was not affected by devazepide treatment. These results indicate that the potency of the CCK satiety-signaling system increases during estrus.
Prior pregastric food stimulation and gastrin-releasing peptide1-27 (GRP) synergize to inhibit sham feeding.
The hypothesis that prior pregastric food stimulation is sufficient to reveal an inhibitory effect of gastrin-releasing peptide1-27 (GRP) on sham feeding was tested in 11 male rats equipped with chronic gastric cannulas. Rats were sham fed a high-carbohydrate solution during a 45-min test session, after 17-h food deprivation. GRP (16 or 32 microg/kg) or saline was injected intraperitoneally either at the onset or 5 or 15 min after the onset of sham feeding. This allowed for a 0-, 5-, or 15-min period of pregastric food stimulation before GRP or saline injections. Sham intake was recorded every 5 min, and behavior was observed every minute. GRP inhibited sham feeding when it was administered after 5 or 15 min of prior pregastric food stimulation, but not when it was administered at test onset. A nonsignificant increase in resting behavior and decrease in feeding behavior were associated with the decrease in sham feeding. No anomalous behaviors were noted. We conclude that a synergy between GRP and prior pregastric, presumably oral, food stimulation is sufficient to inhibit sham feeding.
Effects of glucagon, insulin, amylin and CGRP on feeding.
The roles of the pancreatic peptides glucagon, insulin, and amylin in the inhibitory control of feeding are reviewed. Calcitonin gene-related peptide (CGRP) is also included because it is structurally and functionally related to amylin and because known amylin and CRRP receptors are activated by both peptides. Glucagon-like peptide 1, in contrast, is structurally distinct from pancreatic glucagon and does not cross-react with glucagon receptors, so it is not considered. Several detailed reviews of the feeding effects of these peptides have appeared recently; where appropriate, these are cited rather than the primary literature.
Intracerebroventricular glucagon-like peptide-1 (7-36) amide inhibits sham feeding in rats without eliciting satiety.
Glucagonlike peptide-1 (7-36) amide (GLP-1) and its receptors are present in several brain regions and may play a role in the physiological control of feeding. To investigate the effect of GLP-1 on eating in the absence of postingestive food stimuli, rats were implanted with gastric cannulas for sham feeding and lateral ventricular cannulas for infusion of GLP-1. Rats (n = 10) sham fed 0.8 mol/L sucrose for 45 min, beginning 5 min after intracerebroventricular (icv) infusion of 2.5 microL of artificial cerebrospinal fluid with 0-30 microg of GLP-1 . Behaviors were observed each minute using a time-sampling technique. Additionally, lick-by-lick records of the microstructural pattern of sucrose intake were made during the first 15 min of each test for five rats receiving 3 and 10 microg of GLP-1. GLP-1 decreased sham-fed intake by as much as 50%, but GLP-1 did not terminate sham feeding. The frequency of observations of feeding was decreased, but the frequency of resting, the terminal item in the behavioral sequence of postprandial satiety in real feeding rats, did not reliably increase. No abnormal behaviors were observed. Although GLP-I did not affect the latency to begin sham feeding, it significantly reduced the initial rate of licking. GLP-I did not affect the motor aspects of licking, because the interlick intervals within individual bursts of licking or overall lick efficiency were normal. These data suggest that intracerebroventricular infusions of GLP-1 inhibit sham feeding by decreasing the orosensory positive feedback that drives licking, rather than by activating physiological satiating mechanisms or nonspecific mechanisms such as aversion or motor incapacity.
Behaviorally specific inhibition of sham feeding by amylin.
To further characterize amylin's inhibitory action on feeding, we examined the effects of intraperitoneal injections of amylin on sham feeding of sucrose in food-deprived male rats with chronic gastric cannulas. Thirty and 100 microg/kg amylin reduced sham feeding, but did not terminate it or elicit the behavioral sequence of satiety. Real feeding of sucrose, but not sham feeding, was reduced after injection of 10 microg/kg amylin. Amylin's inhibitory effect on sham feeding appeared behaviorally specific because neither 30 nor 100 microg/kg amylin affected sham drinking of water in thirsty rats and because no abnormal behaviors occurred. We conclude that amylin has a behaviorally specific satiating effect on sucrose sham feeding that is insufficient to elicit satiety in absence of gastric or postgastric food stimulation.
Chronic administration of OB protein decreases food intake by selectively reducing meal size in male rats.
The potent hypophagic effect of OB protein (OB) is well established, but the mechanism of this effect is largely unknown. We investigated the effects of chronic administration of a novel modified recombinant human OB (Mod-OB) with a prolonged half-life (>48 h) on ad libitum food intake, spontaneous meal patterns, and body weight in 24 adult, male Sprague-Dawley rats (body weight at study onset: 292 g). Single daily subcutaneous injections of Mod-OB (4 mg/kg daily) for 8 consecutive days significantly reduced ad libitum food intake compared with vehicle injections from injection day 3 through postinjection day 3. Mod-OB-injected rats ate between 4.5 and 7.1 g (or 13-20%) per day less than controls, with the reduction primarily occurring during the dark period. Body weight gain was significantly decreased in response to Mod-OB from injection day 8 until postinjection day 4, with a maximum difference of 24 g on postinjection day 3. The reduction of food intake by Mod-OB was mainly due to a 21-34% decrease in nocturnal spontaneous meal size. There was no significant effect of Mod-OB on nocturnal meal frequency or duration. Mod-OB also did not reliably affect the size, duration, or frequency of diurnal meals. Mod-OB-injected rats displayed no compensatory hyperphagia after the injection period. These results indicate that chronically administered OB selectively affects the mechanisms controlling meal size in male rats.
Chronic administration of OB protein decreases food intake by selectively reducing meal size in female rats.
The mechanisms by which OB protein controls food intake and energy balance are unknown. Therefore, we investigated the effects of a novel modified human recombinant OB protein (Mod-OB) on spontaneous feeding patterns, body weight, running wheel activity, and ovarian cycling in female rats. Mod-OB or vehicle was injected (4 mg . kg-1 . day-1 sc) for 2 ovarian cycles (8 days) using a within-subjects design. Observations were continued for five ovarian cycles after injections; treatments were then reversed. Mod-OB reduced food intake approximately 20% from injection day 1 to postinjection day 2. Body weight was reduced from injection day 3 to postinjection day 15 (maximum decrease, 25 +/- 4 g, postinjection days 3 and 4). Food intake was reduced due to decreases in nocturnal meal size, which appeared to be superimposed on the normal pattern of spontaneous feeding (i.e., reductions in meal size at estrus). Mod-OB did not significantly affect diurnal food intake or meal patterns, failed to alter wheel running, and did not disrupt the rats' ovarian cycles. We conclude that chronically administered Mod-OB reduces food intake in female rats by selectively affecting the mechanisms controlling meal size.
The effect of estrogen on appetite.
Such eating disorders as anorexia nervosa, bulimia nervosa, and binge eating disorder are associated with significant morbidity and mortality in women. The etiology of these disorders and the causes of women's increased vulnerability to them remain obscure. The lack of understanding of the biological bases of normal and abnormal human eating behavior impedes development of effective pharmacologic treatment for eating disorders. A review of basic research, implicating estradiol in the physiologic control of eating in laboratory animals, shows potential heuristic and mechanistic significance for normal and disordered eating in women. Furthermore, accumulating evidence indicates that estradiol may decrease meal size by increasing the potency of the satiating actions of some gut peptides, especially cholecystokinin. These findings suggest there may be hope for treatment through manipulation of estradiol's interactions with both peripheral psychological and central neural controls of eating.
Ovariectomy and estradiol affect postingestive controls of sucrose licking.
Ovariectomy (OVX) has been shown to increase, and estradiol replacement to decrease, meal size in rats. Because little is known about how estradiol influences meals, we conducted two experiments to examine the effects of OVX and beta-estradiol 3-benzoate (EB) replacement on the microstructure of licking behavior. In both experiments, patterns of licking were analyzed in adult female Sprague-Dawley rats during an 0.8 M sucrose test meal. In Experiment 1, meal microstructure was determined preOVX and 10-12 days postOVX. Rate of licking following OVX was not changed during min 1 of the meal, but was significantly faster during min 2-4 of the meal (p < 0.03). The numbers of bursts (runs of licks separated by 250-500 ms) and numbers of clusters (runs of licks separated by > 500 ms) were significantly increased during min 2-4 (p < 0.05). In Experiment 2, OVX rats received EB replacement. Rate of licking after EB replacement was not changed during min 1 of the meal, but was significantly slower during the remainder of the meal (min 2-4, min 5-7, and min 8-10). Burst size, cluster size, and interburst interval were less after EB replacement during min 5-7 of the test meal (all p < 0.05). Because both OVX and EB replacement failed to alter the rate of licking during min 1, estrogen did not appear to alter the palatability of sucrose. OVX and EB replacement did appear to affect a postingestive mechanism(s) that is engaged within 2-4 min of meal onset.
The satiating potency of hepatic portal glucagon in rats is not affected by [corrected] insulin or insulin antibodies.
To characterize the interactive effects of acute prandial manipulations of insulin and glucagon on spontaneous feeding in adult male rats fed ad lib, glucagon (G) and insulin (1) or insulin antibodies (IAb) were confused into the hepatic portal vein during the first meal of the dark phase. Infusions (3-6 min, 33 microliters/min) were remotely controlled, and a computerized system recorded meal patterns. In Experiment 1, five separate factorial designs were used to test the effects of G (1.3 or 13 micrograms/meal) alone, I (1.3 or 2.7 mU/meal) alone, or both G + I. The peptides were infused either simultaneously or sequentially (G before I). The larger dose of G alone reduced meal size. I neither inhibited feeding nor increased the effects of either G dose. In one test, 13 micrograms/meal G did not block meal size when followed by 2.7 mU I, but this antagonism did not occur in a replication. In several tests, there was a trend for I to decrease the size of the spontaneous meal that followed the meal during which I was infused, but this was statistically significant only once. Intermeal intervals were not affected in any test. Experiment 2 tested coinfusions of 20 micrograms G and polyclonal IAb with an in vitro binding capacity of 40 mU rat insulin. G alone reduced meal size, IAb alone increased meal size, and G + IAb produced an additive effect. These data extend previous investigations of the satiating action of G and I in the rat and indicate 1. that exogenous I does not affect the satiating potency of G; 2. that exogenous G and endogenous I elicit an additive synergistic inhibition of spontaneous meal size; and 3. that G-induced I secretion does not mediate the satiating effect of G.
Speed of glucagon's glycogenolytic effect.
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Estradiol and the control of eating.
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The increased satiating potency of CCK-8 by estradiol is not mediated by upregulation of NTS CCK receptors.
Estradiol benzoate (EB) increases the satiating effect of CCK-8 in ovariectomized rats. It is possible that this effect of EB is due to upregulation of CCKA receptors in the terminals of vagal afferent fibers because these receptors have been implicated in the mediation of the satiating effect of intraperitoneally injected CCK-8. To test this hypothesis, we used in vitro quantitative autoradiography to measure the effects of EB on the binding characteristics of CCK receptors in the nucleus tractus solitarius (NTS), a region that contains central terminal projections of abdominal vagal afferent fibers. As additional measures of EB's effects on CCK receptors, we also characterized EB's effects on CCK.8 binding in the area postrema (AP), a brain region rich in CCKA receptors, the ventromedial hypothalamus (VMH), a region rich in CCKB receptors, and in the pancreas, a gland rich in CCKA receptors. Saturation binding experiments were run using [125I]CCK-8 (approximately 40 pM, 2200 Ci/mmol) and 0.1-100 nM unlabelled CCK-8. EB did not change the number (Bmax) or affinity (Kd) of CCK receptors in the NTS. Furthermore, competition experiments with 500 nM of the selective CCKA receptor antagonist devazepide or the selective CCKB antagonist L365,260 demonstrated that EB failed to affect CCK receptor subtype number in the medial and lateral divisions of the NTS. EB also did not affect binding in the AP or VMH. These results do not confirm our hypothesis. The lack of effect of EB on vagal CCKA receptors in the NTS was not due to inappropriate conditions of tissue sampling or autoradiographic technique because EB increased the number, but not the affinity, of CCKA receptors in the pancreas significantly.
Vena caval bombesin infusion decreases spontaneous meal size in undisturbed rats.
The amphibian tetradecapeptide bombesin (BN) decreases food intake in both humans and animals. Studies have typically examined the effects of BN on scheduled meals in deprived subjects. To investigate the properties of this peptide under more naturalistic conditions, we examined the effects of BN in spontaneously feeding rats. Undisturbed, ad lib-fed male rats (n = 9) with chronic inferior vena caval catheters were infused with saline vehicle and each of 3 doses (2, 4, and 8 micrograms/kg) of BN in counterbalanced order with intervening noninfusion days. Infusions were remotely activated at the onset of the first nocturnal meal and continued for 3 min (34 microliters/min), delivery being completed within the first 2 min of infusion. Feeding was measured via electronic balances linked to a computer. All doses of the peptide significantly decreased the size and duration of the first nocturnal meal. In addition, 4 and 8 micrograms/kg of BN significantly shortened the intermeal interval from the end of the first meal to the beginning of the second meal. Despite this, the satiety ratio (interval/meal size) tended to increase after BN and was significantly increased by the highest dose (8 micrograms/kg), thus indicating a sustained satiety action of the peptide. In summary, these results show that brief, meal-contingent intravenous infusions of BN potently inhibit spontaneous feeding in undisturbed rats.
Brief, meal-contingent infusions of gastrin-releasing peptide1-27 and neuromedin B-10 inhibit spontaneous feeding in rats.
We have previously shown that brief, meal-contingent infusions of the amphibian peptide bombesin (BN) reduce meal size in spontaneously feeding rats. These inhibitory effects presumably reflect actions of BN on receptors for its mammalian homologues, which include gastrin-releasing peptide1-27 (GRP) and neuromedin B-10 (NMB). In the present study, we used the spontaneous feeding paradigm to explore the effects of meal-contingent infusions of these mammalian homologues. Undisturbed, ad lib-fed male rats (n = 12) with chronic inferior vena caval catheters were infused with saline, 5 nmol/kg GRP, 5 nmol/kg NMB, and a mixture of 5 nmol/kg GRP and 5 nmol/kg NMB in counterbalanced order, with intervening noninfusion days. Infusions were remotely activated at the onset of the first nocturnal meal and continued for 3 min (34 microliters/min), delivery being completed within the first 2 min of infusion. Feeding was measured via electronic balances linked to a computer. The effects of all peptide conditions were confined to the first nocturnal meal. Significant and comparable decreases in the size and duration of this meal were observed with GRP, NMB, and GRP + NMB, with no significant effects on the intermeal interval or satiety ratio (intermeal interval/meal size). Thus, brief vena caval infusions of GRP and NMB, given alone or together at the onset of the first nocturnal meal, significantly reduced meal size and duration in spontaneously feeding rats.