Effects of food restriction and adrenalectomy in rats with VMH or PVH lesions

The effects of adrenalectomy in rats with ventromedial or paraventricular hypothalamic lesions have been studied in two experiments. Rats with ventromedial hypothalamic lesions or lesions in the paraventricular nucleus were allowed to gain weight for fourteen days at which time they were adrenalectomized. Before adrenalectomy, animals with VMH lesions ate more, gained significantly more weight than animals with lesions in the paraventricular nucleus, and both were significantly heavier and consumed more food than sham-operated controls. Following adrenalectomy, food intake decreased and both groups of lesioned animals lost weight. The animals with VMH lesions stabilized at weights above the control animals. Implantation of corticosterone enhanced weight gain and food intake in animals with lesions in either the paraventricular nucleus or the ventromedial hypothalamus. In the second experiment, one subgroup of rats with VMH lesions was adrenalectomized, and allowed to eat ad lib. Two other groups of sham-operated rats with VMH lesions served as controls. One group ate ad lib and one group was pair fed to the food intake of the adrenalectomized VMH-lesioned rats. Weight gain in the adrenalectomized VMH-lesioned rats and the pair-fed VMH-lesioned controls was similar and less than the VMH-lesioned rats eating ad lib. GDP binding to interscapular brown adipose tissue was related to the degree of weight gain, not to the presence of the VMH lesion. These data show that corticosterone is essential for the expression of obesity in both PVH- and VMH-lesioned rats. They also argue that the reduction in the activity of the sympathetic nervous system of VMH-lesioned rats as estimated by the GDP binding to mitochondria from brown adipose tissue is associated with hyperphagia.     

Relation between estrogen-induced hyperlipemia and food intake and body weight in rats

Thirteen experiments on 348 ovariectomized female rats examined the relationship between estradiol's effects on food intake and body weight and on plasma triglycerides, free glycerol, and fatty acids. The time course of estradiol benzoate effects on food intake and weight gain differed from the time course of triglyceride elevation. The antiestrogen, nafoxidine, given with estradiol blocked the hypertriglyceridemia, but not the weight loss, resulting from estradiol benzoate. Estradiol benzoate treatment for up to three days had no significant effect on plasma triglyceride levels following intragastric and intravenous triglyceride administration. Changes in plasma triglyceride following Triton WR-1339 indicated that the absolute rates of plasma triglyceride clearance were not impaired by estradiol. These results contradict Wade and Gray's [31] hypothesis about the mechanism of estradiol-induced hypophagia.     

The relationship between body weight and estradiol-induced activity

Estradiol-induced activity was found to be of equal magnitude in ovariectomized rats allowed to achieve supranormal body weight and in ovariectomized animals restricted to preoperative weight. The results suggest that estradiol-induced activity is not weight regulatory.     

Estradiol and insulin: independent effects on eating and body weight in rats.

The effects of ovariectomy and estradiol replacement were determined in streptozotocin-diabetic female rats maintained on daily injections of protamine zinc insulin. Similar changes in food intake and body weight in these animals and in nondiabetic control animals indicate that the effects of estradiol on these measures are probably not dependent on changes in pancreatic insulin secretion. Acute and chronic insulin challenges in ovariectomized rats maintained on estradiol benzoate, nafoxidine or oil were also examined. The effects of insulin were not attenuated by prior estrogen conditioning, and there was no evidence of insulin resistance. These experiments suggest that the effects of estradiol on body weight and food intake in female rats are not dependent upon altered insulin levels nor attenuation of the effects of insulin. Estradiol may exert its influence on eating and body weight via separate and possibly more direct pathways. The data also are consistent with the suggestion that ovariectomy-induced and hypothalamic obesities are separate phenomena.     

Aldosterone-stimulated feeding and weight gain: Interactions with estrogen?

The effects of combined adrenalectomy-ovariectomy and steroid replacement on food intake, spillage, body weight, skeletal growth, and fluid retention were investigated in rats that were fed freely or held to a controlled allotment. The stimulation of feeding and weight gain by aldosterone was not dependent upon the presence of estradiol. Likewise, the suppression of food intake and weight gain brought about by estradiol was not influenced by aldosterone, leading us to conclude that the effects of the two hormones are independent and additive, not interactive. Estradiol and aldosterone each significantly altered the rate of food spillage and in opposite directions. There was a marked reduction in the extent to which estradiol influenced body weight in the controlled feeding situation. Accompanying this was a differential effect of estradiol on body growth. Depending upon feeding condition, estradiol either retarded (free-feeding) or accelerated (restricted) skeletal growth. Aldosterone's stimulation of weight gain was nearly proportional across feeding conditions, and it did not influence body growth.     

Response to glucoprivic and hydrational challenges by normal and hypothalamic hyperphagic rats

Obese VMH-lesioned rats displayed normal, but delayed, increases in food intake to 350 mg/kg 2-deoxy-D-glucose (2-DG) and were hyperresponsive to 4 and 8 U of insulin. Lesioned rats maintained at preoperative body weight responded normally to insulin, but did not increase food consumption to 350 mg/kg 2-DG. Both lean and obese lesioned rats decreased feeding following 750 mg/kg 2-DG. The lesioned animals displayed either no change or an increase in water/food ratios. Those with normal water/food ratios showed a loss in circadian control of water intake and drank less than controls during food deprivation. VMH-lesioned rats responded normally to polyethylene glycol and were hyperresponsive to hypertonic saline regardless of differences in body weight or water/food ratios. The possibility of ventromedial hypothalamic damage producing a general increase in responding, or numerous more specific effects, is discussed.     

Estradiol induced suppression of feeding in the female rat: dependence on body weight

Ovariectomy in the adult female rat leads to a transient increase in food intake and an elevated level of body weight. Estrogen treatment blocks or reverses these changes. Currently, estrogen is seen to suppress feeding directly, but earlier findings suggest that estrogen's effect is dependent upon an elevated level of body weight. We demonstrate that 1 μg estradiol, which has suppressant effects on food intake and body weight in ovariectomized (OVX) rats, has no such effects in ovariectomized-adrenalectomized (OVX-ADX) rats, which do not gain excess weight spontaneously. However, estradiol does have a suppressant effect on these measures in OVX-ADX rats, if they are made mildly obese by dietary means. Therefore, estradiol suppresses feeding only in the face of actual or impending obesity. It probably affects the system(s) concerned with the long-term regulation of body weight; but it does not act directly on the mechanisms which mobilize or inhibit feeding.     

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.     

Progesterone can either increase or decrease weight gain and adiposity in ovariectomized Syrian hamsters

We examined the effects of estradiol and progesterone on weight gain, food intake, and carcass composition in Syrian hamsters (Mesocricetus auratus). In ovariectomized (OVX) hamsters injections of 5 micrograms/day estradiol benzoate (EB) alone decreased weight gain and adiposity, whereas treatment with progesterone alone (1 or 5 mg/day) resulted in increased weight gain and adiposity. However, concurrent treatment with progesterone and EB reduced body fat content to levels significantly below those of hamsters treated with EB alone. In a second experiment, 17 beta-estradiol and progesterone were administered via subcutaneous Silastic capsules in doses which produce physiological levels of steroids. Implants of estradiol significantly decreased body weight gain and fat content. As in the first experiment, these effects of estradiol were exaggerated by concurrent progesterone administration. Implants of progesterone alone did not affect body weight or fatness in OVX hamsters. These data indicate that estradiol and progesterone interact to decrease body lipid stores in hamsters, whereas in rats progesterone reverses the adiposity-reducing actions of estradiol. This species difference in responses to progesterone could help to explain why rats increase, whereas hamsters decrease, their body lipid stores during pregnancy, when circulating progesterone levels are elevated.     

Effects of selective estrogen receptor agonists on food intake and body weight gain in rats

Ovariectomized (OVX) rats eat more and gain weight more rapidly than sham-operated (SO) rats and estradiol (E(2)) treatment attenuates food intake and body weight gain in OVX rats. Studies were designed to test the hypothesis that the alpha subtype of the estrogen receptor (ERalpha) mediates the attenuating effects of E(2) on food intake and body weight gain while the beta subtype (ERbeta) mediates opposing actions that lead to increased food intake and body weight gain. Female rats were SO or OVX and treated daily with vehicle (dimethylsulfoxide, DMSO) or E(2) (10 microg/day), or the ERalpha-selective agonist, 4,4',4'-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT, 0.5 mg/day), or the ERbeta-selective agonist, 2,3-bis(4-hyroxyphenyl)-propionitrile (DPN, 0.5 mg/day) for 14 days. Total food intake was significantly reduced by E(2) and PPT, but not DPN. Total body weight gain was significantly increased in OVX rats compared to SO rats and treatment with E(2) or PPT, but not DPN, significantly decreased total body weight gain to levels that were not significantly different from SO rats. A dose-response study of PPT indicated that at 0.25 mg/day, PPT significantly reduced total 21-day food intake and body weight gain and, at 0.13 and 0.06 mg/day, PPT significantly reduced total body weight gain compared to OVX rats without significantly reducing total food intake. A dose-response study of DPN indicated that none of the three doses of DPN significantly altered total 21-day food intake or total body weight gain. These results suggest ERalpha mediates the attenuating effects of estrogens on food intake and body weight gain while ERbeta has no effect on these variables.     

Ovarian hormone effects on activity, glucoregulation and thyroid hormones in the rat

Ovarian hormonal influences on the range of physiological and behavioral variables which combine to affect overall energy balance are poorly delineated. In the present study 4 groups of virgin, female rats (intact, ovariectomized, ovariectomized with estrogen replacement and ovariectomized with estrogen plus progesterone) were allowed access to running wheels and activity; food intake and weight gain were measured initially under food restricted, then under ad lib conditions. Serum insulin, glucose, thyroxine (T4) and triiodothyronine (T3) were determined on trunk blood samples obtained at the end of the experiment. Ovariectomy resulted in an increased rate of weight gain through reduced activity and T3 but food intake was unchanged. Insulin levels were greatly reduced. Estrogen replacement restored activity to the intact group's level and normalized weight gain. Insulin and T3 were also raised to control levels but T4 was reduced as was serum glucose. Estrogen plus progesterone replacement reduced weight gain markedly and increased T3 with normal T4. Despite the lower body weight this group was hyperglycemic and hyperinsulinemic suggesting insulin resistance. The results have important implications for the glucoregulatory and energy balance perturbations of ovarian hormone fluctuations and focus particularly on progesterone.     

Effects of estradiol on food intake and meal patterns for diets that differ in flavor and fat content

Apart from the well known inhibitory effects of estradiol on food intake, meal size, and body weight in female rats that have been documented over the past thirty years, a more recent report presents the opposite finding; that a large dose of estradiol can increase food intake and weight gain in gonadally intact female rats presented with a palatable diet. The purpose of the present experiment was to further examine this hypothesis by evaluating the ability of estradiol to influence feeding behavior in ovariectomized rats presented with diets that differ in flavor and fat content. Female rats were given a cyclic regimen of estradiol benzoate treatment (5.0 or 20.0 µg) or the oil vehicle and were presented with the standard chow diet or a diet with a higher fat content and chocolate flavor. Food intake, meal size, and meal number were monitored three days after the first injection of estradiol or oil. Compared to the chow diet, food intake increased when animals had access to the chocolate/fat diet during the vehicle treatment condition. Both doses of estradiol significantly decreased food intake, meal size, and body weight gain when animals were presented with either the standard chow diet or the chocolate/fat diet. These findings indicate that estradiol does not stimulate the intake of a palatable diet in ovariectomized rats, and suggest that previous results showing that estradiol enhanced eating and weight gain stemmed from a disruption of the hypothalamic-pituitary-gonadal axis when intact females received a large dose of exogenous estradiol.     

Ventromedial hypothalamus vs. lateral hypothalamic D2 satiety receptors in the body weight increase induced by systemic sulpiride

Two experiments were conducted in order to see if dopamine satiety receptors in the lateral hypothalamus or satiety mechanisms in the ventromedial hypothalamus were involved in the hyperphagia and body weight increase induced by systemic sulpiride. In the first experiment, it was shown that systemic sulpiride (20 mg/kg) does not block the anorexia caused by intraperifornical injections of amphetamine. In the second experiment, sulpiride (20 mg/kg during 18 days) did not produce an additional increase in body weight in previously VMH-lesioned female rats. This last fact cannot be explained by a ceiling effect since insulin (5 U/day during 7 days) increased body weight in the same VMH rats in which sulpiride was not effective. These results do not support the hypothesis that systemic sulpiride reaches the perifornical dopamine D2 receptors to disinhibit feeding, but suggest instead an involvement of the ventromedial hypothalamus. This last suggestion is more in agreement with the hypothesis that sulpiride alters feeding and body weight gain through the induction of a functional gonadectomy.     

Chronic weight loss in lean and obese rats with a brain-enhanced chemical delivery system for estradiol

Studies were undertaken to determine the effects on body weight and food intake of a chemical delivery system which preferentially delivers estradiol (E2) to the brain and there serves as a source for the sustained release of the steroid. We injected intravenously various doses of this estradiol-chemical delivery system (E2-CDS), E2-valerate (E2-VAL) or the dimethyl sulfoxide (DMSO) vehicle to young lean male rats and monitored body weight and 24 hr food intake for 39 days postinjection. E2-VAL caused a transient reduction in food intake and body weight gain. By contrast, a single injection of E2-CDS caused a chronic, dose-dependent reduction in the rate of body weight gain. In these lean rats, the duration of reduced body weight gain was not correlated with the observed transient reduction in food intake. In aged, obese male rats, E2-CDS caused a marked and chronic dose-dependent reduction in body weight. In contrast to lean rats, E2-CDS caused a long-term reduction in food intake in obese rats. To evaluate the importance of the E2-CDS-induced reduction in food intake in the observed persistent weight loss in obese rats, E2-CDS was administered to a group of obese rats and a second group which received the DMSO vehicle was pair-fed an equivalent amount of food daily. The resulting weight loss in both groups was equivalent. These results show that the enhanced delivery of E2 to the brain with the E2-CDS causes sustained reduction in the rate of body weight gain in lean rats and persistent weight loss in obese animals.     

Early weight gain and behavioral responsivity as predictors of dietary obesity in rats

Variance in diet-induced weight gain was examined for possible relationships with variations in early weight gain and three tests of behavioral responsivity. Female Sprague-Dawley rats were reared in litters of 4, 8, or 20. When animals reached adulthood, each animal's acoustic startle reflex, tail-pinch feeding responses and activity in an open field containing a palatable food were assessed. After completing these behavioral tests, rats were exposed to either palatable foods or a control diet for 59 days, following which all subjects were maintained on the control diet for 66 days. Body weights, food intakes, and naso-anal lengths were measured. Preweaning body weight gain for all rats correlated positively with later diet-induced weight gain. Rats reared in litters of 4 or 20 both gained less weight after exposure to palatable foods than did rats reared in litters of 8. Diet-induced weight gain correlated positively with magnitude of acoustic startle reflex and with latency to eat in response to tail pinch. These results tentatively identify specific predictive factors which may be useful in future studies of dietary obesity.     

Ventromedial hypothalamic lesions in rats: Gradual elevation of body weight set-point

Bilateral electrolytic (DC) or radiofrequency (RF) lesions of the ventromedial hypothalamic (VMH) area produced two abnormal stages of fattening in adult female rats. Following a negatively-accelerated, curvilinear phase of weight gain which lasted 10 weeks, a linear phase of fattening continued for an additional 30 weeks at a rate approximately double that of operated control rats of the same age. During this second phase of fattening, lesioned rats were food-restricted between the 20th and 26th weeks postlesion. Compared to the rate of weight gain in the linear phase prior to food restriction, the rate over the same weight range following release from food restriction was significantly greater for both DC and RF-lesioned rats. Furthermore, by the 40th postlesion week, the lesioned rats had approached the weight they would have been if not food restricted. These observations suggest that VMH area lesions induce a gradual climbing of the set-point for body weight which occurs independently of actual food intake or body weight, and which either follows or is superimposed on the immediate elevation of the set-point responsible for the initial, curvilinear phase of weight gain. As a model for human idiopathic obesity, the long-term effect of VMH area lesions may be more important than the immediate effect.     

Estradiol decreases the orexigenic effect of melanin-concentrating hormone in ovariectomized rats

Estradiol exerts an inhibitory effect on food intake via interactions with anorexigenic peptides, like cholecystokinin, that function to decrease meal size. It is currently unknown whether estradiol also interacts with orexigenic compounds implicated in the physiological control of food intake. Thus, the primary goal of this study was to determine whether estradiol decreases the orexigenic effect of melanin-concentrating hormone (MCH), a neuropeptide that, like estradiol, appears to influence food intake by selectively affecting the controls of meal size. Food and water intake were monitored following lateral ventricular (icv) infusions of 5 mug MCH or saline vehicle in oil- and estradiol-treated ovariectomized rats. MCH increased food intake throughout the first 4 h of the dark phase in oil-treated rats, but only for the last 2 h of the same 4-h interval in estradiol-treated rats. As a result, the orexigenic effect of MCH was significantly lower in estradiol-treated rats, relative to oil-treated rats. During this interval of MCH-stimulated feeding, a prandial increase in water intake was not observed in either oil- or estradiol-treated rats. We conclude that estradiol decreases the orexigenic effect of MCH in ovariectomized rats.     

Body weight gain and food intake alterations in crowd-reared rats

The effect of being reared in a crowd for 6 continuous weeks postweaning on body weight gain, food intake and gland weight (thymus, adrenals and testes) was studied in Sprague-Dawley adult male rats. Crowd-reared rats (10 per cage) showed a significantly lower body weight at the end of the crowding period as compared to control rats (5 per cage). After 200 days of being reared under the same conditions (5 per cage), the body weights of crowd-reared rats were still significantly lower than those of control rats. However, the body weight gain during this period was the same for both groups. Crowd-reared rats also had significantly lower thymus weight and higher adrenal gland and testes weights as compared to those weights of control rats. In addition, food intake was similar for both groups.     

Gonadal hormones and behavioral regulation of body weight

Gonadal hormones have important effects on the behaviors that determine body weight in laboratory rats (i.e., eating, locomotor activity, and thermoregulatory behavior). These effects are most evident in the female where there are consistent, predictable changes in these behaviors which are correlated with fluctuations in plasma hormone levels during estrous cycles, puberty, pregnancy, or after gonadectomy and replacement therapy. Estradiol, which seems to be the principal ovarian steroid affecting body weight, may act directly on separate neural loci to: (a) inhibit food intake and (b) stimulate locomotor activity, possibly by lowering the set-point of a hypothalamic lipostat. Estradiol does not affect eating and running in prepubertal female rats, perhaps because of influences of pituitary hormone(s) at this age. Ovarian hormones also alter the taste preferences of rats and may be responsible for the changes in self-selection of dietary components during different reproductive states. Some implications of this research are discussed and possible directions for future research suggested.     

Age, sex and reproductive status alter the severity of anorexia in zinc deficient rats

Food intake and body weight gain in rats fed a zinc-deficient diet are reported. The severity of zinc deficiency-induced anorexia was observed to be dependent upon the age, sex and reproductive status of the animal. Rapidly growing rats such as weanlings, adult males, or ovariectomized females demonstrated more rapid induction of anorexia and more severe effects on cumulative food intake and body weight gain when fed zinc-deficient diets than did slowly growing (nonpregnant female adult) rats given the same diet. These results suggest that feeding in zinc-deficient animals is not regulated by dietary zinc concentration alone, but rather is mediated by one or several as yet undefined factors.