Changes in ingestive behaviors and body weight following intracranial application of 17 alpha-estradiol

The present experiment was conducted to determine if central implants of 17 alpha-estradiol could influence food intake, water intake, and body weight in ovariectomized rats. A total of fifteen animals were fitted with bilateral guide cannulae in the paraventricular nucleus (PVN) and stimulated unilaterally with cholesterol and 17 alpha-estradiol in each side of the brain. Compared with cholesterol treatment, 17 alpha-estradiol implants in the PVN significantly lowered food intake and body weight but did not affect water intake. These findings indicate that the PVN is a brain region responsive to the effects of 17 alpha-estradiol on feeding behavior, and support the hypothesis that the effects of estrogens on ingestive and reproductive behaviors are organized separately within the brain.     

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.     

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.     

Paraventricular hypothalamic clonidine increases rather than decreases susceptibility to activity-based anorexia in the rat.

Anorexia has been related to reduced activity of the paraventricular hypothalamic (PVN) noradrenergic-feeding system. In this study we determined whether clonidine (an alpha 2-adrenergic agonist) infused into the PVN reduced susceptibility to activity-based anorexia (ABA) in the rat. In Experiment 1, clonidine (6 doses) was chronically infused into the PVN of male Sprague-Dawley rats. All animals were exposed to ABA (1.5 hr/day food access; 22.5 hr/day running wheel access) until a 25% body weight loss was reached. Dose-related increases in susceptibility to ABA and decreases in food intake were observed. In Experiment 2, for which heavier animals and 3 doses of clonidine were used, we found no difference in food intake and wheel activity but increased susceptibility to ABA. Chronic clonidine infused into the PVN does not produce hyperphagia and exacerbates rather than attenuates susceptibility to ABA.     

Sleep, brain energy levels, and food intake

Background

The feeling of hunger and feeding, a wake–state-dependent behavior, is regulated by specific centers within the hypothalamus. While paraventricular nucleus (PVN), arcuate nucleus (ARC), and dorso- and ventromedial hypothalamus (DMH/VMH) regulate feeding, the lateral hypothalamus (LH) is associated both with feeding and wake/REM sleep regulation. In order to examine the effects of sleep and wakefulness on food intake and body weight, we also measured hypothalamic ATP concentrations, which are known to be involved in feeding behavior and sleep–wake regulation.

Methods

In rats, food intake and body weight was measured during a 24-h light–dark cycle and during 6 h of sleep deprivation (SD) performed by gentle handling. Tissue samples from the PVN, ARC/DMH/VMH, and LH were collected after 6 h of SD and from time-matched diurnal controls. ATP was measured by luciferin-luciferase bioluminescence assay.

Results

Across the 24-h light–dark period, rats consumed approximately 28.13±4.48 g of food and gained 5.22±1.65 g with a positive correlation between food intake and body weight. During SD, while food intake increased significantly +147.31±6.13%, they lost weight significantly (–93.29±13.64%) when compared to undisturbed controls. SD resulted in a significant decrease in ATP levels only in LH (–44.60±21.13%) with no change in PVN, ARC/DMH/VMH region when compared with undisturbed controls.

Conclusion

The results indicate a strong overall correlation between ATP concentrations in the LH and individual food intake and suggest a sleep–wake dependent neuronal control of food intake and body weight.     

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.     

Exercise during rat pregnancy and lactation: maternal effects and offspring growth

Eighty Sprague-Dawley rats were divided into exercised (E) and sedentary (S) groups. E rats were trained to run on a treadmill (30 m/min, 2 hr/day). Within each group, two subgroups were mated and three served as virgin time controls. Of the mated subgroups, one was terminated within 24 hours of delivery and the other on day 14 of lactation. Subgroups of virgin S and E controls were terminated at times corresponding to the mating, delivery and lactation day 14 of mated rats. MANOVA revealed that exercise significantly affected food intake, body weight and body composition in both virgin and mated animals: generally, E rats ate more, gained more weight, and had less carcass fat than S controls. E rats did not store fat during pregnancy. At parturition, they were 7.0% fat, similar to both E (6.6%) and S (7.6%) controls prior to mating, and less than S rats at parturition (11.9%). Despite diminished fat stores at parturition in E rats, litter size and pup birthweight were similar in E and S rats, as was offspring growth during lactation (mean weights on day 14 of 28.9 g and 29.3 g, respectively). Remaining body fat and increased food intake were adequate to support normal pup growth.     

Effects of age on recovery of body weight following REM sleep deprivation of rats

Chronically enforced rapid eye (paradoxical) movement sleep deprivation (REM-SD) of rats leads to a host of pathologies, of which hyperphagia and loss of body weight are among the most readily observed. In recent years, the etiology of many REM-SD-associated pathologies have been elucidated, but one unexplored area is whether age affects outcomes. In this study, male Sprague-Dawley rats at 2, 6, and 12 months of age were REM sleep-deprived with the platform (flowerpot) method for 10-12 days. Two-month-old rats resided on 7-cm platforms, while 10-cm platforms were used for 6- and 12-month-old rats; rats on 15-cm platforms served as tank controls (TCs). Daily changes in food consumption (g/kg(0.67)) and body weight (g) during baseline, REM-SD or TCs, and post-experiment recovery in home cages were determined. Compared to TCs, REM-SD resulted in higher food intake and decreases in body weight. When returned to home cages, food intake rapidly declined to baseline levels. Of primary interest was that rates of body weight gain during recovery differed between the age groups. Two-month-old rats rapidly restored body weight to pre-REM-SD mass within 5 days; 6-month-old rats were extrapolated by linear regression to have taken about 10 days, and for 12-month-old rats, the estimate was about 35 days. The observation that restoration of body weight following its loss during REM-SD may be age-dependent is in general agreement with the literature on aging effects on how mammals respond to stress.     

Metabolic responses to intracerebroventricular leptin and restricted feeding

Leptin is a hormone secreted by adipocytes, which plays an important role in the control of food intake and metabolic processes. In the current study, a dose-dependent relationship was shown between a bolus intracerebroventricular rat recombinant leptin administration and reductions in food intake and body weight in Sprague-Dawley rats. During the 24 h postinjection period, food intake was decreased by 24, 26, and 52% with 0.625, 2.5, and 10 microg of leptin, respectively. Body weight was reduced by 2, 3, and 5% at 24 h after leptin administration at the doses of 0.156, 2.5, and 10 microg, respectively. Furthermore, indirect calorimetry demonstrated that five daily i.c.v. injections of leptin resulted in an increase in heat production per unit of metabolic body size and fat oxidation by approximately 10 and 48%, respectively. In contrast, food-restricted rats that consumed the equivalent amount of food as leptin-treated rats for 5 days decreased their energy expenditure by 10%. Food restriction was found to decrease respiratory quotient in a similar pattern as the leptin administration. When ad lib feeding was resumed, food-restricted rats quickly recovered their normal food intakes, body weights, and metabolism. Conversely, leptin treatment has prolonged effects on body weight resulting from different metabolic responses than food restriction. Leptin not only suppresses food intake, but also enhances energy expenditure to reduce fat depots.     

Central vs. peripheral effects of estrogen on food intake and lipoprotein lipase activity in ovariectomized rats

The effects of implants of estradiol benzoate (EB) into either the ventromedial nucleus (VMH-EB) or the paraventricular nucleus (PVN-EB) of the hypothalamus were compared to the effects of peripheral EB (Per-EB) replacement in ovariectomized rats. After three days of hormone treatment, the Per-EB group and the PVN-EB group exhibited a decrease in food intake and body weight. Adipose tissue lipoprotein lipase activity was generally suppressed for the Per-EB, PVN-EB, and VMH-EB groups in the left and right parametrial and retroperitoneal fat pads. The finding that the VMH-EB and PVN-EB groups experienced similar peripheral stimulation but differed on the food intake and body weight measures would suggest that these measures are not entirely under peripheral control. The findings support the hypothesis that estrogen exerts its effects via multiple mechanisms, both central and peripheral. In addition, the PVN is shown to be an important site for further research on the modulation of feeding and metabolism by estrogen.     

TRH decreases food intake and increases water intake and body temperature in rats

Thyrotropin-releasing hormone (TRH) is a key regulator of the hypothalamus-pituitary-thyroid axis, which plays an important role in energy homeostasis and is involved in the regulation of feeding behavior. In the present study, we investigated the effects of acute and chronic TRH treatment on water intake, body temperature and feeding behavior in rats. TRH (0, 4, 16 and 64 mg/kg) was injected subcutaneously twice a day (06:00 and 18:00 h) in rats fed ad libitum. TRH decreased food and water intake in the first few hours (P < .05). There was a small reduction in food intake over the 24-h period, but body weight was not affected (P < .05). When TRH was injected at a dose of 32 mg/kg twice a day (06:00 and 18:00 h) for 5 days, T(3) and T(4) concentrations were increased (P < .05). TRH increased body temperature for 2 h after injection. Water intake was markedly increased (P < .05), but there was no effect on food intake or body weight. These results show that whereas a single injection of TRH decreases short-term food and water intake in rats, repeated daily treatments stimulate water intake but not food intake, and, thus, the increase in water consumption is mediated independently of food intake under these conditions.     

MTII administered peripherally reduces fat without invoking apoptosis in rats

The melanocortin (MC) system in the brain is believed to be an important downstream effector of leptin signaling; interference with MC functioning results in severe obesity. Melanotan II (MTII), an MC3/4-receptor agonist, produces similar behavioral and metabolic outcomes to those observed after leptin treatments, which enhance apoptosis in specific fat depots. To determine whether MTII also mediates adipose apoptosis induced by leptin treatment, two groups of rats (n=8) received MTII (2 mg/kg, i.p.) or saline (2 ml/kg) once daily for 4 days and had free access to food and water, and a third group was injected with saline and pair-fed (PF) to MTII treated rats. Food intake, water intake, body temperature, and body weight were measured daily. MTII reduced food and water intake and body weight gain (P<.05) and decreased body temperature compared to PF and saline-treated control groups. Retroperitoneal white adipose tissue (WAT) mass and epididymal WAT mass were reduced 46.3% and 21.1%, respectively (P<.05), after MTII, but not after PF, compared with the saline control rats. Both MTII- (25.0%) and PF (33.3%)-treated rats had decreased brown fat weight (P<.05), whereas muscle mass remained unchanged. Free fatty acid concentrations in serum were not different between MTII and control groups, but increased by 56.4% in PF group. DNA fragmentation assay did not support a role for MTII as an apoptotic signal in any of the fat tissues tested. These results show that in addition to reducing food intake and inhibiting body weight gain, intraperitoneal administration of MTII reduces fat mass, most likely by accelerated lipid mobilization, but not by apoptosis.     

Effects of mild food deprivation on the estrous cycle of rats

It has long been known that severe food deprivation disrupts the estrous cycle. One of the main problems with behavioral tasks that use food for reinforcement is the requirement that the animal be food deprived. This manipulation could be problematic in studies using female animals, since it may interfere with the estrous cycle of the animals. The purpose of the present study was to investigate: (1) the effect of mild food deprivation on four different strains of rats, (2) factors in the food deprivation procedure that could affect the estrous cycle, and (3) the possible effect of enriched diets during food deprivation on the estrous cycle. A comparison of the estrous cycle in four different rat strains revealed differences in the reliability of the estrous cycle even before the onset of food deprivation. Fischer, Long-Evans, and Sprague-Dawley rats all showed reliable cycle patterns. This was not the case for Brown Norway rats. During food deprivation, the cycle of the Fischer rats was disrupted, whereas the Long-Evans and Sprague-Dawley animals continued to cycle. Both the rate of weight loss and the percent of ad libitum body weight were related to cessation of the estrous cycle. However, enriching an animal's diet with sugar or oil additives delayed the disruption of the estrous cycle. Additionally, animals resumed cycling when returned to ad libitum weight levels. The present findings suggest that when animals need to be food deprived, preference should be given to using Long-Evans or Sprague-Dawley rats. If Fischer rats must be used, they should not be deprived below 90-95% of their ad libitum body weight. Strategies for future food deprivation studies are discussed, as well as a comparison of the effects of mild and severe food deprivation.     

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.     

Time-dependent effects of neuropeptide Y infusion in the paraventricular hypothalamus on ingestive and associated behaviors in rats

In this study the role of neuropeptide Y (NPY) in the paraventricular nucleus of the hypothalamus (PVN) in the daily regulation of feeding, drinking, locomotor activity, and nestbox occupation was investigated. These behaviors were recorded during and after bilateral infusion of NPY into the PVN of rats during the early (E) or late (L) part of the light phase. Administration of NPY caused a significant increase in feeding behavior at E, but not at L. In contrast to the feeding at E, L feeding was associated with increased water intake following NPY infusion. While locomotor activity was similar in sCSF- and NPY-infused rats at all times of the daily cycle, administration of NPY at L, but not at E increased nestbox occupation during the first few hours of the dark phase. This increased nestbox occupation was not associated with altered food intake or drinking behavior, implying that NPY-treated rats made frequent excursions between nestbox and food hopper/water bottle. Thus, feeding-associated drinking and explorative behavior are time-dependently modulated by NPY in the PVN, independent of locomotor activity.     

Use of peripheral blood transcriptome biomarkers for epilepsy prediction

Fenfluramine reduces hunger and promotes body weight loss by increasing central serotonin (5-HT) signaling. More recently, neuropeptides have been linked to the regulation of feeding behavior, metabolism and body weight. To examine possible interactions between 5-HT and neuropeptides in appetite control, fenfluramine (200 nmol/0.5 μl/side) was administered directly into the hypothalamic paraventricular nuclei (PVN) of male rats. Bilateral fenfluramine produced significant hypophagia and increased expression of PVN corticotropin releasing factor (CRF) mRNA and neuropeptide Y (NPY) mRNA in the arcuate nucleus within the first hour after drug administration. Fenfluramine's effects on feeding behavior and mRNA expression were blocked by PVN injections of a 5-HT(1-2) receptor antagonist, metergoline (15 nmol/0.5 μl/side). These data suggest that 5-HT neurons targeting hypothalamic paraventricular CRF neurons may participate in an appetite control circuit for reducing food intake.     

Lack of influence of hysterectomy on meal size and meal number in Fischer-344 rats.

Based on our previous observation that, when eating the same amount of food per 100 g b.wt., male rats gain five to seven times more weight than females who have an estrous cycle every 4 to 5 days, we questioned whether lower weight gain seen in female rats could be the result of increased energy cost in preparing endometrium for anticipated fertilization. Because the uterus modulates estrogenic effects on other hormone-dependent behaviors, for example, sexual receptivity and lordosis, we performed this study to determine if estrogen-mediated cyclical changes in food intake and feeding pattern occur after hysterectomy. Fifteen female Fischer 344 rats were randomized during the estrous phase to either hysterectomy with ovarian preservation or sham operation. A rat eater meter was used to continuously measure food intake, meal number, and meal size for two estrous cycles before and four cycles after surgery. Both groups showed the estrous phase linked cycling in meal number, meal size, and food intake. No differences existed between the two groups in these indices either before or after surgery. No differences existed between groups in rate of body weight gain after surgery, 0.95 +/- 0.13 g/day in hysterectomized and 0.77 +/- 0.1 g/day in sham-operated rats. We conclude that hysterectomy has no effect on rate of weight gain, food intake, and estrus linked cyclical feeding pattern in Fischer 344 rats.     

Differential effect of vitamin K and vitamin D supplementation on bone mass in young rats fed normal or low calcium diet

The purpose of this study was to clarify the differential effect of vitamin K and vitamin D supplementation on bone mass in young rats fed a normal or low calcium diet. Ninety female Sprague-Dawley rats, 6 weeks of age, were randomized by stratified weight method into nine groups with 10 rats in each group: baseline control, and 0.5% (normal) or 0.1% (low) calcium diet, either alone, or with vitamin K (30 mg/100g, food intake), vitamin D (25 micro g/100 g, food intake), or vitamin K + vitamin D. After 10 weeks of feeding, bone histomorphometric analyses were performed on cortical bone of the tibial shaft and cancellous bone of the proximal tibia. Vitamin K supplementation increased the maturation-related cancellous bone gain and retarded the reduction in the maturation-related cortical bone gain in rats fed a low calcium diet, and increased the maturation-related cortical bone gain in rats fed a normal calcium diet. Vitamin D supplementation reduced the maturation-related cancellous bone gain, prevented the reduction in periosteal bone gain, and enhanced the enlargement of the marrow cavity, with no significant effect on the reduction in the maturation-related cortical bone gain in rats fed a low calcium diet, and increased the maturation- related cancellous and cortical bone gains with increased periosteal bone gain in rats fed a normal calcium diet. An additive effect of vitamin K and vitamin D on the maturation- related cortical bone gain was found in rats fed a normal calcium diet. This study shows the differential effects of vitamin K and vitamin D supplementation on cancellous and cortical bone mass in young rats fed a normal or low calcium diet, as well as the additive effect on cortical bone under calcium sufficient condition.     

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.     

Effects of chronic intrahypothalamic infusion of insulin on food intake and diurnal meal patterning in the rat

In Experiment 1, rats were chronically infused with insulin (2.7, 27, or 270 ng/hr) or 0.9% saline into the ventromedial (VMH), medial perifornical (PF), or lateral (LH) hypothalamus. VMH infusions of insulin caused a significant, dose-dependent decrease in food intake and body weight; PF infusion of insulin was less effective, but significant; whereas LH infusions of insulin were ineffective. In Experiment 2, rats were chronically infused with insulin (0.54 ng/hr) or 0.9% saline into the VMH, paraventricular (PVN), or posterior (PN) hypothalamic nucleus. Subjects that received VMH or PN infusions of insulin failed to regain weight lost as a result of surgery even 2 weeks after infusion; subjects that received PVN infusions of insulin regained their preoperative weights faster than did controls. All of the groups that received insulin significantly increased their daytime food intake during the infusion period and decreased their night food intake slightly; 24-hr food intake remained unchanged.