Dietary self-selection in intact, ovariectomized, and estradiol-treated female rats

The effects of estrogenic stimulation on diet selection were examined in intact, estrous cycling rats, ovariectomized (OVX) rats, and OVX rats given estradiol benzoate (EB) hormone replacement therapy. In Experiment 1, OVX was associated with the nearly exclusive choice of the more calorically dense diet of a pair of diets varying in the concentration of one of the three basic macronutrients (i.e., fat, carbohydrate, and protein), an effect that was decreased by EB administration. In the second experiment, dietary self-selection was examined in intact, estrous cycling rats given access to an isocaloric diet triplet of fat, carbohydrate (CHO), and protein. Total caloric intake and body weight did not vary across the estrous cycle. However, diet selection did vary. Fat intake increased; CHO and, to a lesser extent, protein intake decreased during estrus. An opposite diet selection occurred during diestrus. In Experiment 3, OVX resulted in progressive increases in CHO and protein intake, with a concurrent decrease in fat consumption. The EB treatment partially reversed this diet selection profile (Experiment 4). These results were confirmed by diet pairs with both naturally occurring and experimentally produced estrogenic stimulation (Experiments 5 and 6). These data are consistent with the findings of previous research demonstrating estrogenic reduction in CHO intake with standard high-CHO commercial diets. In addition, an increase in fat intake during estrogenic stimulation was found.     

Selective effects of CGS 10686B, dl-fenfluramine or fluoxetine on nutrient selection

We compared the effects of CGS 10686B (a new drug that blocks serotonin reuptake), on nutrient selection and total food consumption with those of two other serotoninergic drugs, dl-fenfluramine and fluoxetine. The animals were given simultaneous free access to two isocaloric 40%-carbohydrate diets in separate food pans; one of these diets (5% protein) was shown to enhance brain serotonin synthesis by raising brain tryptophan levels; the other (45% protein) did not. CGS 10686B (4-7.5 mg/kg) markedly decreased (60-70%) consumption of the 5% protein diet, with a smaller effect (20-30%) on consumption of the 45% protein diet. Hence, it increased the ratio of protein to carbohydrate in the total food consumed. Higher doses (12.5-15 mg/kg) were no longer nutritionally-specific. Fluoxetine, which also blocks serotonin reuptake, and dl-fenfluramine, which both releases serotonin and suppresses its reuptake, had similar effects on nutrient intake; dl-fenfluramine was most potent and fluoxetine least. None of the drugs selectively affected carbohydrate or protein intake if the composition of the test diets provided was such that neither diet, eaten alone, would increase brain serotonin. These observations affirm that drugs which enhance serotoninergic neurotransmission selectively suppress the intake of high-carbohydrate, low-protein meals which increase brain serotonin synthesis.     

Meal composition influences subsequent food selection in the young rat

Food selection one-half hour after the ingestion (2 g) of either a protein containing or a protein-free (carbohydrate) diet was studied in young rats. Following a 12 hr fast the rats were allowed 15 minutes to consume the meal (premeal). Thirty minutes later, they had access to two isocaloric diets that differed only in protein and carbohydrate content. During the first hour of ad lib feeding, protein intake and protein concentration selected were lower in the 45% casein prefed group compared to the carbohydrate group. A further reduction in protein intake and protein concentration occurred when the protein content of the premeal was increased to 70% from 45% casein. Rats prefed with the 70% casein diet significantly reduced their daily total food intake (12 hr) compared to either the 45% casein or carbohydrate prefed group. It is concluded that both quantity and composition of food selected is influenced by the composition of the preceding meal.     

Galanin in the PVN increases nutrient intake and changes peripheral hormone levels in the rat

In self-selection feeding paradigms, rats display differential patterns of nutrient (protein, carbohydrate or fat) intake. Factors known to influence this selection include brain peptides as well as circadian parameters. In this series of experiments we investigated the role of PVN galanin in nutrient intake during the early and late dark periods in the rat. Rats were allowed to select between three isocaloric diets enriched in protein, carbohydrate or fat. Following a 2-week adaptation period, the animals' 24-h intake was monitored for 4 weeks. Galanin was injected into the PVN and food intake was measured 1, 2 and 24 h post-injection. Galanin significantly increased the 1 h total food intake but it failed to increase the intake of any particular nutrient. Galanin had no effect 2 or 24 h post-injection. Analysis of the data grouped by preference based on the rats 24 h baseline selection patterns over the 4-week period revealed that galanin seem to increase the preferred nutrient. That is, galanin preferentially increased the intake of the carbohydrate- or fat-rich diet in animals with high (over 40% of the total food intake) 24-h baselines in this particular nutrient. Finally, analysis of the plasma hormone levels after paraventricular galanin administration revealed a significant increase in noradrenaline levels, a small reduction in plasma insulin with no effects on adrenaline, glucose or corticosterone. The data revealed that galanin in the PVN influences both food intake and metabolic functioning. PVN galanin significantly increases sympathetic outflow and seems to stimulate the intake of the individual rat's preferred macronutrient.     

Protein selection, food intake, and body composition in response to the amount of dietary protein

Though not universally observed, moderately low-protein diets have been found to increase caloric intake and body fat. It appears that animals overeat in calories in order to obtain more dietary protein. For animals to control protein intake, they must be able to distinguish between two isocaloric diets containing different percentages of protein and make the appropriate dietary selection on the basis of their previous history of protein intake. Experiment 1 examined the 24-h diet selection (5 vs. 35% casein) of Sprague-Dawley rats that had been previously fed diets containing various percentages of dietary protein (5, 10, 20, 35, or 60% casein). Animals fed 5, 10, or 20% dietary protein showed a preference for the higher protein selection diet. In contrast, no significant diet preference was found in animals pre-fed the two higher levels of dietary protein (35 or 60% casein). In this study, daily food intake and body fat of rats fed the low-protein diets (5 and 10% casein) were similar to rats fed the 20% casein diet. Experiment 2 examined the effects of the level of methionine supplementation on rats fed 10% casein. In this study, food intake and body fat were increased by approximately 20% in rats fed 10% casein diets, regardless of the level of methionine supplementation (0.3 vs. 0.15%). Together, the results suggest that the presence of low-protein-induced hyperphagia helps maintain body protein levels in the face of moderately low dietary protein and promotes an increase in the amount of body fat and energy.     

L-tryptophan injection fails to alter nutrient selection by rats

Nutritional studies on rats given a choice between two diets differing in protein content have led to the proposal that brain 5-HT content regulates protein intake [2]. Pharmacologic studies under similar conditions of dietary self-selection suggest that brain 5-HT controls carbohydrate intake [41]. We tested the effect of elevating brain 5-HT via tryptophan injection (100 mg/kg) on short-term food intake and selection by rats choosing between two diets differing in protein and carbohydrate content. Under these conditions neither total food intake nor protein and carbohydrate selection were affected despite increases of 50% in brain concentrations of 5-HT and 5-HIAA. The effect of Trp administration was selective to serotonin metabolism as brain concentrations of NE, DA and DOPAC were not affected. These results suggest that alterations in brain 5-HT content which may occur following meal ingestion may not be of physiological importance in regulating nutrient intake and selection.     

The anorectic effect of fenfluramine is increased by estradiol treatment in ovariectomized rats

The emergence of sex- and estrous cycle-related differences in the anorectic effect of fenfluramine, a serotonin (5-HT) agonist, prompted us to investigate whether these behavioral changes are mediated by estradiol. Rats were ovariectomized and housed in cages that permitted the analysis of feeding and locomotor activity via an automated, computerized system. Using a within-subjects design, we investigated the effects of 1 mg/kg d-fenfluramine and saline vehicle on food intake and wheel running in ovariectomized rats following estradiol benzoate (EB) and oil vehicle treatment. A cyclic regimen of EB treatment was used to mimic the changes in endogenous estradiol secretion over the rat's 4-day estrous cycle. The decrease in food intake following fenfluramine treatment was greater in EB-treated rats, relative to oil-treated rats. Fenfluramine also produced a small but significant decrease in wheel running in ovariectomized rats that was not modulated by EB treatment. Thus, EB's ability to increase the anorectic effect of this dose of fenfluramine appears behaviorally specific. Although the inhibition of food intake by fenfluramine is largely attributed to its ability to increase synaptic levels of 5-HT, additional research involving selective 5-HT receptor agonists and antagonists is necessary to determine whether estradiol interacts with the endogenous 5-HT system to control food intake in the female rat.     

Food intake and selection after peripheral tryptophan

Two studies investigated the effects of peripheral (IP) administration of the dietary indispensible amino acid tryptophan, on food intake and macronutrient selection in rats adapted to a 12 hr nocturnal feeding period and a choice of 10% and 60% casein diets. In a dose-response study (35, 55, 75, 95, 115 mg/kg), the threshold dose of 75 mg/kg produced a significant reduction in total food intake (3.6 to 2.3 g, p less than 0.05) during the first hour of feeding. The reduction in carbohydrate intake (2.1 vs. 1.2 g, p less than 0.05) was greater than that for protein intake (1.6 vs. 1.1 g, p less than 0.05). Twelve hr total food intake was also decreased (20.9 to 19.5 g, p less than 0.05) and this was attributable to decreased carbohydrate intake (13.2 to 11.8 g, p less than 0.05). In a second study designed to determine if tryptophan's effects were mediated by the central nervous system, brain tryptophan uptake was blocked by co-injecting valine with tryptophan. The significant reduction in first hour total food intake by tryptophan was not prevented by co-injection of an equal quantity of valine (3.5 to 1.8 g, p less than 0.05). Again the suppression of carbohydrate intake (2.0 to 0.9 g p less than 0.05) was greater than that for protein intake (1.5 to 0.9 g, p less than 0.05). This dose of valine significantly reduced brain tryptophan uptake by 16% (21.3 to 17.8 micrograms/g, p less than 0.05) and when administered alone did not affect first hour total food intake (3.1 vs 3.2 g).(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased food intake and carbohydrate preference in the rat following treatment with the serotonin antagonist metergoline

The effect on feeding of antagonism of the serotonergic system was studied. Intraperitoneal injection of one of 8 doses of the serotonin antagonist metergoline (MET) (0.06-1.5 mg.kg-1) given prior to a 3 h food deprivation produced a significant dose-related increase in intake of a standard laboratory diet throughout a 2 h measurement period. A 1 mg/kg dose of MET administered prior to one of 3 isocaloric powdered diets a medium carbohydrate, a high carbohydrate, and a non-carbohydrate diet - produced a significant increase in the intake by rats of all 3 diets in the first hour after food presentation. However, in the second hour MET continued to increase consumption of the high carbohydrate diet, whereas intakes of the medium carbohydrate and non-carbohydrate diets were no longer affected by MET treatment. These data suggest that the serotonergic system is a tonic inhibitor of food intake and of carbohydrate preference.     

Devazepide fails to reverse the inhibitory effect of interleukin-1beta on food intake in female rats

Proinflammatory cytokines released during the course of infection elicit numerous behavioral and metabolic changes. The decrease in food intake that accompanies infection is mediated in part by interleukin-1 (IL-1). Cholecystokinin (CCK) is a neuropeptide released during a meal, decreases food intake, and previous research suggests that CCK mediates the anorectic action of IL-1. The effects of estrogen on food intake are also thought to involve CCK, as the satiety action of CCK is increased by estradiol in both intact and ovariectomized rats. Estradiol also modulates many of the behavioral and physiological effects of IL-1. The present experiment examined the ability of the CCK(A) receptor antagonist devazepide to block the effects of IL-1 and estradiol on food intake in female rats. Adult animals were ovariectomized and given two daily subcutaneous injections of estradiol benzoate (EB; 5.0 microg) or the oil vehicle 3 weeks after surgery. Three days after treatment onset, animals were pretreated with devazepide or its vehicle 30 min prior to intraperitoneal injections of IL-1beta (4.0 microg/kg) or saline given 1 h before light offset. Food and water intake was measured following 2 h of spontaneous feeding. The results indicate that devazepide failed to reverse the anorectic action of IL-1beta, although the effects of estradiol on food intake were blocked by devazepide. These data do not support a role for CCK in IL-1-induced anorexia, and suggest that cytokines may act directly on neural systems involved in the control of food intake.     

Estrogen influences stimulated water intake by ovariectomized female rats

To further elucidate the influence of estrogen on water consumption, we examined water intake by adult female rats stimulated by water deprivation, injection of hypertonic saline or injection of isoproterenol (ISOP), a beta-adrenergic agonist that activates the renin-angiotensin system (RAS). Rats were ovariectomized (OVX) then injected with estradiol benzoate (EB; 10 microg/0.1 ml oil) or the oil vehicle (OIL; 0.1 ml) for 2 consecutive days. Twenty-four hours after the second injection, rats were deprived of food and water. On the following day, rats were given water and intake was measured after 2 h. EB significantly decreased water intake compared with that by OIL-treated rats following water deprivation. Two additional groups of adult female rats were OVX and treated with EB or OIL. Forty-eight hours after EB or OIL treatment, rats were injected with hypertonic saline (1 ml of 2 M NaCl) or ISOP (30 microg/kg in 0.15 M saline) and water intake was measured after 2 h. EB significantly attenuated water intake following ISOP but not after hypertonic saline. Finally, we examined plasma sodium concentration (pNa) after hypertonic saline and plasma renin activity (PRA) after ISOP in EB- and OIL-treated rats and found no differences in pNa or PRA. These results suggest that the stimuli for water intake after hypertonic saline and ISOP were comparable in EB- and OIL-treated rats. Taken together, these results raise the possibility that EB attenuation of stimulated water intake is specific to water intake elicited by activation of the RAS.     

Sex hormones differentially influence voluntary running activity, food intake and body weight in aging female and male rats

The aim of this study was to examine the longer-term effects of reduced gonadal hormones on food intake, food efficiency, voluntary running activity and body weight in mature male and female rats, compared to age-matched controls. We hypothesized that hormonal effects would differ for rats that were not rapidly growing and our results are consistent with this hypothesis. 6-8?month male and female rats were divided into four groups: Female and male control groups and a female and male experimental group. Control groups were intact for 46?weeks. Experimental groups were intact during Phase I (16?weeks), ovariectomized or orchidectomized during Phase II (20?weeks), and received estrogen or testosterone hormone replacement therapy (HRT) during the final Phase III (10?weeks). Food intake and running distance were monitored daily and body weight was recorded weekly for 46?weeks. Contrary to findings for young and growing animals, we did not observe a (1) stabilization of food intake in female rats following OVX, (2) loss of body weight with ORX in males, or (3) complete restoration of running activity in ORX males given testosterone, compared to females given estrogen. Feeding efficiency was not affected by aging in females or males. Loss of estrogen increased energy intake whereas reduced testosterone in males resulted in a negative energy balance. Findings suggest variable hormonal effects for aging male/female rats.     

Dietary effects upon food and water intake and responsiveness to estrogen, 2-deoxy-glucose and glucose in female rats

Female rats were maintained on three different diets—chow (C), high-dextrose (D) and high-fat (F) diets—and effects upon feeding of ovariectomy, estradiol benzoate (EB), 2-deoxy-glucose (2-DG) and ad lib glucose solutions were followed. F-fed rats responded significantly more to EB, 2-DG and to ad lib glucose than did C- or D-fed rats; increased responses to EB were not explainable on the basis of increased body weight (BWt). D-fed rats chronically maintained a lowered caloric intake, water intake, and BWt, in spite of a high palatability of the D-diet. Responses of D-fed rats to EB showed a high correlation with BWt, suggesting an augmented influence of a BWt-related signal upon feeding regulation in D-fed rats. A possible relationship between carbohydrate metabolism and responsiveness to EB is discussed.     

Estrogens inhibit food intake in CCK-1 receptor-deficient rats

In human and many other animals, estrogens inhibit food intake and increases spontaneous activity. Previous studies hypothesized that the anorexigenic effect of estrogens is mediated by the cholecystokinin (CCK)-induced satiety effect. In the present study, we investigated whether estrogens-induced anorexigenic and hyper-active effects are present in Otsuka-Long-Evans-Tokushima-Fatty (OLETF) rat, which is deficient in the CCK1 receptor. In OLETF rats with a regular 4-day estrous cycle, food intake decreased and spontaneous activity increased significantly more during estrus than diestrus as compared to control Long-Evans-Tokushima-Otsuka (LETO) rats. Subcutaneous injection of estradiol benzoate into ovariectomized OLETF rats significantly decreased feeding and increased spontaneous activity to the same extent as in LETO rats. These results suggest that the anorexigenic and hyper-active effects of estrogen can be mediated via pathways other than CCK-CCK1 receptor signaling pathway in CCK1 receptor-deficient rats.     

Food intake and behavioral caloric compensation after protein repletion in the rat

The food intake response of rats to intragastrically infused or orally consumed protein was characterized and compared to the response to similarly administered carbohydrate. In Experiment 1, protein hydrolysate loads administered at the beginning of the dark phase via chronic intragastric cannulae led to rapid (complete within 3–4 hr), dose-related suppressions of food intake in comparison to sham loads or to urea loads controlling for volume, concentration and pH. The suppression remained evident in cumulative intake records through 24 hr and represented a greater than caloric compensation for the amount of metabolizeable energy delivered (1.38 and 1.12 kcal/kcal in Experiments 1a and 1b, respectively). In Experiment 2, protein hydrolysate loaded by gavage suppressed food intake significantly more than isocaloric glucose loads (1.32 vs 0.81 kcal/kcal after 24 hr). Water intake in both experiments was elevated by protein loads, although this occurred after the food intake suppression. Differential satiety responses to protein and carbohydrate repletion were shown in Experiment 3 to extend to orally consumed, naturally occurring macronutrients—casein vs starch and disaccharide diets. These data suggest that satiety in the rat is not solely graded with respect to the energy delivered by the preceding meal but rather that repletion with different macronutrients leads to quantitatively (or perhaps qualitatively) different satieties.     

The effect of naloxone on nocturnal food intake in female and male rats

Previous studies have shown that estradiol and progesterone can alter the response of female rats to naloxone. For example, ovariectomized rats receiving estradiol were found to be less sensitive to the anorexic effect of naloxone than ovariectomized rats receiving oil (vehicle) or progesterone. In the present paper, we evaluated the effect of naloxone on nocturnal food intake in female rats during each stage of the estrous cycle to determine whether changing levels of gonadal hormones in intact female rats would affect their response to naloxone. To evaluate the role testosterone might play in modulating the male rat's feeding response to naloxone we studied the effect of peripherally administered naloxone (0.1, 1.0 and 10 mg/kg) on nocturnal food intake of intact, castrate and castrate + testosterone propionate male rats. During late metestrus, diestrus and proestrus, female rats decreased nocturnal food intake following the administration of naloxone (1.0 and 10 mg/kg) SC (p less than 0.05). During estrus, female rats failed to decrease food intake following any of the doses of naloxone administered. The male rat's response to naloxone does not appear to be altered by the presence or absence of testosterone. Thus, the level of estradiol and progesterone at different stages of the estrous cycle may affect the female rat's response to the satiety effect of naloxone.     

Dietary influences on the acute effects of anorectic drugs

The effects of acute administration of d-amphetamine sulfate (0.0, 0.5, 1.0 and 2.0 mg/kg) and dl-fenfluramine hydrochloride (0.0, 1.5, 3.0 and 6.0 mg/kg) on food intake were examined in male Sprague-Dawley rats fed either a high-carbohydrate diet (carbohydrate equaled 65% of total calories) or a high-fat diet (fat equaled 65% of total calories). Animals were given ad lib access to the diets throughout the experiment. Drug injections were given at 0900 on experimental days and food intakes were measured at 1, 3 and 6 h postinjection. Amphetamine led to dose-related decreases in food intake for animals on both diets. The effects of amphetamine were most noticeable at 1 and 3 h postinjection. No differences in amphetamine's effects on food intake were found as a function of diet. Fenfluramine injections also led to dose-related reductions in food intake for animals in both dietary conditions. In contrast to amphetamine, however, fenfluramine led to greater reductions in food intake for rats fed the high-fat diet than for rats fed the high-carbohydrate diet. These data demonstrate that dietary variables must be considered when evaluating the anorectic actions of psychopharmacological agents.     

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.     

Dietary self-selection and intake of protein and energy is altered by the form of the diets

The technique of dietary self-selection has been widely used to investigate proposed mechanisms of protein and carbohydrate regulation and to substantiate theories relating nutrients, brain chemistry and behaviour. These experiments have produced conflicting results which might be accounted for by differences in experimental variables or in the different techniques used to measure self-selection. The possibility that the sensory qualities of diets might alter dietary self-selection was examined in three groups of rats self-selecting protein and carbohydrate from pairs of isocaloric diets in which the physical form (finely-milled casein/corn starch powder, granular casein/corn starch powder and gelled finely-milled casein/corn starch), but not the nutrient composition of each pair was varied. In addition, since the serotonergic drug fenfluramine has been frequently used to influence dietary selection, the effects of this drug on the selection of protein and carbohydrate from the three diets were also examined. The selection of particular diets and consequently protein and carbohydrate intake was markedly altered by the form of the diet. Furthermore, the effects of fenfluramine on diet selection were also modified significantly by the form of the diet. These results suggest that intake of certain nutrients is not strictly regulated at a particular fixed value and that drug-induced changes of self-selection behaviour must be interpreted cautiously.     

MSG intake suppresses weight gain, fat deposition, and plasma leptin levels in male Sprague-Dawley rats

Monosodium l-glutamate (MSG), an umami taste substance, may be a key molecule coupled to a food intake signaling pathway, possibly mediated through a specific l-glutamate (GLU) sensing mechanism in the gastrointestinal tract. Here we investigated the effect of the spontaneous ingestion of a 1% MSG solution and water on food intake and body weight in male Sprague-Dawley rats fed diets of varying caloric density, fat and carbohydrate contents. Fat mass and lean mass in the abdomen, blood pressure, and several blood metabolic markers were also measured. Rats given free access to MSG and water showed a high preference (93-97%) for the MSG solution, regardless of the diet they consumed. Rats ingesting MSG had a significantly smaller weight gain, reduced abdominal fat mass, and lower plasma leptin levels, compared to rats ingesting water alone. Naso-anal length, lean mass, food and energy intakes, blood pressure, blood glucose, and plasma levels of insulin, triglyceride, total cholesterol, albumin, and GLU were not influenced by the ingestion of the MSG solution. These same effects were observed in a study of adult rats. Together, these results suggest that MSG ingestion reduces weight gain, body fat mass, and plasma leptin levels. Moreover, these changes are likely to be mediated by increased energy expenditure, not reduced energy intake or delayed development. Conceivably, these effects of MSG might be mediated via gut GLU receptors functionally linked to afferent branches of the vagus nerve in the gut, or the afferent sensory nerves in the oral cavity.