Effect of estradiol and progesterone on daily rhythm in food intake and feeding patterns in Fischer rats

The product of meal number x meal size, over time, is food intake. Because estrogens modulate feeding activity via their action on the hypothalamus, and because there is a diurnal rhythm in the expression of cytoplasmic estrogen receptors and in estrogen binding activity, the present study examined the effects of ovariectomy and later hormone therapy on acute changes in body weight, and on the meal number-to-meal size relationship as reflected by food intake in the dark/light feeding patterns, in adult female rats in the intact state and after ovariectomy. Twelve female Fischer rats were randomized into ovariectomy and sham operation groups. A rat eater meter measured the feeding indexes for 15 days before and 25 days after ovariectomy, and later for 35 days with hormone therapy. We report: (a) mean body weight gain was linear before and up to ovariectomy, while exponential after ovariectomy; (b) increase in daily food consumption is mainly via an increase in food intake during the light phase; (c) light phase meal number remains unchanged, meal size significantly increases, with the resultant increase in overall food intake; (d) during the dark phase, meal size also significantly increases, but is accompanied by a proportional decrease in meal number, resulting in unchanged dark-phase food intake; and (e) estrogen restoration with either estradiol valerate or estradiol-progesterone combination, reversed the above changes. Data show that in the female Fischer 344 rat: (a) changes in daily rhythm in food intake are brought about by differential effects of the hormones on both meal size and meal number in both the total daily levels as well as in the dark-to-light distribution; (b) estadiol appears to have a tonic inhibitory effect on the light phase meal size and a phasic effect on the dark phase meal size and number, but no significant effect on the light-phase meal number; and (c) in the Fischer rats, progesterone augments estradiol's effect on these indicies.     

Effects of jejunoileal bypass on meal patterns in genetically obese and lean rats.

Jejunoileal bypass surgery, designed to reproduce the human operation (long bypass) was contrasted with a short bypass of only a few centimeters of ileum in both genetically obese rats and their lean littermates. In comparison with the short-bypassed rats, long-bypassed rats of both genotypes lost weight and reduced food intake. When adjustments were made for group differences before surgery, no significant differences were detected in the effectiveness of the operation on the two genotypes. The reduction in food intake was accomplished by a decrease in meal size and an increase in intermeal interval. Food intake gradually returned in the long-bypassed rats toward its level in the short-bypassed rats. This increase was accomplished by an increase in meal size alone. Intermeal intervals remained prolonged. In the long-bypassed rats, compared with the short, meal duration was initially elevated and gradually increased more than did meal size, indicating a great slowing of eating rate. Water intake was unaffected, but water-to-food ratio was elevated initially and gradually declined in the long-bypassed rats. Learned food aversion, dehydration, and gastrointestinal and metabolic alterations due to malabsorption are mentioned as possible contributors to the reduction in food intake, but none of these alone can account for all the changes in meal pattern by which intake reduction is accomplished.     

Infusion of cholecystokinin between meals into free-feeding rats fails to prolong the intermeal interval

The sulfated octapeptide of cholecystokinin (CCK-8) was infused intraperitoneally into 7 free-feeding male Sprague Dawley rats over a 6-day period. Infusions were given near the end of each free-feeding meal (1.87 microgram/meal/rat), and also during the intermeal interval in gradually increasing doses (0.10-0.63 microgram/5 min/rat). Food intake was continuously monitored and the infusions were controlled by microcomputer. Meal patterns, total food intake, and body weights during drug infusion were compared with data collected during a baseline period when only saline was infused. Meal-contingent CCK-8 infusion produced a significant 29.9% decrease in meal size which persisted throughout the drug-infusion period. Intermeal infusion of CCK-8 failed to prolong the intermeal interval (IMI) but it did initially prevent the compensatory decrease in IMI and increased feeding frequency expected after meal size was reduced. By the last day of drug infusion, total daily food intake recovered to baseline levels due to increased feeding frequency. Body weight was only transiently reduced by CCK-8 infusion. These findings show that tolerance does not develop to the action of CCK-8 to suppress meal size, and the administration of exogenous CCK-8 to free-feeding rats does not persistently prolong the intermeal interval.     

Spontaneous meal patterns in female rats with and without access to running wheels

Rats display strong behavioral rhythms during the ovarian cycle. During estrus, food intake is minimal due to a decrease in meal size, and locomotor activity is maximal. To investigate how activity influences feeding patterns across the ovarian cycle, we used a computerized system to monitor spontaneous meal patterns in intact, cycling female rats with and without access to running wheels. We found that running wheel access decreased dark meal frequency, increased dark meal size, and increased 24-h water intake during each phase of the ovarian cycle. In contrast, body weight, 24-h food intake, and the ovarian rhythms of reduced food intake, meal size, and body weight during estrus were not affected by running wheel access. In particular, the reduction in food intake during estrus was due to a selective reduction in dark meal size, not dark meal frequency, and this occurred independent of wheel access. These data indicate that estrus-related changes in spontaneous meal patterns and locomotor activity are independently controlled and that the reduction in food intake during estrus involves a selective change in the neurobiological controls of meal size.     

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.     

The ovarian hormone estradiol plays a crucial role in the control of food intake in females

Despite a strong male bias in both basic and clinical research, it is becoming increasingly accepted that the ovarian hormone estradiol plays an important role in the control of food intake in females. Estradiol's feeding inhibitory effect occurs in a variety of species, including women, but the underlying mechanism has been studied most extensively in rats and mice. Accordingly, much of the data reviewed here is derived from the rodent literature. Adult female rats display a robust decrease in food intake during estrus and ovariectomy promotes hyperphagia and weight gain, both of which can be prevented by a physiological regimen of estradiol treatment. Behavioral analyses have demonstrated that the feeding inhibitory effect of estradiol is mediated entirely by a decrease in meal size. In rats, estradiol appears to exert this action indirectly via interactions with peptide and neurotransmitter systems implicated in the direct control of meal size. Here, I summarize research examining the neurobiological mechanism underlying estradiol's anorexigenic effect. Central estrogen receptors (ERs) have been implicated and activation of one ER subtype in particular, ERα, appears both sufficient and necessary for the estrogenic control of food intake. Future studies are necessary to identify the critical brain areas and intracellular signaling pathways responsible for estradiol's anorexigenic effect. A clearer understanding of the estrogenic control of food intake is prerequisite to elucidating the biological factors that contribute to obesity and eating disorders, both of which are more prevalent in women, compared to men.     

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.     

Patterns of food intake in the monkey during free or restricted feeding and in response to 2-DG or insulin injection.

When given free access to food, the restrained macaque monkey establishes a pattern of ingestion characterized by frequent meals and a stable caloric intake of 26–33 g/kg/day. When the availability of food is restricted to eight hours per day, the number of meals decreases but the mean daily intake as well as the first meal size increases. No consistent correlation is found between meal size and either the pre- or post-meal interval. A subcutaneous injection of 300 mg/kg 2-deoxy-D-glucose (2-DG) causes a 100% increase in the size of the monkey's first meal but a reduction in the number of meals eaten with no change in its daily food intake. This compensatory adjustment to the large first meal is made through a decrease in the number of meals eaten with the insertion of one extremely long post-meal interval. Insulin (1.0 or 5.0 U/kg) similarly injected evokes an increase in both the size of the first meal and the monkey's daily food intake; however, this occurs only in the female macaque. The failure to regulate caloric intake accurately in this case is due to an increase in the magnitude of at least two meals. Thus, although both insulin and 2-DG do augment the size of the following meal, only insulin enhances the total daily intake of food. The differential patterning of food intake after an injection of either 2-DG or insulin suggests that a meal eaten under the influence of 2-DG results in a greater satiation than normal, whereas a meal consumed during insulin-induced hypoglycemia could be less satiating.     

The effect of ethanol on the normal food intake and eating behaviour of the rat

A computerised system was used to continually monitor the food intake and meal patterns of six rats over eighteen days. The effect of replacing the normal drinking water with a 10% ethanol solution for the second six-day period was assessed. Fluid intake decreased by 29% and resulted in a mean ethanol consumption of 6 ml/kg/rat/day. Energy intake remained unchanged with food intake being significantly reduced (p less than 0.05) in proportion to the calories consumed as ethanol. The reduction in food intake was achieved by a significant decrease in mean meal size (p less than 0.01), whilst meal frequency demonstrated a nonsignificant increase. Withdrawal of the ethanol solution resulted in highly variable feeding behaviour. It is concluded that rats will adapt their meal patterns to regulate their energy intake when a 10% ethanol solution is the sole fluid source. It is suggested that the caloric potential of ethanol is recognised through the release of CCK and consequently meal pattern adaptations are the result of premature satiety.     

The effect of dexamethasone-21-acetate on meal size, meal frequency and macronutrient self-selection in rats

In Experiment 1, the measurement of 24-hour food intake in two rats showed that treatment with dexamethasone-21-acetate (DEX) (0.5 mg/kg IP) produced a decrease in body weight which was at least partially due to a decrease in food intake (both meal frequency and meal size). In Experiment 2, the daily intake of three macronutrient sources was measured. These data showed that treatment with DEX (0.5 and 1.0 mg/kg IP) led to an acute increase in protein intake, a sustained decrease in fat intake and no change in carbohydrate consumption. We suggest that this change in macronutrient selection may be an adaptive response which serves to ameliorate some of the effects of DEX treatment.     

Influence of anterior subdiaphragmatic vagotomy and TPN on rat feeding behavior.

Total parenteral nutrition (TPN) inhibits food intake and feeding behavior. Whether caloric sensory function of the liver contributes to this food intake and feeding behavior regulation via vagal-afferent innervation was tested after performing anterior hepatic vagotomy or sham operation in rats infused with a TPN solution providing 100% of daily energy needs, given continuously for 4 days. Food intake, meal number, size, duration, meal and intermeal sniffs, and eating activity were measured using an automated computerized rat eater meter (ACREM). TPN infusion resulted in a significant decrease of food intake and feeding indexes in both groups. The vagotomized rats showed a significantly higher food consumption, achieved by greater meal frequency, larger meal size, and longer meal duration. Thus, vagotomized rats consumed more than their controls by eating larger meals more often and of longer duration. Data suggest that anterior hepatic vagotomy interrupts hepatic caloric sensory feedback loop, diminishing inhibitory vagal effects on food intake with TPN, leading to an overall increase in food intake.     

Feeding behavior during sialodacryoadenitis viral infection in rats

Sialodacryoadenitis (SDA) is a highly contagious common viral infection in rats, akin to mumps in humans. Anorexia occurs during such viral infection. But the pattern of the decrease in food intake (a decrease in either meal size and meal number or both) during spontaneous viral infection has not been previously characterized. We observed the onset of anorexia and an abnormal feeding pattern during an opportunistic SDA viral infection in our rat colony. We thus studied seven male rats. Before the viral infection there was a positive association between food intake and meal number (P<.05). After infection food intake decreased by 68%. This occurred via a significant decrease in meal size (by 69%) (P<.05); and a nonsignificant decrease in meal number (P=.71). This pattern of decreased food intake is similar to that occurring during indomethacin-induced ulcerative ileitis, where we previously measured an increase in plasma tumor-necrosis factor (TNF)-alpha. Anorexia in response to bacterial lipopolysaccharide administration, which is also linked to plasma TNF-alpha, is however, caused only via a decrease in meal number. The differences in the decrease in the feeding pattern between the SDA viral and a bacterial infection suggest that factors other than TNF-alpha alone play a significant role in the mechanism of anorexia during a viral infection.     

Ontogeny of feeding behavior in the Zucker obese rat

Increased food intake in Zucker obese rats has been reported as early as 16 days of age. To determine if the feeding behavior of Zucker obese rats differs from that of lean rats by weaning, or if the differences develop with age, feeding patterns of Zucker obese and lean rats were compared from 3–10 weeks of age. Increased food intakes of obese rats at 3 weeks of age were due to a trend toward increased frequency while at 4 weeks of age were due to increased meal size. Meal size subsequently increased at a faster rate in obese than lean rats and meal frequencies did not differ. While always greater in obese than lean rats meal durations decreased and rates of eating increased with age and were not different for obese and lean rats. The adult patterns of diurnal variation in obese and lean rats were apparent by 3 weeks of age. Thus, in the Zucker obese rat the characteristic of increased meal size did not occur until 4 weeks of age after increased food intake and body weight were evident, and the characteristic of decreased meal frequency did not occur by 10 weeks of age. While increased meal size is associated with early differences in feeding behaviors, decreased meal frequency may be a consequence of obesity.     

Meal patterning in the lactating rat

The present study was undertaken to investigate feeding behaviour of the lactating rat over the day-night cycle. Food intake was recorded continuously in six pregnant and subsequently lactating female rats with 10 pups each. Although there was a twofold increase of food intake during the first post partum week, the meal frequency did not increase above the level of previous weeks. Only the mean meal size increased. After this week food intake increased to three times the normal intake, meal size did not change but meal frequency increased in favour of daytime meals. It is suggested that with moderate caloric demands food intake regulation in the rat occurs through changes in meal size. With higher energy requirements, however, meal frequency is also affected. The possible causal factors involved in the change in feeding are discussed.     

Feeding conditions and intermeal relationships

The free feeding pattern of rats was examined as a function of decreasing the accessibility of the meal. Meal frequency decreased and meal size increased proportionally resulting in a constant food intake per unit time. Various characteristics of the feeding pattern were dramatically affected by these procedures. A diurnal variation in meal size and meal frequency was observed when food was most accessible, but the variation in meal size and meal frequency disappeared when accessibility was slightly hampered. Moreover, no correlation between meal size and postmeal interval was observed in the free feeding situation, but did occur when mean accessibility was decreased. Finally, a regular periodic feeding pattern emerged when accessibility was maximally hindered. A second experiment showed that these changes in the characteristics of the meal eating pattern produced in Experiment 1 were more related to the increase in meal size than to the particular feeding situation. The data also suggested that a minimum calorie intake at a meal of approximately seven calories was necessary to obtain a significant meal size-postmeal interval correlation for dry diets and a minimum intermeal interval of four hours was necessary to obtain a meal size-premeal interval relationship.     

Estradiol and the control of food intake

Gonadal steroids are among the many factors that influence food intake and body weight in mammals. Hormonal effects on these processes are particularly striking in female rats, which show large increases in food intake and body weight after ovariectomy. A key role of estradiol in the control of food intake and energy balance in humans is evidenced by the fact that the incidence of obesity increases greatly after menopause [American College of Obstetricians and Gynecologists. Body mass index and insulin resistance. Obstet Gynecol 2004;104:5s-10]. The actions of estradiol on neural systems that regulate eating may also account in part for sex differences in food intake and eating disorders, which occur much more frequently in young women [Sodersten P, Bergh C. Anorexia nervosa: towards a neurobiologically based therapy. Eur J Pharmacol 2003;480:67-74]. This paper presents a minireview of research examining the changes in feeding that occur during the ovarian cycle, the effects of estradiol withdrawal and replacement on food intake and body weight, and the neurobiological mechanisms by which estradiol influences feeding behavior. A model of hormone action on food intake that emerges from this research views estradiol as an indirect control of eating and meal size, producing changes in feeding behavior by modulating the central processing of both satiating and orexigenic peptides that represent direct controls of eating. Some of the shortcomings of the model and directions for future research are discussed.     

The orexigenic effect of melanin-concentrating hormone (MCH) is influenced by sex and stage of the estrous cycle

Recently, it was shown that the orexigenic effect of melanin-concentrating hormone (MCH) is attenuated by estradiol treatment in ovariectomized (OVX) rats. This suggests that female rats may be less responsive than male rats to the behavioral effects of MCH. To investigate this hypothesis, the effects of lateral ventricular infusions of MCH on food intake, water intake, meal patterns, and running wheel activity were examined in male and female rats. To further characterize the impact of estradiol on MCH-induced food intake, female rats were OVX and tested with and without 17-beta-estradiol benzoate (EB) replacement. In support of our hypothesis, food and water intakes following MCH treatment were greater in male rats, relative to female rats. Specifically, the orexigenic effect of MCH was maximal in male rats and minimal in EB-treated OVX rats. In both sexes, the orexigenic effect of MCH was mediated by a selective increase in meal size, which was attenuated in EB-treated OVX rats. MCH-induced a short-term (2 h) decrease in wheel running that, unlike its effects on ingestive behavior, was similar in males and females. Thus, estradiol decreases some, but not all, of the behavioral effects of MCH. To examine the influence of endogenous estradiol, food intake was monitored following MCH treatment in ovarian-intact, cycling rats. As predicted by our findings in OVX rats, the orexigenic effect of MCH was attenuated in estrous rats, relative to diestrous rats. We conclude that the female rat's reduced sensitivity to the orexigenic effect of MCH may contribute to sex- and estrous cycle-related differences in food intake.     

Variation of fat intake with estrous cycle, ovariectomy and estradiol replacement in hamsters (Mesocricetus auratus) eating a fractionated diet

Intakes of fats, proteins, and carbohydrates were measured daily for a 3 month period in female hamsters maintained on a fractionated diet consisting of the dietary constituents, dextrose, fat and soybean meal. In the first study, hamsters showed variations in body weight and fat intake across the estrous cycle and following ovariectomy, with elevations during diestrous and after ovariectomy when endogenous estrogens are reduced. In the second study, the effects of exogenous estradiol or cholesterol on intake patterns of ovariectomized hamsters were determined. Hamsters lost weight and decreased fat intake when implanted with a silastic containing estradiol and gained weight and increased fat intake when exposed to cholesterol treatment. In neither of the two studies were the intakes of protein or carbohydrates significantly affected by the animals' hormonal status. These results suggest that in the hamster, estrogenic effects on food intake are specific to some dietary constituents and not to others.     

Feeding rate and meal patterns in the laboratory rat

Many manipulations used in the study of feeding (e.g., changes of food taste or texture, anorectic drugs) affect the rate of food consumption. Consequent changes in meal patterning might reflect either direct effects of the manipulation or alternatively might result from indirect effects of the changed rate of intake. In the experiment reported here a direct reduction in the permitted rate of food intake resulted in a clear reduction of meal size and an increase in meal frequency in rats. We explore the extent to which this finding is predicted by quantitative models of the regulation of food intake.     

Estradiol-mediated increases in the anorexia induced by intraperitoneal injection of bacterial lipopolysaccharide in female rats

Lipopolysaccharide (LPS) derived from the cell walls of gram-negative bacteria causes a robust acute phase response (APR) that includes fever, anorexia, and many other elements. Because immune system function, including some models of illness anorexia, is sexually differentiated, we investigated the sexual differentiation of the anorexia induced by intraperitoneal LPS injections in rats. Cycling female Long-Evans rats tested either during diestrus or estrus ate less following 6.25 microg/kg LPS than did intact males. Following 12.5 microg/kg LPS, females in estrus ate less than either females during diestrus or males. Similarly, a more pronounced anorexia occurred following 12.5, 25, and 50 microg/kg LPS in ovariectomized females that received cyclic estradiol treatment and were tested on the day modeling estrus than in untreated ovariectomized rats. LPS also increased the length of the rats' ovarian cycles, usually by a day, especially when injected during diestrus. As in male rats, when LPS injections were repeated in the same rats, both estradiol-treated and untreated rats failed to display any significant anorexia. The inhibitory effects of LPS on eating in intact and ovariectomized rats were expressed solely as decreases in spontaneous meal frequency, without significant alteration of spontaneous meal size. These data indicate that anorexia following peripheral LPS administration is sexually differentiated and that estradiol is sufficient to produce this response. The mechanism of the pathophysiological effect of estradiol on meal frequency appears to be different from the physiological effect of estradiol on food intake because the latter is expressed solely as a change in meal size.