Metabolic consequences of food restriction in rats

Some aspects of carbohydrate metabolism were studied in rats subjected to food restriction (single daily meal offered during two hours, either diurnal or nocturnal) for a week. Nocturnal preference for the nocturnal meal was patent in spite of food restriction, inasmuch as the rats fed from 8:00 to 10:00 p.m. ingested significantly more than those fed from 8:00 to 10:00 a.m. The amount of food ingested by rats of both groups was lower than that ingested by the animals with free access to food (as evaluated in 24 hours); nevertheless, both food-restricted groups did not lose weight for the duration of the experiments. The more prominent carbohydrate metabolic adaptations to food-restriction were: (1) high hepatic glycogen concentration during the intermeal periods; (2) hyperglycemia in the 12, 14 and 16 hour intermeal periods; (3) insulinemia was lower than in rats having free access to food all day long; (4) gastric emptying was delayed.     

Metabolic performance of free fed rats subjected to prolonged fast as compared to the metabolic pattern in rats under long term food restriction

Glycemia, free fatty acids, insulinemia, hepatic glycogen, adrenal ascorbic acid, the amount of food ingested and of feces eliminated, gastric emptying and body weight were measured in two groups of rats of the same age. The F, free fed group was subjected to fast during 22 hours and then had a final meal for two hours. The R rats, subjected to food restriction from one to four weeks, had also a final two hour meal after the regular period of 22 hours with no access to food, and then both groups were treated equally. Coincidently, gastric emptying was more delayed, liver glycogen concentration was highest and glycemia was better maintained in the R than the F rats, particularly after three and four weeks of training. Probably due to their greater dependence upon the more frequent supply of nutrients, the F group had a larger free fatty acids mobilization during fast. Adrenal hyperactivity was induced in both groups and the amount of food ingested progressively increased in the R group and decreased in the F group. In general the metabolic efficiency tended to converge to a similar order of magnitude in both groups of animals by the end of the third week. A delayed gastric emptying seems to be a major factor in the adaptations to food restriction.     

Lifelong food restriction prevents senile osteopenia and hyperparathyroidism in F344 rats

Studies were carried out on male F344 rats to examine the influence of aging and life-prolonging food restriction on bone and circulating parathyroid hormone levels. In ad libitum fed animals, the weight, density and calcium content of the femur increased with age and achieved their peak levels by 12 months of age. These levels remained stable until about 24 months and by 27 months of age the ad libitum fed animals had lost appreciable amounts of bone. The maturation of the femurs of the animals maintained on 60% of the ad libitum food intake was delayed and their bones were lighter, less dense and contained less calcium than bones from ad libitum fed rats of corresponding ages. But at 6, 12 and 24 months of age, the femur strength to body weight ratios were very highly significantly greater (P < 0.0001) for the restricted animals compared to the ad libitum fed controls. Circulating immunoreactive parathyroid hormone increased progressively with aging in the animals fed ad libitum and the animals that experienced bone loss at advanced age also had the highest level of the hormone. In contrast, in the food restricted animals aging was not associated with a marked increase in serum parathyroid hormone or with senile bone loss. The data are discussed in relation to the mechanism of the observed changes.     

Carbohydrate metabolism and food intake in food restricted rats: effects of an unexpected meal

Rats subjected to a daily single-meal feeding schedule were presented with an unexpected meal at three different times of the day and the effects on the carbohydrate metabolic patterns were determined. The results indicate that it is the actual metabolic moment of the organism, rather than the duration of the inter-meal period and the degree of gastric emptying, that determines the amount of food ingested.     

Changes of behavioral parameters during long-term food restriction in middle-aged Wistar rats

Food restriction (FR) has a beneficial effect on aging process and exerts a significant effect on the responses of rodents to standard behavioral tasks. The aim of this study was to assess the cumulative influence of FR on the behavioral and biochemical parameters in Wistar rats. Six-month-old rats were subjected to restrictive feeding (50% of the daily food intake, every-other-day feeding regimen) for one month or for six months until ages of 7 and 12 months, respectively. We examined the habituation of exploratory movement, amphetamine (AMPH)-induced motor activity, as well as changes in serum corticosterone (CORT) and glucose levels. The results obtained from FR animals were compared with ad libitum (AL)-fed age-matched control rats. Habituation of motor activity was only affected by six months of restrictive feeding. The sensitization of the motor response to AMPH that was observed in animals exposed to FR for one month was not observed in animals that were exposed to the same feeding regimen for six months. Serum CORT was increased and serum glucose was decreased in both FR groups. These results clearly show that despite the similarity of the biochemical changes that were induced by one and six months of FR, the nature of the changes in motor activities in these two groups of animals during habituation and after AMPH treatment was different. Our findings indicate that long-term FR has complex behavioral consequences that need to be carefully evaluated with respect to animal age, duration of FR and severity of the diet.     

Changes of carbohydrate metabolism caused by food restriction,as detected by insulin administration

Metabolic changes induced in the rat by food restriction were assessed by administration of insulin (0.025 U/kg BW). The animals subjected to a 2 hr feeding/22 hr fasting schedule during one week have a greater capacity to recover from hypoglycemia even after 4 and 8 hr of fasting, whereas those with free access to food have a far lesser capacity to recover. Food restriction also caused a greater resistance to hepatic glycogen depletion during the hypoglycemic phase. It is likely that the metabolic adaptation during food restriction is important for glucose homeostasis and for rapid mobilization of energetic substrate during prolonged fasting.     

Increased efficiency of food utilization following weight loss

The efficiency of food utilization following a period of restricted caloric intake was examined under controlled feeding conditions. By restricting caloric intake, the body weight of two groups of rats was reduced to either 92 or 81% of that of an unrestricted control group. For one week, all animals were then fed daily an amount of food equal to their prerestriction intake, adjusted for the intervening change in metabolic mass ($\text{FI}\text{BW}{}_{\mathrm{kg}}{}^{0.75}\text{=}\text{K}$). During this period of realimentation, the control animals gained an average of 1.6 g body weight while ingesting 156.1 g of food. The two restricted groups gained 21.4 g on 154.2 g food and 29.6 g on 140.4 g food, respectively. This inverse relationship between weight gain and food intake provides evidence that underweight animals utilize food more efficiently than do undeprived control animals.     

Effects of early cold adaptation on food efficiency and dietary-induced thermogenesis in the adult rat

The food intakes of male and female rats (Harvard strain) adapted to cold (5°C) starting at weaning were studied in the cold and during reacclimation to 25°C. Following 24 hr food deprivation, the male rats regained the weight they had lost without making up for the food they had missed (increased food efficiency), while the female rats ate 75% more food than they had missed in regaining their body weights (decreased food efficiency), independent of the temperature at which the animals were housed. On a high fat diet, both cold groups gained less weight than did the two control groups. However, each female group gained significantly less weight than its same temperature male group. Dietary-induced thermogenesis was significantly enhanced in male cold adapted rats 3 months after reacclimation to the zone of thermal neutrality but not in cold adapted female rats. Sex and strain differences are discussed. These data indicate that early chronic cold exposure results in both immediate and long-term changes in food efficiency and metabolism in adult rats, but the effects vary with the sex of the animal.     

Nociceptive thresholds following food restriction and return to free-feeding

Nine rats were placed on a restricted food diet for 14 days and nociceptive thresholds were measured by the tail-flick procedure. After 24 hr of food restriction nociceptive thresholds increased. This initial increase in nociceptive threshold was followed by a decrease in pain threshold on the second day of food restriction. Nociceptive thresholds returned to pre-deprivation levels on the remaining 11 days of food restriction. When the rats were given free access to food after 14 days of food restriction, nociceptive thresholds increased 24 hr after the reintroduction of food and decreased during the next 24 hr. Thus, the results of the present experiment demonstrate that both food restriction and a return to free feeding after 14 days of food restriction produced the same biphasic pattern of changes in nociceptive thresholds.     

Opposing effects of NaCl restriction and carbohydrate loading on urine volume in diabetic rats

Aim: To test the effects of dietary NaCl and carbohydrate content on urine volume in diabetic rats. Methods: Streptozotocin‐induced diabetic rats were subjected to NaCl restriction using either a NaCl‐deficient carbohydrate‐rich synthetic diet (Altromin C1036) supplemented to contain 0.16% NaCl (C1036 + lowNaCl) or a modified normal cereal‐based diet (Altromin 1320) containing 0.086% NaCl (lowNaCl‐1320). Normal diet contained 0.2683% NaCl. Results: Using the C1036 + lowNaCl diet, earlier reported paradoxical increases in water intake and urine volume of diabetic rats were reproduced. However, water intake and urine volume also increased in diabetic rats offered the synthetic C1036 diet supplemented with NaCl to normal levels. Using the lowNaCl‐1320 diet, water intake and urine volume were markedly reduced. Highly significant correlations between urine volume and both osmotic output and urinary glucose excretion were found in diabetic rats on normal diet, but these correlations were absent in diabetic rats on synthetic diet, which showed higher urine volumes than expected from the correlations. In contrast, urine volume was significantly correlated with carbohydrate intake in diabetic rats, irrespective of the diet. Conclusions: (i) The synthetic diet dramatically increases the urine volume in STZ‐DM rats irrespectively of NaCl content. (ii) Rats with STZ‐DM on a normal diet show reduced water intake and urine volume in response to dietary NaCl restriction. (iii) A shift to high carbohydrate diet induces polyuria in STZ‐DM rats. (iv) Urine volume in all STZ‐DM rats only shows correlation with dietary carbohydrate intake. (v) Glucose‐driven osmotic diuresis is unlikely to explain the carbohydrate‐induced polyuria.     

The effects of subdiaphragmatic vagotomy on circadian corticosterone rhythmicity in rats with continuous or restricted food access

Plasma corticosteroid circadian periodicity was determined in three groups of individual adult male rats. Categories were: postsubdiaphragmatic vagotomy, sham-operated, and controls. Blood was sampled every 4 hours over a 48-hour period with ad lib feeding and after a 13-day period on daytime (0930–1330) restriction of food and water availability. Plasma corticosterone circadian periodicity was normal under ad lib conditions in control, sham-operated, and vagotomized animals. Under food-restricted conditions, both the sham-operated and vagotomized animals exhibited the 12-hour shift in the circadian peak of plasma corticosterone levels that we have previously described in normal animals under such conditions. There were no differences between groups in the total amount of food and water consumed or the percentage of nocturnal food intake on an ad lib feeding schedule. Both vagotomized and sham-operated animals manifested reductions in food intake under conditions of food restriction, although vagotomized consumed less than sham-operated animals. The present data indicate that an intact vagus nerve is not necessary for the establishment of circadian periodicity of plasma corticosterone levels or the shift in the periodicity of corticosteroid secretion produced by a restricted feeding regimen.     

Adaptation to water restriction through dietary selection in weanling rats

For each of five pair of diets, 20 weanling rats were equally divided into ad lib and restricted water groups. Caloric density, palatability, as well as nutrient composition of the diet pairs were manipulated. Though lower in absolute food intake than controls, water-restricted rats took a larger proportion of their food from diets lower in protein content and higher in fat content, regardless of caloric content or palatability. The results demonstrate both a quantitative and qualitative dietary adaptation to water restriction.     

Effects of adult-onset calorie restriction on anxiety-like behavior in rats

Calorie restriction (CR) has consistently been shown to increase lifespan and ameliorate disease outcomes. Its effects on behavior are less clear, although anxiolytic-like effects have been observed. Rats were subjected to 1 of 4 dietary regimens: control, CR25%, CR50% and, an acute episode of CR and tested in 3 tests of anxiety: the open field test, the elevated plus maze, and the modified open field test. In the open field test, the CR25% and CR50% groups made more central zone entries than the control and Acute groups, which was primarily due to differences in the initial 5 min of the test. Moreover, both CR groups engaged in greater exploration of the central zone than the control group in the initial 5 min of the test. The Acute group also exhibited significantly longer latencies to leave the central zone at test onset than the control and CR50% group. In the elevated plus maze, the Acute group also displayed longer latencies to open arm entry as compared to the control and CR50% group and showed a lower ratio of open to total arm entries compared to all other groups. There were no effects of CR on any variable of the modified open field test. Possible neurochemical mechanisms underlying the anxiolytic-like effect of CR are discussed.     

Characterization of age-related malondialdehyde oxidation: the effect of modulation by food restriction

Age-related in vitro malondialdehyde (MDA) oxidation by liver was investigated. It was established that mitochondria are the major site of oxidation, and that the oxidation process was catalyzed by aldehyde dehydrogenase as indicated by inhibitory action of disulfiram. The reaction of MDA oxidation requires Mg²⁺ and NAD as cofactors. The capacity for MDA oxidation was progressively lost with increasing age and the extent of the loss was modulated by food restriction.     

Chronic food restriction: enhancing effects on drug reward and striatal cell signaling

Chronic food restriction (FR) increases behavioral sensitivity to drugs of abuse in animal models and is associated with binge eating, which shares comorbidity with drug abuse, in clinical populations. Behavioral, biochemical and molecular studies conducted in this laboratory to elucidate the functional and mechanistic bases of these phenomena are briefly reviewed. Results obtained to date indicate that FR increases the reward magnitude and locomotor-activating effects of abused drugs, and direct dopamine (DA) receptor agonists, as a result of neuroadaptations rather than changes in drug disposition. Changes in striatal DA dynamics, and postsynaptic cell signaling and gene expression in response to D-1 DA receptor stimulation have been observed. Of particular interest is an upregulation of NMDA receptor-dependent MAP kinase and CaM Kinase II signaling, CREB phosphorylation, and immediate-early and neuropeptide gene expression in nucleus accumbens (NAc) which may facilitate reward-related learning, but also play a role in the genesis of maladaptive goal-directed behaviors. Covariation of altered drug reward sensitivity with body weight loss and recovery suggests a triggering role for one of the endocrine adiposity hormones. However, neither acute nor chronic central infusions of leptin or the melanocortin 3/4 receptor agonist, MTII, have attenuated d-amphetamine reward or locomotor activation in FR rats. Interestingly, chronic intracerebroventricular leptin infusion in ad libitum fed (AL) rats produced a sustained decrease in food intake and body weight that was accompanied by a reversible potentiation of rewarding and locomotor-activating effects of d-amphetamine. This raises the interesting possibility that rapid progressive weight loss is sufficient to increase behavioral sensitivity to drugs of abuse. Whether weight loss produced by leptin infusion produces the same neuroadaptations as experimenter-imposed FR, and whether any of the observed neuroadaptations are necessary for expression of increased behavioral responsiveness to acute drug challenge remain to be investigated.     

Effects of gastric acidity on food intake in rats

Intragastric infusion of hydrochloric acid lowered rats' intragastric pH, but failed to produce any increase or decrease in food intake. Conversely, infusions of base (aluminum and magnesium hydroxide) increased pH without altering food intake.     

Augmentation of drug reward by chronic food restriction: behavioral evidence and underlying mechanisms

Chronic food restriction and maintenance of low body weight have long been known to increase the self-administration and motor-activating effects of abused drugs. Using a lateral hypothalamic self-stimulation (LHSS) rate-frequency method, it is shown that chronic food restriction augments the rewarding (i.e., threshold lowering) effect of diverse drugs of abuse. Further, the effect is attributed to increased sensitivity of a neural substrate, rather than a change in drug bioavailability or pharmacokinetics, because it is preserved when drugs are injected directly into the lateral cerebral ventricle (intracerebroventricularly). The food restriction regimen that augments drug reward also increases the induction of c-fos, by intracerebroventricular amphetamine, in limbic forebrain dopamine (DA) terminal areas. The possibility of increased DA receptor function is suggested by findings that rewarding and motor-activating effects of direct DA receptor agonists are augmented by food restriction, and the augmented behavioral effects of amphetamine are reversed by an otherwise subthreshold dose of D-1 antagonist. Initial studies of DA receptor-mediated signal transduction, that are focused on the D-2 receptor, suggest increased functional coupling between receptor and G-protein (i.e., quinpirole-stimulated [(35)S]GTPgammaS binding) in dorsal striatum. Unlike behavioral sensitization induced by intermittent stress or psychostimulant treatment, which persist indefinitely following induction, the augmenting effect of food restriction abates within 1 week of restored ad libitum feeding and weight gain. The possible involvement of endocrine hormones and/or 'feeding-related' neuropeptides, whose levels change dynamically with depletion and repletion of adipose stores, is therefore under investigation. Initial tests have been limited to acute treatments aimed at attenuating the effects of hypoinsulinemia, hypoleptinemia and elevated corticosterone levels in food-restricted rats. None of these treatments has attenuated the behavioral effect of food restriction. While a melanocortin receptor agonist has been found to enhance drug reward, melanocortin receptors do not seem to mediate the augmenting effect of food restriction. Continuing investigations of endocrine adiposity signals, 'feeding-related' neuropeptides and dopaminergic signal transduction may further elucidate the way in which drugs of abuse exploit mechanisms that mediate survival-related behavior, and help explain the high comorbidity of drug abuse and eating disorders.     

Melatonin and estradiol effects on food intake, body weight, and leptin in ovariectomized rats

OBJECTIVE: The study in ovariectomized (Ovx) rats, as a model of menopausal status, of the effects of melatonin (M) and/or estradiol (E), associated or not with food restriction, on body weight (BW) and serum leptin levels. METHODS: Female SD rats (200-250 g) were Ovx and treated with E, M, E+M or its diluents. Control sham-Ovx rats were treated with E-M diluents. After 7 weeks being fed ad libitum, the animals were exposed for 7 more weeks to a 30% food restriction. We measured: food intake, BW, nocturnal and diurnal urinary excretion of sulphatoxymelatonin (aMT6s), leptin in midday and midnight blood samples, glucose, total cholesterol, LDL, HDL and triglycerides. RESULTS: Day/night rhythm of aMT6s excretion was preserved in all cases. The increase of aMT6s excretion in M-treated animals basically affected the nocturnal period. In animals fed ad libitum, E fully prevented Ovx-induced increase of BW, leptin and cholesterol. Melatonin reduced food intake and partially prevented the increase of BW and cholesterol, without changing leptin levels. Under food restriction, M was the most effective treatment in reducing BW and cholesterol. Leptin levels were similar in M, E or E+M treated rats, and lower than in untreated Ovx rats. CONCLUSIONS: Our result gives a preliminary experimental basis for a post-menopausal co-treatment with estradiol and melatonin. It could combine the effectiveness of estradiol (not modified by melatonin) with the positive effects of melatonin (improvement of sleep quality, prevention of breast cancer, etc.). The possible beneficial effects of melatonin which could justify its use, need to be demonstrated in clinical trials.     

Resting oxygen consumption in rats during food restriction,starvation and refeeding

Oxygen consumption was measured in male rats during starvation and during different regimens of restricted feeding and refeeding after starvation. Changes in oxygen consumption and body mass were mostly parallel, but rats with a very reduced food intake displayed the same reduction in oxygen consumption as starved rats, despite the smaller reduction in body mass. Also, rats fed different amounts of food after starvation had different oxygen consumptions, but displayed the same changes in body mass. Two different refeeding regimens with restricted food amounts either induced a further depression of oxygen consumption (i.e. below starvation oxygen consumption), or a stabilizing of oxygen consumption on the level of starvation. The changes in oxygen consumption during restriction and feeding after starvation indicate that reductions in resting metabolic rate may not always be predicted from either body mass change or food intake.     

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.