Energy cost of wheel running in house mice: implications for coadaptation of locomotion and energy budgets

Laboratory house mice (Mus domesticus) that had experienced 10 generations of artificial selection for high levels of voluntary wheel running ran about 70% more total revolutions per day than did mice from random-bred control lines. The difference resulted primarily from increased average velocities rather than from increased time spent running. Within all eight lines (four selected, four control), females ran more than males. Average daily running distances ranged from 4.4 km in control males to 11.6 km in selected females. Whole-animal food consumption was statistically indistinguishable in the selected and control lines. However, mice from selected lines averaged approximately 10% smaller in body mass, and mass-adjusted food consumption was 4% higher in selected lines than in controls. The incremental cost of locomotion (grams food/revolution), computed as the partial regression slope of food consumption on revolutions run per day, did not differ between selected and control mice. On a 24-h basis, the total incremental cost of running (covering a distance) amounted to only 4.4% of food consumption in the control lines and 7.5% in the selected ones. However, the daily incremental cost of time active is higher (15.4% and 13.1% of total food consumption in selected and control lines, respectively). If wheel running in the selected lines continues to increase mainly by increases in velocity, then constraints related to energy acquisition are unlikely to be an important factor limiting further selective gain. More generally, our results suggest that, in small mammals, a substantial evolutionary increase in daily movement distances can be achieved by increasing running speed, without remarkable increases in total energy expenditure.     

The effects of prior weight reduction on the running wheel-induced feeding suppression in rats

Adult male rats given ad lib access to food and a running wheel show an initial feeding and weight suppression. Over 6-10 days feeding recovers, but body weight remains low. It is not clear which effect is primary, the wheel-induced feeding or weight change. To test this, rats were first restricted to 15 g of food a day for 8 or 16 days to reduce their weight relative to control non-restricted rats. They were then returned to ad lib feeding and half the restricted and non-restricted control rats were introduced to the wheel either immediately (Experiment 1) or 4 days later (Experiment 2). Food intake, body weight, and wheel running were monitored throughout the experiments. At the return to ad lib feeding, prior food restriction elevated feeding. Both immediate and delayed wheel access suppressed feeding in both groups of wheel access rats compared to the appropriate control rats. Feeding history did not have a significant effect on wheel running. The wheel-induced reductions in feeding from baseline were similar in the weight reduced and normal weight animals suggesting that prior weight restriction did not prevent the onset of the wheel-induced feeding suppression. It is therefore suggested that the feeding suppression is not driven by a reduced weight set point.     

Effects of foraging effort on body fat and food hoarding in Siberian hamsters

Food hoard size varies inversely with body fat levels in Siberian hamsters. If food hoarding only increases when body fat decreases, then hamsters foraging for their food should only increase food hoarding when foraging efforts decrease body fat ("lipostatic hypothesis"); however, if food hoarding increases whenever there is an energy flux away from fat storage, then it should increase regardless of significant body fat decreases ("metabolic hypothesis"). Female Siberian hamsters (Phodopus sungorus) earned food pellets after completion of a programmed number of wheel revolutions (Immobilized Wheel [free access to food], Free Wheel [wheel active, free food], and 10, 50, 100, and 200 revolutions/pellet). Hamsters were killed after 19 days and inguinal, retroperitoneal, and parametrial white adipose tissue (WAT) pads (IWAT, RWAT, and PWAT, respectively) were harvested and carcass composition determined. Food hoard size increased fourfold with the availability of running wheels alone (Free Wheel), increased threefold with low foraging levels (10 and 50 revolutions/pellet), but was nearly abolished at the highest foraging level (200 revolutions/pellet). Surplus food (earned, not eaten or hoarded) was significantly greatest at the lowest level of foraging. As foraging effort increased, PWAT mass decreased the most (<10 revolutions/pellet), while RWAT and IWAT mass only were decreased at the highest foraging effort. Carcass lipid content only was significantly decreased at the highest foraging effort, yet food hoarding was nearly abolished at that level. Collectively, these results demonstrate that body fat levels and food hoarding can be uncoupled with increases in foraging effort. J. Exp. Zool. 289:162-171, 2001.     

Adiponectin is regulated differently by chronic exercise than by weight-matched food restriction in hyperphagic and obese OLETF rats

This study was intended to investigate the effects of chronic exercise on blood adiponectin level. Male Otsuka Long Evans Tokushima Fatty (OLETF) rats (26 weeks old) were divided to undergo either regular 12-week wheel running exercise (EX) or to have food restriction (FR) that resulted in body weight reduction similar to that in EX. Both EX and FR induced similar reductions in body weight, abdominal fat volume and plasma leptin concentration compared with ad libitum control. At the end of the study, although plasma adiponectin level was increased in FR, the adiponectin level did not change in EX. Plasma testosterone level was higher in EX than in either of the other two groups. A significant inverse relationship existed between plasma levels of adiponectin and testosterone for all groups. Our results suggested that 12-week voluntary wheel running exercise induces different effects on plasma adiponectin level than does food restriction, despite similar reduction in body weight, fat tissue mass and plasma leptin concentration. We speculate that the elevated plasma testosterone concentration might offset any hyperadiponectinemic effect of body weight and fat volume reduction in exercising rats.     

Dorsomedial hypothalamic corticotropin-releasing factor mediation of exercise-induced anorexia

Running wheel access and resulting voluntary exercise alter food intake and reduce body weight. The neural mechanisms underlying these effects are unclear. In this study, we first assessed the effects of 7 days of running wheel access on food intake, body weight, and hypothalamic gene expression. We demonstrate that running wheel access significantly decreases food intake and body weight and results in a significant elevation of CRF mRNA expression in the dorsomedial hypothalamus (DMH) but not the paraventricular nucleus. Seven-day running wheel access also results in elevated arcuate nucleus and DMH neuropeptide Y gene expression. To assess a potential role for elevated DMH CRF activity in the activity-induced changes in food intake and body weight, we compared changes in food intake, body weight, and hypothalamic gene expression in rats receiving intracerebroventricular (ICV) CRF antagonist alpha-helical CRF or vehicle with or without access to running wheels. During a 4-day period of running wheel access, we found that exercise-induced reductions of food intake and body weight were significantly attenuated by ICV injection of the CRF antagonist. The effect on food intake was specific to a blockade of activity-induced changes in meal size. Central CRF antagonist injection further increased DMH CRF mRNA expression in exercised rats. Together, these data suggest that DMH CRF play a critical role in the anorexia resulting from increased voluntary exercise.     

Multiple exposure to activity anorexia in rats: effects on eating,weight loss,and wheel running

Animals were given five cycles of an activity anorexia (AA) procedure in order to determine the effect of additional experience on eating, running, and weight loss. Female Sprague-Dawley rats were given a 1h meal and allowed access to a running wheel for the remainder of each day. Upon reaching 75% of free-feeding body weight, each animal was denied wheel access and given ad libitum food until it regained the lost weight. Then, food was again restricted and wheel access provided. Sedentary control animals were placed on the restricted feeding schedule for the median number of days experimental animals required to reach weight loss criterion. Experimental animals showed adaptation by increasing food consumption and decreasing the rate of weight loss despite an increase in running across cycles. Additionally, the distribution of running shifted gradually so that during the later cycles, much of the running occurred in the hours just before feeding. The results support the hypothesis that running interferes with adaptation to the restricted feeding schedule and also that the marked increase in anticipatory behavior during the later cycles is primarily responsible for the maintenance of AA.     

Effect of short-term prefeeding and body weight on wheel running and responding reinforced by the opportunity to run in a wheel

A biobehavioural analysis of activity anorexia suggests that the motivation for physical activity is regulated by food supply and body weight. In the present experiment, food allocation was varied within subjects by prefeeding food-deprived rats 0, 5, 10 and 15 g of food before sessions of lever pressing for wheel-running reinforcement. The experiment assessed the effects of prefeeding on rates of wheel running, lever pressing, and postreinforcement pausing. Results showed that prefeeding animals 5 g of food had no effect. Prefeeding 10 g of food reduced lever pressing for wheel running and rates of wheel running without a significant change in body weight; the effect was, however, transitory. Prefeeding 15 g of food increased the animals' body weights, resulting in a sustained decrease of wheel running and lever pressing, and an increase in postreinforcement pausing. Overall the results indicate that the motivation for physical activity is regulated by changes in local food supply, but is sustained only when there is a concomitant change in body weight.     

Identifying Predictors of Activity Based Anorexia Susceptibility in Diverse Genetic Rodent Populations

Animal studies are very useful in detection of early disease indicators and in unravelling the pathophysiological processes underlying core psychiatric disorder phenotypes. Early indicators are critical for preventive and efficient treatment of progressive psychiatric disorders like anorexia nervosa. Comparable to physical hyperactivity observed in anorexia nervosa patients, in the activity-based anorexia rodent model, mice and rats express paradoxical high voluntary wheel running activity levels when food restricted. Eleven inbred mouse strains and outbred Wistar WU rats were exposed to the activity-based anorexia model in search of identifying susceptibility predictors. Body weight, food intake and wheel running activity levels of each individual mouse and rat were measured. Mouse strains and rats with high wheel running activity levels during food restriction exhibited accelerated body weight loss. Linear mixed models for repeated measures analysis showed that baseline wheel running activity levels preceding the scheduled food restriction phase strongly predicted activity-based anorexia susceptibility (mice: Beta  =  −0.0158 (±0.003 SE), P<0.0001; rats: Beta  =  −0.0242 (±0.004 SE), P<0.0001) compared to other baseline parameters. These results suggest that physical activity levels play an important role in activity-based anorexia susceptibility in different rodent species with genetically diverse background. These findings support previous retrospective studies on physical activity levels in anorexia nervosa patients and indicate that pre-morbid physical activity levels could reflect an early indicator for disease severity.     

Feeding history and obese-prone genotype increase survival of rats exposed to a challenge of food restriction and wheel running

We hypothesized that obese-prone genotype and history of food restriction confer a survival advantage to genetically obese animals under environmental challenge. Male juvenile JCR:LA-cp rats, obese-prone and lean-prone, were exposed to 1.5 h daily meals and 22.5-h voluntary wheel running, a procedure inducing activity anorexia (AA). One week before the AA challenge, obese-prone rats were freely fed (obese-FF), or pair fed (obese-PF) to lean-prone, free-feeding rats (lean-FF). Animals were removed from protocol at 75% of initial body weight (starvation criterion) or after 14 days (survival criterion). AA challenge induced weight loss in all rats, but percent weight loss was more rapid and sustained in lean-FF rats than in obese-FF or obese-PF animals (P < 0.04). Weight loss was significantly higher in obese-FF rats than obese-PF rats, 62% of which achieved survival criterion and stabilized with zero weight loss. Obese-PF rats survived longer, on average (12.0 ± 1.1 day) than obese-FF (8.2 ± 1.1 day) and lean-FF rats (3.5 ± 0.2 day) (P < 0.02). Wheel running increased linearly in all groups; lean-FF increased more rapidly than obese-FF (P < 0.05); obese-PF increased at an intermediate rate (P < 0.02), and those rats that survived stabilized daily rates of wheel running. Prior food restriction of juvenile obese-prone rats induces a survival benefit beyond genotype, that is related to achievement of homeostasis. This metabolic adaptive process may help explain the development of human obesity in the presence of an unstable food environment which subsequently transitions to an abundant food supply.     

Food consumption and body composition in mice selected for high wheel-running activity

The effects of genetic selection for high wheel running (13th generation) and prolonged access (8 weeks) to running wheels on food consumption and body composition were studied in house mice (Mus domesticus). Mice from four replicate lines selected for high wheel-running activity ran over twice as many revolutions per day on activity wheels as did mice from four replicate control lines. At approximately 49 days of age, all mice were placed individually in cages with access to wheels and monitored for 6 days, after which wheels were prevented from rotating for the "sedentary" individuals. During the experiment, five feeding trials were conducted and body mass was measured weekly. After 8 weeks, body composition was measured by hydrogen isotope dilution. Across the five feeding trials, mice in the "active" group (wheels free to rotate) consumed 22.4% more food than mice in the "sedentary" group (wheels locked); mice from the selected lines consumed 8.4% more food than mice from the control lines (average of all trials; body mass-corrected values). In females, but not males, we found a significant interaction between selection and wheel access treatments: within the "active" group the difference in food consumption between selected and control animals was greater than in the "sedentary" group. At the end of the study, mice from the "active" and "sedentary" groups did not differ significantly in body mass; however, mice from the selected lines were approximately 6% smaller in body mass. Estimated lean body mass did not differ significantly either between selected and control lines or between wheel-access groups (P>0.3). Mice from selected lines had lower total body fat compared to mice from control lines (P=0.05; 24.5% reduction; LSMEANS) as did mice from the "active" compared to "sedentary" group (P= 0.03; 29.2% reduction; LSMEANS). Under these conditions, a sufficient explanation for the difference in body mass between the selected and control lines was the difference in fat content.     

Body weight manipulation,reinforcement value and choice between sucrose and wheel running: A behavioral economic analysis

Twelve female Long-Evans rats were exposed to concurrent variable (VR) ratio schedules of sucrose and wheel-running reinforcement (Sucrose VR 10 Wheel VR 10; Sucrose VR 5 Wheel VR 20; Sucrose VR 20 Wheel VR 5) with predetermined budgets (number of responses). The allocation of lever pressing to the sucrose and wheel-running alternatives was assessed at high and low body weights. Results showed that wheel-running rate and lever-pressing rates for sucrose and wheel running increased, but the choice of wheel running decreased at the low body weight. A regression analysis of relative consumption as a function of relative price showed that consumption shifted toward sucrose and interacted with price differences in a manner consistent with increased substitutability. Demand curves showed that demand for sucrose became less elastic while demand for wheel running became more elastic at the low body weight. These findings reflect an increase in the difference in relative value of sucrose and wheel running as body weight decreased. Discussion focuses on the limitations of response rates as measures of reinforcement value. In addition, we address the commonalities between matching and demand curve equations for the analysis of changes in relative reinforcement value.     

Body temperatures of house mice artificially selected for high voluntary wheel-running behavior: repeatability and effect of genetic selection

We studied rectal body temperatures of house mice (Mus domesticus) that had been artificially selected for high voluntary wheel running.1. At generation 17, mice from the four replicate selected lines ran, on average, 2.5-times as many revolutions/day as did mice from the four random-bred control lines.2. During the day, repeatability of individual differences in body temperature measured 4 days apart was low; at night, repeatability was statistically significant across three time scales (1 day, 1 week, 2 weeks).3. During the day, body temperatures of selected and control animals did not differ; at night, mice from selected lines had higher body temperatures. However, when amount of wheel running immediately prior to measurement was included as a covariate, the difference was no longer statistically significant.Higher body temperatures, associated with increased activity, might enhance locomotor abilities through Q10 effects, increase metabolic rate and food requirements, affect sleep patterns, and alter expression of heat-shock proteins.     

Using the Activity-based Anorexia Rodent Model to Study the Neurobiological Basis of Anorexia Nervosa

Anorexia nervosa (AN) is a psychiatric illness characterized by excessively restricted caloric intake and abnormally high levels of physical activity. A challenging illness to treat, due to the lack of understanding of the underlying neurobiology, AN has the highest mortality rate among psychiatric illnesses. To address this need, neuroscientists are using an animal model to study how neural circuits may contribute toward vulnerability to AN and may be affected by AN. Activity-based anorexia (ABA) is a bio-behavioral phenomenon described in rodents that models the key symptoms of anorexia nervosa. When rodents with free access to voluntary exercise on a running wheel experience food restriction, they become hyperactive – running more than animals with free access to food. Here, we describe the procedures by which ABA is induced in adolescent female C57BL/6 mice. On postnatal day 36 (P36), the animal is housed with access to voluntary exercise on a running wheel. After 4 days of acclimation to the running wheel, on P40, all food is removed from the cage. For the next 3 days, food is returned to the cage (allowing animals free food access) for 2 hr daily. After the fourth day of food restriction, free access to food is returned and the running wheel is removed from the cage to allow the animals to recover. Continuous multi-day analysis of running wheel activity shows that mice become hyperactive within 24 hr following the onset of food restriction. The mice run even during the limited time during which they have access to food. Additionally, the circadian pattern of wheel running becomes disrupted by the experience of food restriction. We have been able to correlate neurobiological changes with various aspects of the animals’ wheel running behavior to implicate particular brain regions and neurochemical changes with resilience and vulnerability to food-restriction induced hyperactivity.     

Ultrastructural morphometry of matrical changes induced by exercise and food restriction in the rat calcaneal tendon.

The ultrastructural morphometry of collagen fibril populations in 24 calcaneal tendons obtained from 12 Fischer 344 rats were studied to elucidate matrical changes induced by food restriction and/or endurance exercise. Rats were randomly assigned to four equal groups: ad libitum control (AC), ad libitum exercise (AE), restricted diet control (RC) and restricted diet exercise (RE) groups. Beginning from 6 weeks of age, animals in the two food restriction groups were fed 60% of the mean food consumption of ad libitum fed rats. Then, starting from 6-7 months of age, the rats in the two exercise groups performed 40-50 min of treadmill running at 1.2-1.6 miles h-1 every day for a total of 10 weeks. Endurance training did not significantly alter body weight, but food restriction with or without exercise resulted in a significant loss of body weight. In ad libitum fed controls, food restriction alone did not significantly alter the mean collagen fibril CSA, but predisposed a preponderance of small-sized collagen fibrils. Endurance training per se induced a significant (32%) increase in mean fibril CSA (P less than 0.05), but this adaptive response to exercise was prevented by food restriction, as indicated by a 33% decline in fibril CSA (P less than 0.05). These findings demonstrate that dietary restriction modifies the adaptation of tendon collagen morphometry in response to endurance training, and that weight loss is better achieved with food restriction than endurance exercise.     

The effect of food deprivation on drinking and running in Mongolian gerbils

Three experiments are reported in which adult male Mongolian gerbils (Meriones unguiculatus) were subjected to various degrees of partial food deprivation, with or without simultaneous access to a running wheel. Experiment 1 showed that restricted feeding caused drinking to increase and running to decrease, and it offered no support for the idea that running might substitute for drinking. Experiment 2 showed that running declined, and then at least partly recovered, as a function of body weight loss, in gerbils that were not allowed to become hyperdipsic. Experiment 3 showed that drinking remained at a high level during prolonged exposure to restricted feeding, but reverted to baseline level more rapidly than did body weight when free feeding was reinstated. The results do not support the idea that drinking and running are interchangeable members of a set of activities facilitated by food deprivation, and they show that neither drinking nor running is related to degree of body weight loss in a simple manner.     

Induction of voluntary prolonged running by rats

The rat is widely used in studies of the metabolic and physiological effects of physical exercise. The most commonly used form of exercise is running on treadmills or mechanically driven running wheels. Rats will not voluntarily run significant distances, under normal circumstances. If rats are exposed to running wheels with food freely available, only very limited activity normally occurs. When rats with access to a running wheel are restricted to a fixed amount of food, presented once per day, consistent running occurs. The running is spontaneous and very sensitive to the amount of food provided. Six 6-wk-old rats of 197 g mean body wt were induced to run for 139 days. The distance run increased rapidly over a 20-day initial period on a food supply of 15 g/day (vs. 19.5 g/day consumption by sedentary controls). From day 20 to day 139 the mean distance run was described by the regression equation distance (m/day) = 10,410 - 37.9 X days. Food provided was varied according to distance run, ranging from 15 to 18 g/day, and was normally 17.5 g/day. Thus a food deprivation of 10% of normal consumption will result in mean distances run of approximately 8,000 m/day. The use of pair-fed control animals without access to a wheel allows the conduct of experiments to test the effects of chronic long-distance running. The running is spontaneous; thus the technique avoids the complications accompanying techniques that force running.     

Systemic injections of gastro-intestinal peptides alter behavior in rats

Twenty-four male albino rats were given daily intraperitoneal injections of vasoactive intestinal polypeptide (VIP), motilin, human gastrin I (1–17) or the diluent control vehicle at a dose of 100 μg/kg for four consecutive days and food intake, water intake, body weight, and running wheel activity were determined every 24 hours. Animals injected with motilin or human gastrin I (1–17) exhibited decreased food intake relative to those injected with VIP or diluent, which did not differ from each other, although food intake increased reliably over days. The mean water consumption followed the same pattern as that of food intake. As expected from the above results, VIP produced weight gains as compared with rats injected with motilin or gastrin but not reliably more than after diluent. A reliable effect of trials for weight gain was the greatest on day three. Running wheel activity was not affected by injections of human gastrin I (1–17), motilin, or diluent but was reliably decreased by VIP. No significant differences existed across days. Although the results indicate that GI peptides may affect behavior when injected systemically and that like other peptides they have multiple effects, caution is urged in the interpretation of behavioral results at this time.     

Genetic selection of mice for high voluntary wheel running: effect on skeletal muscle glucose uptake.

Effects of genetic selection for high wheel-running activity (17th generation) and access to running wheels on skeletal muscle glucose uptake were studied in mice with the following treatments for 8 wk: 1) access to unlocked wheels; 2) same as 1, but wheels locked 48 h before glucose uptake measurement; or 3) wheels always locked. Selected mice ran more than random-bred (nonselected) mice (8-wk mean +/- SE = 8,243 +/- 711 vs. 3,719 +/- 233 revolutions/day). Body weight was 5-13% lower for selected vs. nonselected groups. Fat pad/body weight was ~40% lower for selected vs. nonselected and unlocked vs. locked groups. Insulin-stimulated glucose uptake and fat pad/body weight were inversely correlated for isolated soleus (r = -0.333; P < 0.005) but not extensor digitorum longus (EDL) or epitrochlearis muscles. Insulin-stimulated glucose uptake was higher in EDL (P < 0.02) for selected vs. nonselected mice. Glucose uptake did not differ by wheel group, and amount of running did not correlate with glucose uptake for any muscle. Wheel running by mice did not enhance subsequent glucose uptake by isolated muscles.     

Food restriction and refeeding in growing rats.

1. The interrelationship between food intake, body weight and oxygen consumption was analysed at 25 degrees C in growing rats. 3. The experiment was divided into two phases lasting four weeks each. During the first phase the animals were subjected to energy restriction and during the second phase they were allowed ad lib energy intake. Four groups of rats were studied: Control with ad lib food intake and three restricted groups R4, R5, and R6 which received during the first phase 4, 5, and 6 g per day of stock diet in a single meal. 3. The results showed a decrease in body weight and oxygen consumption during the restriction period and a recovering of the latter during the refeeding period, without body weight recovering. 4. It is concluded that an energy conservation mechanism is present during food restriction and for some time after refeeding.     

High-fat diet offsets the long-lasting effects of running-wheel access on food intake and body weight in OLETF rats

We have previously demonstrated that running-wheel access normalizes the food intake and body weight of Otsuka Long-Evens Tokushima Fatty (OLETF) rats. Following 6 wk of running-wheel access beginning at 8 wk of age, the body weight of OLETF rats remains reduced, demonstrating a lasting effect on their phenotype. In contrast, access to a high-fat diet exacerbates the hyperphagia and obesity of OLETF rats. To determine whether diet modulates the long-term effects of exercise, we examined the effects of high-fat diet on food intake and body weight in OLETF rats that had prior access to running wheels for 4 wk. We found that 4 wk of running exercise significantly decreased food intake and body weight of OLETF rats. Consistent with prior results, 4 wk of exercise also produced long-lasting effects on food intake and body weight in OLETF rats fed a regular chow. When running wheels were relocked, OLETF rats stabilized at lower levels of body weight than sedentary OLETF rats. However, access to a high-fat diet offset these effects. When OLETF rats were switched to a high-fat diet following wheel relocking, they significantly increased food intake and body weight, so that they reached levels similar to those of sedentary OLETF rats fed a high-fat diet. Gene expression determination of hypothalamic neuropeptides revealed changes that appeared to be appropriate responses to the effects of diet and running exercise. Together, these results demonstrate that high-fat diet modulates the long-lasting effects of exercise on food intake and body weight in OLETF rats.