Cost-based anorexia: A novel framework to model anorexia nervosa.

Anorexia nervosa (AN) is an eating disorder that is thought to emerge through biological predisposition(s) within sociocultural context(s). Practical and ethical concerns limit study of the etiology of this disorder in humans, and in particular the biological aspects. Laboratory animal models have a pivotal role in advancing our understanding of the neurobiological, physiological and behavioral aspects of this disorder, and developing new treatment strategies. One shortcoming of animal models, including activity based anorexia (ABA) in rodents, is that they cannot fully capture the contextual aspects of AN. In this article we discuss the merits of an alternate approach, cost-based anorexia (CBA). CBA is conceptually founded in behavioral economics and its magnitude is influenced by several relevant contextual aspects of feeding.

Restricted temporal access to food and anorexia in mice: Microstructure of eating within feeding opportunities.

Intake and body weight were recorded in a closed economy as male and female C57BL/6 mice progressed through either fixed interval (FI) or fixed unit price (FUP) schedules of cost for 20-mg food pellets. Access to food was constrained to four 40 min food opportunities (FOs) per day, spaced 4-h apart through the dark phase. Nose poke responses and pellet deliveries were collected at 10-s resolution to allow pellet-by-pellet analysis. In the FI protocol, mice maintained adequate food intake and body weight through the study, even though at the highest FI (50-s) they spent the entire 40-min FOs engaged in eating at or near the maximum rate allowed by the schedule. In the FUP protocol, mice greatly reduced their intake and lost weight at the highest FUP (50 responses/pellet). The analysis of response and pellet distributions showed these mice were not filling the FOs with responding and ate less at dusk (FO #1) and dawn (FO #4) than at FOs #2 and 3 in the middle of the night. The principal, and unexpected, sex difference was that females tended to eat more than males despite lower body weight, but behavioral changes as a function of feeding cost or schedule were qualitatively similar in both sexes. These results show that slow eating as imposed by an FI is not sufficient to produce hypophagia and, in the FUP protocol, hypophagia cannot be explained by slowed eating due to response requirements. We discuss the role of effort or time in FUP-induced anorexia, and suggest this murine model may emulate some aspects of human anorexia nervosa better than current activity-based protocols.

Differences in temporal aspects of food acquisition between rats and two strains of mice in a closed operant economy.

Rats and mice were studied for changes in meal-taking structure in a closed operant food economy, in which the consummatory or unit prices for food were increased. In experiment 1, as food price increased, male rats modestly decreased the number of meals per day and increased mean meal size. Female rats were similar to males but had smaller meal size and, at low costs, took more meals per day. In experiment 2, male and female B6 mice reduced food intake as price increased, accompanied by decreased meal number without change in meal size. They showed grazing-like behavior in the first part of the night. In contrast, we report in experiment 3, a large increase in intake and meal size during the final trimester of pregnancy. In experiment 4, we report that CD1 male mice subjected to a unit price series performed comparably to rats, and not like B6 mice. Other CD1 mice were tested using an interval schedule, and we found that mice were able to adapt eating patterns to greatly increased time demands without compromising total intake. Data are discussed in terms of the intercalation of food acquisition with global patterns of activity. Such interactions of organism and food environment are in particular need of mechanistic investigation.

A novel aminotetralin-type serotonin (5-HT) 2C receptor-specific agonist and 5-HT2A competitive antagonist/5-HT2B inverse agonist with preclinical efficacy for psychoses.

Development of 5-HT2C agonists for treatment of neuropsychiatric disorders, including psychoses, substance abuse, and obesity, has been fraught with difficulties, because the vast majority of reported 5-HT2C selective agonists also activate 5-HT2A and/or 5-HT2B receptors, potentially causing hallucinations and/or cardiac valvulopathy. Herein is described a novel, potent, and efficacious human 5-HT2C receptor agonist, (-)-trans-(2S,4R)-4-(3'[meta]-bromophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine (-)-MBP), that is a competitive antagonist and inverse agonist at human 5-HT2A and 5-HT2B receptors, respectively. (-)-MBP has efficacy comparable to the prototypical second-generation antipsychotic drug clozapine in three C57Bl/6 mouse models of drug-induced psychoses: the head-twitch response elicited by [2,5]-dimethoxy-4-iodoamphetamine; hyperlocomotion induced by MK-801 [(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (dizocilpine maleate)]; and hyperlocomotion induced by amphetamine. (-)-MBP, however, does not alter locomotion when administered alone, distinguishing it from clozapine, which suppresses locomotion. Finally, consumption of highly palatable food by mice was not increased by (-)-MBP at a dose that produced at least 50% maximal efficacy in the psychoses models. Compared with (-)-MBP, the enantiomer (+)-MBP was much less active across in vitro affinity and functional assays using mouse and human receptors and also translated in vivo with comparably lower potency and efficacy. Results indicate a 5-HT2C receptor-specific agonist, such as (-)-MBP, may be pharmacotherapeutic for psychoses, without liability for obesity, hallucinations, heart disease, sedation, or motoric disorders.

Effects of caloric restriction on nitrogen and carbon stable isotope ratios in adult rat bone.

RATIONALE: Stable isotope analysis is a valuable technique for dietary estimation in ecological and archaeological research, yet many variables can potentially affect tissue stable isotope signatures. Controlled feeding studies across a range of species have consistently demonstrated impacts of caloric restriction on tissue stable isotope ratios, but most have focused on juvenile, fasting, and/or starving individuals, and most have utilized soft tissues despite the importance of bone for paleodietary analyses. The goal of this study was to determine whether temporally defined, moderate food restriction could affect stable carbon and/or nitrogen isotope ratios in adult mammalian bone - a tissue that arguably reflects long-term dietary signals. METHODS: Adult rats fed a standard laboratory diet were restricted to 45% of ad libitum intakes for 3 or 6 months. Relevant anatomical and physiological parameters were measured to confirm that the restriction protocol resulted in significant nutritional stress and to provide independent data to facilitate interpretation of stable isotope ratios. Femoral bone δ(13)Ccollagen, δ(15)Ncollagen, and δ(13)Capatite values were determined by isotope ratio mass spectrometry. RESULTS: Calorie-restricted animals exhibited a small, yet significant enrichment in (15)Ncollagen compared with control animals, reflecting protein-calorie stress. While the δ(13)Ccollagen values did not differ, the δ(13)Capatite values revealed less enrichment in (13)C than in controls, reflecting catabolism of body fat. Independent anatomical and physiological data from these same individuals support these interpretations. CONCLUSIONS: Results indicate that moderate caloric restriction does not appreciably undermine broad interpretations of dietary signals in adult mammalian bone. Significant variability among individuals or groups, however, is best explained by marked differences in energy intake over variable timescales. An inverse relationship between the δ(13)Capatite and δ(15)Ncollagen values observed in this study indicates that a more robust pattern is expected with more severe or prolonged restriction and suggests this pattern may have utility as a marker of food deprivation in archaeological populations.

Neurobehavioral Mechanisms of Sodium Appetite.

The objectives of this paper are to first present physiological and ecological aspects of the unique motivational state of sodium appetite, then to focus on systemic physiology and brain mechanisms. I describe how laboratory protocols have been developed to allow the study of sodium appetite under controlled conditions, and focus on two such conditions specifically. The first of these is the presentation a sodium-deficient diet (SDD) for at least one week, and the second is accelerated sodium loss using SDD for 1-2 days coupled with the diuretic furosemide. The modality of consumption is also considered, ranging from a free intake of high concentration of sodium solution, to sodium-rich food or gels, and to operant protocols. I describe the pivotal role of angiotensin and aldosterone in these appetites and discuss whether the intakes or appetite are matched to the physiological need state. Several brain systems have been identified, most recently and microscopically using molecular biological methods. These include clusters in both the hindbrain and the forebrain. Satiation of sodium appetite is often studied using concentrated sodium solutions, but these can be consumed in apparent excess, and I suggest that future studies of satiation might emulate natural conditions in which excess consumption does not occur, using either SDD only as a stimulus, offering a sodium-rich food for the assessment of appetite, or a simple operant task.

Action of a serotonergic anorectic in meal-fed mice working for food.

The aim of this study was to examine the effects of a serotonergic anorectic agent, dexnorfenfluramine (DNOR), on food intake in mice whose meals were constrained to specified periods each day and by effort. Mice were forced to adopt a human-like pattern of regular meals by making food available for four periods of 40 min/24-h period, mostly at night. They lived in behavior test chambers with a closed economy for food and were required to emit a fixed unit price (FUP) of either 2 or 25 nose pokes (FUP2, FUP25) to receive a 20 mg pellet of food. Once responding and intake were stable, mice were injected with a vehicle or DNOR (3 or 6 mg/kg) 1 h before a specified feeding opportunity. Food intake was dose-dependently suppressed at the next meal and to a greater extent when the cost of food was high (FUP25). Within a meal, the effect of the drug was the greatest in the first half of the available time. Therefore, the anorectic effect of DNOR was modified by the concurrent cost of food.

Effects of meal frequency and snacking on food demand in mice.

Ad libitum feeding patterns in mice show substantial differences between laboratories, in addition to large individual and time-of-day differences. In the present study, we examine how mice work for food when access to food is temporally restricted and so they are forced to take discrete meals. In a first experiment, separate groups of ICR:CD1 mice were given access to food for 4, 8 or 16 opportunities or meals per day, with the duration of access at each opportunity adjusted reciprocally so that the total time of availability was 160 min per day in all three conditions. During the periods of availability, mice were able to earn food pellets by nose poke responses, according to an incrementing series of fixed unit prices (FUP: 2, 5, 10, 25) with each schedule in force for 3-4 days. Total food intake was similar in all three groups, indicating that mice generally were able to adjust their intake to a range of temporal availabilities. In each group, food demand fell as FUP increased. In the 8 and 16 meal groups, no food was eaten in many of the opportunities. Within an opportunity, the rate of intake generally declined with time, indicative of satiation. At low FUPs, later opportunities in each day were associated with smaller meals than earlier opportunities; in contrast, at high FUPs the first opportunity was also a small meal. Collectively, these results show that mice eat less at higher costs but not because of time constraints of the schedule: instead, they exhibit an elective anorexia. In the second experiment, we examined whether snacking between imposed meals would affect subsequent meal(s). Mice were adapted to the foregoing 8 opportunity protocol. Then, half the mice received free snacks of sugar cubes after the 3rd, 4th and 5th meal opportunities and the intakes of sugar and pellets were examined at low and high unit costs for pellets (FUP2 and 25). At FUP2, mice decreased demand for pellets and compensated energetically for the sugar they consumed. At FUP25, mice also decreased demand, but by less than the energy obtained from sugar. These data show that choice for pellets over a free palatable snack, and subsequent compensation of energy intake, is modified by effort and demand.

Food demand and meal size in mice with single or combined disruption of melanocortin type 3 and 4 receptors.

Mice with homozygous genetic disruption of the melanocortin-4 receptor gene (MC4R-/-) are known to be hyperphagic and become obese, while those with disruption of the melanocortin-3 receptor gene (MC3R-/-) do not become markedly obese. The contribution of MC3R signaling in energy homeostasis remains little studied. In the present work, we compare MC3R-/- mice with wild-type (WT), MC4R-/-, and mice bearing disruption of both genes (double knockout, DKO) on select feeding and neuroanatomical dimensions. DKO mice were significantly more obese than MC4R-/-, whereas MC3R-/- weighed the same as WT. In a food demand protocol, DKO and MC4R-/- were hyperphagic at low unit costs for food, due primarily to increased meal size. However, at higher costs, their intake dropped below that of WT and MC3R-/-, indicating increased elasticity of food demand. To determine whether this higher elasticity was due to either the genotype or to the obese phenotype, the same food demand protocol was conducted in dietary obese C57BL6 mice. They showed similar elasticity to lean mice, suggesting that the effect is of genotypic origin. To assess whether the increased meal size in MC4R-/- and DKO might be due to reduced CCK signaling, we examined the acute anorectic effect of peripherally administered CCK and subsequently the induction of c-Fos immunoreactivity in select brain regions. The anorectic effect of CCK was comparable in MC4R-/-, DKO, and WT, but it was unexpectedly absent in MC3R-/-. CCK-induced c-Fos was lower in the paraventricular nucleus in MC3R-/- than the other genotypes. These data are discussed in terms of demand functions for food intake, MC receptors involved in feeding, and their relation to actions of gut hormones, such as CCK, and to obesity.

Protocols Using Rodents to Model Eating Disorders in Humans.

Dysfunctional feeding behavior has a bidirectional aspect, too little and too much. The former reflects restricted eating and, in extreme, becomes an eating disorder such as anorexia nervosa (AN). The latter reflects lack of restraint and leads to obesity and life-shortening metabolic syndrome. Both of these dysfunctions have proven extremely difficult to prevent or treat, and the use of animal models that have translational validity may be one of the most cost-effective ways of advancing. This chapter describes some of the laboratory protocols using rodents that are available to model human eating dysfunctions.

Analytic and Interpretational Pitfalls to Measuring Fecal Corticosterone Metabolites in Laboratory Rats and Mice.

Minimization and alleviation of stress are generally viewed as desirable aspects of laboratory animal management and use. However, achieving that goal requires an unambiguous and valid measure of stress. Glucocorticoid concentrations are commonly used as a physiologic index of stress. Measurement of glucocorticoids in blood, serum or plasma clearly reflects many types of both acute and chronic stress. However, the rapid rise in concentrations of circulating glucocorticoids that occurs even with relatively simple manipulations such as handling has led to the increased use of fecal glucocorticoid metabolite (FCM) assays, which provide a temporally integrated measure that may allow a more accurate interpretation of chronic stressors. In this review, we consider 3 aspects of glucocorticoids as a measure of stress. First, we discuss the analytic and interpretational pitfalls of using FCM concentrations as an index of stress in mice and rats. Second, we consider evidence that some degree of stress may benefit animals by priming physiologic and behavioral adaptations that render the animals more resilient in the face of stress. Finally, we use 2 situations-social housing and food restriction-to illustrate the concept of hormesis-a biologic phenomenon in which a low dose or intensity of a challenge has a beneficial effect, whereas exposure to high doses or intensities is detrimental.

Male and female mice show equal variability in food intake across 4-day spans that encompass estrous cycles.

The exclusion of female rodents from biomedical research is well documented and persists in large part due to perceptions that ovulatory cycles render female traits more variable than those of males, and females must be tested at each of four stages of the estrous cycle to generate reliable data. These beliefs are not empirically based. The magnitude of trait variance associated with the estrous cycle may be sufficiently low and of little impact, or trait variability of males tested on 4 consecutive days may be as great as that of females over the 4 days of the estrous cycle. Here, we analyzed food intake data from mice in 4-day blocks, corresponding to the females' 4-day estrous cycle in several schedules of food procurement or reward. Variance was compared within and across individual mice. In no instance did the overall variance differ by sex under any of the food reward schedules. This extends earlier observations of trait variability in body temperature and locomotor activity of mice and supports the claim that there is no empirical basis for excluding female rodents from biomedical research.

Effect of Food Predictability on Life Span in Male Mice.

The purpose of this study is to compare the effect of unpredictable (U) or predictable (P) food delivery on health and longevity in mice. From 2 months of age until end of life, singly-housed male C57BL/6 mice were fed a semisynthetic diet either ad libitum (AL), or as imposed meals delivered as small pellets at either P or U times, frequencies, or amounts. The total daily food consumed by all groups was the same. The AL group gained body weight faster than either P or U groups, and had ~12% shorter median life span compared with either P or U groups. Bimonthly noninvasive body composition determinations showed that the differences in body weights were due to differences in fat and lean mass. Postmortem examinations revealed that the organ pathologies were similar in all groups, but a larger fraction of P and U mice were euthanized due to end-of-life suffering. There were no systematic differences in outcome measures between P and U groups suggesting that, within the range studied, the temporal pattern of food delivery did not have a significant metabolic effect.

High temporal resolution of amino acid levels in rat nucleus accumbens during operant ethanol self-administration: involvement of elevated glycine in anticipation.

Capillary electrophoresis coupled with laser-induced fluorescence detection (CE-LIF) provides 15-s temporal resolution of amino acid levels in microdialysate, which, for the first time, allows almost real time measurement of changes during episodes of behavior. We trained Sprague-Dawley rats to self-administer either 10% ethanol-containing gelatin or non-alcoholic gelatin in a typical operant chamber. After rats reached stable daily levels of responding, microdialysis probes were inserted into nucleus accumbens and samples were collected before, during and after operant sessions with on-line analysis via CE-LIF. During the first 15 min of the operant session, there was a significant increase in taurine that correlated with the amount of ethanol consumed (R(2)=0.81) but no change in rats responding for plain gel. There were large, consistent increases in glycine in both the ethanol and plain gel groups which correlated with the amount of gel consumed. A smaller increase was observed in rats with free non-operant access to plain gel compared to the increase seen with the same amount of gel consumed under operant conditions. When rats were given a time out after each delivery of gel in the operant protocol, the greatest increase of glycine was obtained with the longest time out period. Thus, increases in glycine in nucleus accumbens appear to be related to anticipation of reinforcement.

Nicotine analog inhibition of nicotine self-administration in rats.

RATIONALE: Partial agonists and antagonists of addictive drugs have been useful in the treatment of dependence. OBJECTIVE: The purpose of this study is to determine whether nicotine analogs with partial agonist or antagonist properties at alpha4beta2 nicotinic acetylcholine receptors (nAChRs) inhibit self-administration of nicotine in rats. MATERIALS AND METHODS: Male Sprague-Dawley rats were trained to self-administer nicotine (unit dose 0.017 mg/kg) intravenously contingent upon the completion of five lever presses. Once stable responding was established, rats were administered test agents, either as a subcutaneous injection before the daily session or co-infused with nicotine. RESULTS: The number of nicotine injections taken per session was reduced to approximately 50% of baseline after either pre-treatment with the broad spectrum nicotinic receptor antagonist, mecamylamine, or by substituting saline for nicotine (extinction). 4'-Trans-methyl-nicotine, a strong partial agonist, inhibited nicotine self-administration and substituted for nicotine to support self-administration. Partial agonists, prepared by substitution at the 1'-N-position with either ethyl or cyclopropylmethyl moieties, potently inhibited self-administration. Antagonists formed by 5'-methyl substitution also inhibited self-administration, with the 5'-trans-methyl enantiomer about ten times more potent than the 5'-cis-methyl enantiomer. In contrast, antagonists formed by aryl substitution at the 5 position of the pyridyl ring of nicotine did not inhibit self-administration. Intravenous co-infusions had similar effects to the pre-injections. In most instances, doses of the analogs that reduced nicotine self-administration had no effect on food intake when measured using a similar FR5 protocol. CONCLUSIONS: Nicotine analogs with alpha4beta2 nAChR partial agonist and antagonist efficacies can inhibit self-administration and may be considered as prototypical smoking-cessation agents.

Feeding behavior, obesity, and neuroeconomics.

For the past 50 years, the most prevalent theoretical models for regulation of food intake have been based in the physiological concept of energy homeostasis. However, several authors have noted that the simplest form of homeostasis, stability, does not accurately reflect the actual state of affairs and most notably the recent upward trend in body mass index observed in the majority of affluent nations. The present review argues that processes of natural selection have more likely made us first and foremost behavioral opportunists that are adapted to uncertain environments, and that physiological homeostasis is subservient to that reality. Examples are presented from a variety of laboratory studies indicating that food intake is a function of the effort and/or time required to procure that food, and that economic decision-making is central to understanding how much and when organisms eat. The discipline of behavioral economics has developed concepts that are useful for this enterprise, and some of these are presented. Lastly, we present demonstrations in which genetic or physiologic investigations using environmental complexity will lead to more realistic ideas about how to understand and treat idiopathic human obesity. The fact is that humans are eating more and gaining weight in favorable food environments in exactly the way predicted from some of these models, and this has implications for the appropriate way to treat obesity.

Effect of (-)-trans-PAT, a novel 5-HT2C receptor agonist, on intake of palatable food in mice.

(1R,3S)-(-)-trans-1-phenyl-3-dimethylamino-1,2,3,4-tetrahydronaphthalene (PAT) is a novel compound that has full-efficacy agonist activity at human 5-HT2C receptors and inverse agonist/antagonist activity at 5HT2A and 5HT2B receptors. In the present paper we describe its effects on food intake in non-deprived C57BL/6 mice adapted to eating a palatable dessert meal each day. PAT showed a dose-related inhibition of food intake with a 50% inhibitory dose of 4.2 mg/kg. The dose-effect curve was similar to that obtained using WAY-161503. Abnormal behaviors were not observed by casual inspection following administration of PAT. The anorectic effect of PAT was additive with that of amphetamine. When PAT, or PAT+amphetamine, were injected 2 h before access to food, most of the anorectic activity had dissipated, indicating that PAT has a biologically effective period of about 1 h. Four daily injections of PAT were associated with some, but not complete loss of the initial anorectic effect; this differs from the rapid tolerance that has been reported to fenfluramine anorexia and suggests that different mechanism(s) are involved in the loss of anorexia.

PKU is a reversible neurodegenerative process within the nigrostriatum that begins as early as 4 weeks of age in Pah(enu2) mice.

Phenylketonuria (PKU) is a common genetic disorder in humans that arises from deficient activity of phenylalanine hydroxylase (PAH), which catalyzes the conversion of phenylalanine to tyrosine. There is a resultant hyperphenylalanemia with subsequent impairment in cognitive abilities, executive functions and motor coordination. The neuropathogenesis of the disease has not been completely elucidated, however, oxidative stress is considered to be a key feature of the disease process. Hyperphenylalanemia also adversely affects monoaminergic metabolism in the brain. For this reason we chose to evaluate the nigrostriatum of Pah(enu2) mice, to determine if alterations of monoamine metabolism resulted in morphologic nigrostriatal pathology. Furthermore, we believe that recent developments in adeno-associated virus (AAV)-based vectors have greatly increased the potential for long-term gene therapy and may be a viable alternative to dietary treatment for this metabolic disorder. In this study we identified neurodegenerative changes with regenerative responses in the nigrostriatum of Pah(enu2) mice that are consistent with oxidative injury and occurred as early as 4 weeks of age. These neuropathologic changes were reversed following portal vein delivery of a recombinant adeno-associated virus-mouse phenylalanine hydroxylase-woodchuck hepatitis virus post-transcriptional response element (rAAV-mPAH-WPRE) vector to Pah(enu2) mice and corresponded to rapid reduction of serum Phe levels.

Food or fluid restriction in common laboratory animals: balancing welfare considerations with scientific inquiry.

Deprivation or restricted access to either food or fluids is a common research procedure in laboratory animals. The purpose of the present review is to present and summarize some of the important physiologic effects of such procedures and to assess their effect on the well-being of the animal. This assessment is presented within a context of the typical research objectives of such procedures. Specific suggestions are made that are intended to strike a balance between meeting these research objectives and ensuring the physiologic and behavioral welfare of the animals under study. Most of the information presented is specifically related to rats and mice but, with appropriate adjustments, the principles likely will generalize to other laboratory species. I present evidence that after 12 to 24 h without access, animals efficiently reduce further fluid or energy losses by a combination of behavioral and physiologic adjustments. These adjustments likely minimize the additional physiologic or psychologic stress of deprivation. Animals have endogenous nycthemeral rhythms that make them particularly adaptable to once-daily occurrences, such as food or water access. Longer periods of acute deprivation or chronic restriction are acceptable procedures, but only with suitable monitoring protocols, such as routine weighing and target weights. In the case of chronic food restriction, the use of species-, age-, and strain-specific target growth rates is more appropriate than using a fraction of age-matched free-fed animal weights as a target.

Temporal relationships between food acquisition and voluntary exercise in mice.

Patterns of operant food acquisition in a closed economy and bouts of either voluntary wheel running (WR) or spontaneous locomotor activity in a standard condition (SC) with no wheel were examined in young adult male and female C57BL/6 mice across a range of nose poke prices (FUP) per food pellet. Both sexes showed vigorous WR or locomotor activity. At each FUP, WR groups had higher food intake than SC groups. Despite substantially higher mean body weight of males compared with females, intakes and activity did not differ by sex in the SC groups and males lost weight more rapidly as FUP increased. In contrast, WR males ran ∼33% further per day than females, increased their food intake (above that of SC counterparts) more than females, and lost less body weight than SC males. By parsing the night in four 3h epochs it was found that food intake declined progressively through the night in both WR and SC mice and that the hyperphagia of WR relative to SC groups was most evident early in the night, coincident with highest activity. No large or systematic sex differences were revealed in these temporal analyses. Analysis of data at 60s resolution showed that pellet acquisition occurred in many small or short bouts, the timing of which was either intercalated or concurrent with either locomotor activity or WR. The results show that increased eating due to WR occurs concurrently with maximum running, and with no evidence of delayed compensation.