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• W2571719897 abstract "•Introduction of a running wheel increased daily energy expenditure in mice•This plateaued after 1 week, despite further increments in wheel use•The amount of wheel use did not correlate with total daily energy expenditure Exercise is a common component of weight loss strategies, yet exercise programs are associated with surprisingly small changes in body weight [1Byrne N.M. Wood R.E. Schutz Y. Hills A.P. Does metabolic compensation explain the majority of less-than-expected weight loss in obese adults during a short-term severe diet and exercise intervention?.Int. J. Obes. 2012; 36: 1472-1478Crossref PubMed Scopus (40) Google Scholar, 2Church T.S. Martin C.K. Thompson A.M. Earnest C.P. Mikus C.R. Blair S.N. Changes in weight, waist circumference and compensatory responses with different doses of exercise among sedentary, overweight postmenopausal women.PLoS ONE. 2009; 4: e4515Crossref PubMed Scopus (204) Google Scholar, 3Ross R. Janssen I. Physical activity, total and regional obesity: dose-response considerations.Med. Sci. Sports Exerc. 2001; 33: S521-S527Crossref PubMed Scopus (243) Google Scholar, 4Shaw K. Gennat H. O’Rourke P. Del Mar C. Exercise for overweight or obesity.Cochrane Database Syst. Rev. 2006; : CD003817PubMed Google Scholar]. This may be due in part to compensatory adaptations, in which calories expended during exercise are counteracted by decreases in other aspects of energy expenditure [1Byrne N.M. Wood R.E. Schutz Y. Hills A.P. Does metabolic compensation explain the majority of less-than-expected weight loss in obese adults during a short-term severe diet and exercise intervention?.Int. J. Obes. 2012; 36: 1472-1478Crossref PubMed Scopus (40) Google Scholar, 5Johannsen D.L. Knuth N.D. Huizenga R. Rood J.C. Ravussin E. Hall K.D. Metabolic slowing with massive weight loss despite preservation of fat-free mass.J. Clin. Endocrinol. Metab. 2012; 97: 2489-2496Crossref PubMed Scopus (162) Google Scholar, 6Westerterp K.R. Meijer G.A. Janssen E.M. Saris W.H. Ten Hoor F. Long-term effect of physical activity on energy balance and body composition.Br. J. Nutr. 1992; 68: 21-30Crossref PubMed Scopus (188) Google Scholar, 7Ridgers N.D. Timperio A. Cerin E. Salmon J. Compensation of physical activity and sedentary time in primary school children.Med. Sci. Sports Exerc. 2014; 46: 1564-1569Crossref PubMed Scopus (85) Google Scholar, 8Drenowatz C. Grieve G.L. DeMello M.M. Change in energy expenditure and physical activity in response to aerobic and resistance exercise programs.Springerplus. 2015; 4: 798Crossref PubMed Scopus (22) Google Scholar, 9Mansoubi M. Pearson N. Biddle S.J. Clemes S.A. Using sit-to-stand workstations in offices: is there a compensation effect?.Med. Sci. Sports Exerc. 2016; 48: 720-725Crossref PubMed Scopus (57) Google Scholar, 10King N.A. Caudwell P. Hopkins M. Byrne N.M. Colley R. Hills A.P. Stubbs J.R. Blundell J.E. Metabolic and behavioral compensatory responses to exercise interventions: barriers to weight loss.Obesity (Silver Spring). 2007; 15: 1373-1383Crossref PubMed Scopus (233) Google Scholar]. Here we examined the relationship between a rodent model of voluntary exercise— wheel running— and total daily energy expenditure. Use of a running wheel for 3 to 7 days increased daily energy expenditure, resulting in a caloric deficit of ∼1 kcal/day; however, total daily energy expenditure remained stable after the first week of wheel access, despite further increases in wheel use. We hypothesized that compensatory mechanisms accounted for the lack of increase in daily energy expenditure after the first week. Supporting this idea, we observed a decrease in off-wheel ambulation when mice were using the wheels, indicating behavioral compensation. Finally, we asked whether individual variation in wheel use within a group of mice would be associated with different levels of daily energy expenditure. Despite a large variation in wheel running, we did not observe a significant relationship between the amount of daily wheel running and total daily energy expenditure or energy intake across mice. Together, our experiments support a model in which the transition from sedentary to light activity is associated with an increase in daily energy expenditure, but further increases in physical activity produce diminishingly small increments in daily energy expenditure. Exercise is a common component of weight loss strategies, yet exercise programs are associated with surprisingly small changes in body weight [1Byrne N.M. Wood R.E. Schutz Y. Hills A.P. Does metabolic compensation explain the majority of less-than-expected weight loss in obese adults during a short-term severe diet and exercise intervention?.Int. J. Obes. 2012; 36: 1472-1478Crossref PubMed Scopus (40) Google Scholar, 2Church T.S. Martin C.K. Thompson A.M. Earnest C.P. Mikus C.R. Blair S.N. Changes in weight, waist circumference and compensatory responses with different doses of exercise among sedentary, overweight postmenopausal women.PLoS ONE. 2009; 4: e4515Crossref PubMed Scopus (204) Google Scholar, 3Ross R. Janssen I. Physical activity, total and regional obesity: dose-response considerations.Med. Sci. Sports Exerc. 2001; 33: S521-S527Crossref PubMed Scopus (243) Google Scholar, 4Shaw K. Gennat H. O’Rourke P. Del Mar C. Exercise for overweight or obesity.Cochrane Database Syst. Rev. 2006; : CD003817PubMed Google Scholar]. This may be due in part to compensatory adaptations, in which calories expended during exercise are counteracted by decreases in other aspects of energy expenditure [1Byrne N.M. Wood R.E. Schutz Y. Hills A.P. Does metabolic compensation explain the majority of less-than-expected weight loss in obese adults during a short-term severe diet and exercise intervention?.Int. J. Obes. 2012; 36: 1472-1478Crossref PubMed Scopus (40) Google Scholar, 5Johannsen D.L. Knuth N.D. Huizenga R. Rood J.C. Ravussin E. Hall K.D. Metabolic slowing with massive weight loss despite preservation of fat-free mass.J. Clin. Endocrinol. Metab. 2012; 97: 2489-2496Crossref PubMed Scopus (162) Google Scholar, 6Westerterp K.R. Meijer G.A. Janssen E.M. Saris W.H. Ten Hoor F. Long-term effect of physical activity on energy balance and body composition.Br. J. Nutr. 1992; 68: 21-30Crossref PubMed Scopus (188) Google Scholar, 7Ridgers N.D. Timperio A. Cerin E. Salmon J. Compensation of physical activity and sedentary time in primary school children.Med. Sci. Sports Exerc. 2014; 46: 1564-1569Crossref PubMed Scopus (85) Google Scholar, 8Drenowatz C. Grieve G.L. DeMello M.M. Change in energy expenditure and physical activity in response to aerobic and resistance exercise programs.Springerplus. 2015; 4: 798Crossref PubMed Scopus (22) Google Scholar, 9Mansoubi M. Pearson N. Biddle S.J. Clemes S.A. Using sit-to-stand workstations in offices: is there a compensation effect?.Med. Sci. Sports Exerc. 2016; 48: 720-725Crossref PubMed Scopus (57) Google Scholar, 10King N.A. Caudwell P. Hopkins M. Byrne N.M. Colley R. Hills A.P. Stubbs J.R. Blundell J.E. Metabolic and behavioral compensatory responses to exercise interventions: barriers to weight loss.Obesity (Silver Spring). 2007; 15: 1373-1383Crossref PubMed Scopus (233) Google Scholar]. Here we examined the relationship between a rodent model of voluntary exercise— wheel running— and total daily energy expenditure. Use of a running wheel for 3 to 7 days increased daily energy expenditure, resulting in a caloric deficit of ∼1 kcal/day; however, total daily energy expenditure remained stable after the first week of wheel access, despite further increases in wheel use. We hypothesized that compensatory mechanisms accounted for the lack of increase in daily energy expenditure after the first week. Supporting this idea, we observed a decrease in off-wheel ambulation when mice were using the wheels, indicating behavioral compensation. Finally, we asked whether individual variation in wheel use within a group of mice would be associated with different levels of daily energy expenditure. Despite a large variation in wheel running, we did not observe a significant relationship between the amount of daily wheel running and total daily energy expenditure or energy intake across mice. Together, our experiments support a model in which the transition from sedentary to light activity is associated with an increase in daily energy expenditure, but further increases in physical activity produce diminishingly small increments in daily energy expenditure. Exercise is commonly recommended in weight loss strategies for people with obesity [11Centers for Disease Control and Prevention. (2015). Physical activity for a healthy weight. https://www.cdc.gov/healthyweight/physical_activity/.Google Scholar]. Although important for overall health [12Michigan A. Johnson T.V. Master V.A. Review of the relationship between C-reactive protein and exercise.Mol. Diagn. Ther. 2011; 15: 265-275Crossref PubMed Google Scholar, 13Benatti F.B. Pedersen B.K. Exercise as an anti-inflammatory therapy for rheumatic diseases-myokine regulation.Nat. Rev. Rheumatol. 2015; 11: 86-97Crossref PubMed Scopus (273) Google Scholar, 14Roemmich J.N. Lambiase M.J. Balantekin K.N. Feda D.M. Dorn J. Stress, behavior, and biology: risk factors for cardiovascular diseases in youth.Exerc. Sport Sci. Rev. 2014; 42: 145-152Crossref PubMed Scopus (24) Google Scholar, 15Silverman M.N. Deuster P.A. Biological mechanisms underlying the role of physical fitness in health and resilience.Interface Focus. 2014; 4: 20140040Crossref PubMed Scopus (191) Google Scholar], exercise generally falls short on the goal of weight loss (effect size is typically less than 5% of body weight, even in studies lasting more than a year) [1Byrne N.M. Wood R.E. Schutz Y. Hills A.P. Does metabolic compensation explain the majority of less-than-expected weight loss in obese adults during a short-term severe diet and exercise intervention?.Int. J. Obes. 2012; 36: 1472-1478Crossref PubMed Scopus (40) Google Scholar, 2Church T.S. Martin C.K. Thompson A.M. Earnest C.P. Mikus C.R. Blair S.N. Changes in weight, waist circumference and compensatory responses with different doses of exercise among sedentary, overweight postmenopausal women.PLoS ONE. 2009; 4: e4515Crossref PubMed Scopus (204) Google Scholar, 3Ross R. Janssen I. Physical activity, total and regional obesity: dose-response considerations.Med. Sci. Sports Exerc. 2001; 33: S521-S527Crossref PubMed Scopus (243) Google Scholar, 4Shaw K. Gennat H. O’Rourke P. Del Mar C. Exercise for overweight or obesity.Cochrane Database Syst. Rev. 2006; : CD003817PubMed Google Scholar]. This is surprising, as physical activity is associated with acute increases in energy expenditure [16Booyens J. Keatinge W.R. The expenditure of energy by men and women walking.J. Physiol. 1957; 138: 165-171Crossref PubMed Scopus (37) Google Scholar, 17Carter S.E. Jones M. Gladwell V.F. Energy expenditure and heart rate response to breaking up sedentary time with three different physical activity interventions.Nutr. Metab. Cardiovasc. Dis. 2015; 25: 503-509Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar]. One explanation for the limited effect of exercise on weight is that exercise increases hunger, and the calories burned through exercise are thus recovered by increased food intake [18Stensel D. Exercise, appetite and appetite-regulating hormones: implications for food intake and weight control.Ann. Nutr. Metab. 2010; 57: 36-42Crossref PubMed Scopus (116) Google Scholar]. An alternative explanation suggests that compensatory adaptations counteract the calories expended during exercise [1Byrne N.M. Wood R.E. Schutz Y. Hills A.P. Does metabolic compensation explain the majority of less-than-expected weight loss in obese adults during a short-term severe diet and exercise intervention?.Int. J. Obes. 2012; 36: 1472-1478Crossref PubMed Scopus (40) Google Scholar, 5Johannsen D.L. Knuth N.D. Huizenga R. Rood J.C. Ravussin E. Hall K.D. Metabolic slowing with massive weight loss despite preservation of fat-free mass.J. Clin. Endocrinol. Metab. 2012; 97: 2489-2496Crossref PubMed Scopus (162) Google Scholar, 6Westerterp K.R. Meijer G.A. Janssen E.M. Saris W.H. Ten Hoor F. Long-term effect of physical activity on energy balance and body composition.Br. J. Nutr. 1992; 68: 21-30Crossref PubMed Scopus (188) Google Scholar, 7Ridgers N.D. Timperio A. Cerin E. Salmon J. Compensation of physical activity and sedentary time in primary school children.Med. Sci. Sports Exerc. 2014; 46: 1564-1569Crossref PubMed Scopus (85) Google Scholar, 8Drenowatz C. Grieve G.L. DeMello M.M. Change in energy expenditure and physical activity in response to aerobic and resistance exercise programs.Springerplus. 2015; 4: 798Crossref PubMed Scopus (22) Google Scholar, 9Mansoubi M. Pearson N. Biddle S.J. Clemes S.A. Using sit-to-stand workstations in offices: is there a compensation effect?.Med. Sci. Sports Exerc. 2016; 48: 720-725Crossref PubMed Scopus (57) Google Scholar, 10King N.A. Caudwell P. Hopkins M. Byrne N.M. Colley R. Hills A.P. Stubbs J.R. Blundell J.E. Metabolic and behavioral compensatory responses to exercise interventions: barriers to weight loss.Obesity (Silver Spring). 2007; 15: 1373-1383Crossref PubMed Scopus (233) Google Scholar]. Additive models of energy expenditure predict that changes in physical activity result in proportional changes in daily energy expenditure [19Food and Agriculture Organization of the United NationsHuman energy requirements: report of a joint FAO/WHO/UNU expert consultation.Food Nutr. Bull. 2005; 26: 166Crossref PubMed Google Scholar]. However, these models fail to account for biomechanics or the kinetics of movement, whereby the transition from immobile to mobile involves a large conversion of potential energy to kinetic energy, whereas maintenance of mobile states requires less energy [20Cavagna G.A. Heglund N.C. Taylor C.R. Mechanical work in terrestrial locomotion: two basic mechanisms for minimizing energy expenditure.Am. J. Physiol. 1977; 233: R243-R261PubMed Google Scholar]. Additionally, they discount the role of muscle training, in which repetition of a given movement increases muscle efficiency [21Gibala M.J. Little J.P. van Essen M. Wilkin G.P. Burgomaster K.A. Safdar A. Raha S. Tarnopolsky M.A. Short-term sprint interval versus traditional endurance training: similar initial adaptations in human skeletal muscle and exercise performance.J. Physiol. 2006; 575: 901-911Crossref PubMed Scopus (761) Google Scholar]. Perhaps most importantly, these models fail to account for alterations in other aspects of energy expenditure. Here we examined this energy compensation of physical activity with a rodent model of voluntary exercise, wheel running. Male C57BL/6 mice (n = 15) were housed for 9 days in indirect calorimetry chambers equipped with running wheels. The first 3 days were considered a habituation period and data were not included in further analyses. Days 3–6 were considered a “baseline” phase, in which the running wheels were mechanically locked to prevent use, and days 6–9 were considered the “wheel access” phase, in which the wheels were unlocked (Figure 1A). Five mice did not regularly use the wheels (average of 1.0 ± 0.7 wheel turns per day, mean ± SEM), whereas the remaining mice used them consistently (5,645 ± 1,485 wheel turns per day, equating to ∼1.5 km/day; Figure 1B). The total energy expenditure increased by ∼4% between the baseline and wheel phases for the mice that used the wheel (termed “runners”; 10.6 ± 0.1 to 11.0 ± 0.3 kcal/day; t (9) = 2.6, p = 0.03; Figures 1C and 1D). In contrast, total energy expenditure did not increase significantly for the mice that did not use the wheels regularly (termed “non-runners”; 10.7 ± 0.4 to 10.8 ± 0.2 kcal/day; t (4) = 0.6, p = 0.57). Subsequent analyses examined only runners to focus on the effect of wheel running on energy intake and utilization. Importantly, body weight did not decrease during their time in the calorimetry chambers, but rather increased non-significantly by ∼2% (one-way repeated-measures [RM] ANOVA, F (2, 18) = 2.6, p = 0.10; Figure 1E). Despite the lack of a reduction in body weight, the average daily respiratory exchange ratio (RER, ratio of CO2 production to O2 consumption [VCO2:VO2]) slightly but significantly decreased during the wheel access phase (0.93 ± 0.00 to 0.91 ± 0.01; t (9) = 4.0, p = 0.003; Figure 1F), suggesting a shift toward the consumption of residual fat stores. This was consistent with an ∼10% reduction in food intake throughout the wheel phase (11.5 ± 0.3 to 10.4 ± 0.2 kcal/day; t (9) = 3.7, p = 0.005; Figure 1G) and supports the reported anorexic effects of short-term wheel running [22Lewis D.Y. Brett R.R. Activity-based anorexia in C57/BL6 mice: effects of the phytocannabinoid, Delta9-tetrahydrocannabinol (THC) and the anandamide analogue, OMDM-2.Eur. Neuropsychopharmacol. 2010; 20: 622-631Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar]. Together, the decrease in food intake and increase in energy expenditure resulted in an average deficit of ∼0.8 kcal/day throughout the wheel access phase. This deficit would be predicted to reduce body fat by ∼0.25 g in 3 days. However, we did not detect any change in body weight, most likely due to the short duration of the experiment (Figure 1E). We examined whether the above effects would propagate into a larger energy deficit across a longer period of wheel access. Male C57BL/6 mice (n = 7) were habituated to home cages for 1 week, after which data were collected during a baseline phase (1 week); at the end of the baseline phase, running wheels were added to each cage and were freely available throughout the wheel access phase (3 weeks; Figure 2A). Throughout this and all of the following experiments, energy expenditure was estimated using an energy balance technique (see the Experimental Procedures), whereby the change in somatic energy stores was subtracted from total caloric intake to estimate energy expenditure [23Ravussin Y. Gutman R. LeDuc C.A. Leibel R.L. Estimating energy expenditure in mice using an energy balance technique.Int. J. Obes. 2013; 37: 399-403Crossref PubMed Scopus (56) Google Scholar, 24Guo J. Jou W. Gavrilova O. Hall K.D. Persistent diet-induced obesity in male C57BL/6 mice resulting from temporary obesigenic diets.PLoS ONE. 2009; 4: e5370Crossref PubMed Scopus (113) Google Scholar]. We observed a significant effect of week on energy expenditure (RM ANOVA, F (3, 18) = 4.1, p = 0.02), which we linked to an increase of ∼30% in weekly energy expenditure from baseline to week 1 of the wheel access phase (8.5 ± 0.2 to 11.0 ± 0.5 kcal/day; p = 0.003); however, despite increments in wheel running of 52,000 turns between weeks 1 and 2 and an additional 44,000 between weeks 2 and 3 (Figure 2D), there was no further increase in energy expenditure (Figures 2B and 2C). This was surprising, and it suggests that mice may compensate for the increased energetic demand of wheel running by reducing energy burned through other means. Consistent with our indirect calorimetry experiment, we observed a slight reduction in food intake across the first 3 days of wheel use (7.2 ± 0.7 to 6.1 ± 0.1 kcal/day), although this was not significant (p = 0.18). However, when analyzed across weeks, food intake increased significantly from 8.2 ± 0.3 in the baseline phase to 9.7 ± 0.3 kcal/day by week 3 (F (3, 18) = 6.6, p = 0.003; Figure 2E). Energetic balance (energy intake − energy expenditure) did not significantly change overall (F (3, 18) = 1.3, p = 0.29). However, independent t tests revealed a significant deficit in caloric balance during the first (p = 0.04), but not second or third week of wheel access relative to baseline (both p > 0.24; Figure 2F). Finally, there was a reduction in body mass across the experiment (F (3, 18) = 28.14, p < 0.0001), which was attributable to a significant decrease in body fat (4.4 ± 0.2 to 2.5 ± 0.2 g, F (3, 18) = 14.24, p < 0.0001), but not lean mass (21.6 ± 0.2 to 20.9 ± 0.2 g, F (3, 18) = 1.75, p = 0.19; Figure 2G). These results support a model in which the transition from sedentary to mild activity is associated with increased total energy expenditure, but further increases in activity do not result in additional changes in total energy expenditure. To gain a better understanding of the time course of changes in energy utilization with wheel access, we employed a mathematical model encompassing food intake (measured continuously, with sampling every other day) and weekly body composition measurements to make daily predictions about energy expenditure, fat oxidation rates, oxygen consumption, carbon dioxide production, and RER [25Guo J. Hall K.D. Estimating the continuous-time dynamics of energy and fat metabolism in mice.PLoS Comput. Biol. 2009; 5: e1000511Crossref PubMed Scopus (48) Google Scholar]. In contrast to the linear increase in wheel running across days, changes in modeled energy expenditure peaked in the first days of wheel access and plateaued across the next 2 weeks (Figure 2H), resulting in an energy deficit for the first week that recovered over the next two weeks despite increased wheel running (Figure S1). RER and fat oxidation also changed most strongly in the first week and then regressed toward basal values, despite further increases in wheel running (Figures 2I and S1). Next, we repeated the prior experiment in behavioral chambers (Noldus PhenoTypers, see the Experimental Procedures) that were equipped with overhead cameras for continuous video monitoring and quantification of off-wheel locomotion and physical inactivity (Figure 3A). In these mice (male C57BL/6 mice; n = 8), wheel running did not progressively increase as in our prior experiment, but instead stabilized after week 2 (F (3, 21) = 11.60, p = 0.0001; Figure 3B). Again, changes in wheel running were not accompanied by increases in total energy expenditure (F (3, 21) = 1.41, p = 0.27; Figure 3C) or food intake (F (3, 21) = 0.81, p = 0.50; Figure 3D). Body fat decreased by 16% during the wheel access phase (2.4 to 2.0 g; F (3, 21) = 15.60, p < 0.0001), while lean mass (21.9 to 22.0 g; F (3, 21) = 0.43, p = 0.73) did not change (Figure 3E). The decrease in body fat is consistent with the shift in RER that we observed in the indirect calorimetry experiment, as well as in our modeling analysis. Energy balance also followed a similar pattern as in our prior experiment, with a deficit following the initial addition of running wheels that rebounded by the end of week 3 (F (3, 21) = 11.07, p = 0.002; Figure 3F). Off-wheel ambulation decreased significantly after the addition of running wheels, an effect that persisted throughout the wheel access phase (F (25, 175) = 9.67, p = 0.0002; Figure 3G), possibly reflecting a compensatory adaptation to the energetic demand of increased wheel use. Finally, we investigated whether natural variation in wheel running would be associated with different levels of total daily energy expenditure. Male C57BL/6 mice (n = 41) were habituated to home cages for 1 week, after which data were collected during a baseline phase (1 week); at the end of the baseline phase, running wheels were added to each cage and were freely available throughout the wheel access phase (2–3 weeks). There was a large variance in daily wheel use among mice (Figure 4A). However, the amount of daily wheel use did not correlate with total energy expenditure (R2 = 0.08, p = 0.08; Figure 4B) or food intake (R2 = 0.00, p = 0.93; Figure 4C). We identified a slight but significant inverse correlation between wheel running and body mass (R2 = 0.12, p = 0.02; Figure 4D), which appeared to be attributed to mice with very low wheel counts having higher body fat (R2 = 0.49; Figure 4E) and not differences in lean mass (Figure 4F). We conclude that natural variation in wheel running does not translate into detectable differences in energy intake or expenditure but may underlie differences in body composition. In these experiments, the transition from sedentary to mild activity caused an increase in daily energy expenditure, while further increments in activity translated into diminishingly small increases in daily energy expenditure. The incremental cost of wheel use in mice has been estimated at ∼100 to 200 calories per 1,000 wheel counts, accounting for ∼5%–10% of daily energy demands [26Koteja P. Swallow J.G. Carter P.A. Garland Jr., T. Energy cost of wheel running in house mice: implications for coadaptation of locomotion and energy budgets.Physiol. Biochem. Zool. 1999; 72: 238-249Crossref PubMed Scopus (94) Google Scholar, 27Chappell M.A. Garland Jr., T. Rezende E.L. Gomes F.R. Voluntary running in deer mice: speed, distance, energy costs and temperature effects.J. Exp. Biol. 2004; 207: 3839-3854Crossref PubMed Scopus (81) Google Scholar, 28Rezende E.L. Gomes F.R. Chappell M.A. Garland Jr., T. Running behavior and its energy cost in mice selectively bred for high voluntary locomotor activity.Physiol. Biochem. Zool. 2009; 82: 662-679Crossref PubMed Scopus (66) Google Scholar]. Without compensatory mechanisms, these increases in wheel counts would have been predicted to increase daily energy expenditure by ∼10%–20%, an effect size that we observed in the early phases of wheel access. However, this effect failed to propagate across subsequent weeks, despite further increases in wheel use. The contribution of physical activity to daily energy expenditure in humans and mice cover a large range, estimated at ∼10%–30% of daily energy expenditure [29Abreu-Vieira G. Xiao C. Gavrilova O. Reitman M.L. Integration of body temperature into the analysis of energy expenditure in the mouse.Mol. Metab. 2015; 4: 461-470Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar, 30Maclean P.S. Bergouignan A. Cornier M.A. Jackman M.R. Biology’s response to dieting: the impetus for weight regain.Am. J. Physiol. Regul. Integr. Comp. Physiol. 2011; 301: R581-R600Crossref PubMed Scopus (266) Google Scholar]. Unlike humans, thermogenesis represents the greatest contributor to energy expenditure for mice housed below thermoneutrality [29Abreu-Vieira G. Xiao C. Gavrilova O. Reitman M.L. Integration of body temperature into the analysis of energy expenditure in the mouse.Mol. Metab. 2015; 4: 461-470Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar, 31Garland Jr., T. Schutz H. Chappell M.A. Keeney B.K. Meek T.H. Copes L.E. Acosta W. Drenowatz C. Maciel R.C. van Dijk G. et al.The biological control of voluntary exercise, spontaneous physical activity and daily energy expenditure in relation to obesity: human and rodent perspectives.J. Exp. Biol. 2011; 214: 206-229Crossref PubMed Scopus (324) Google Scholar]. Active skeletal muscle is a highly thermogenic organ, converting the bulk of utilized energy into heat and a minority into work [32Gaesser G.A. Brooks G.A. Muscular efficiency during steady-rate exercise: effects of speed and work rate.J. Appl. Physiol. 1975; 38: 1132-1139Crossref PubMed Scopus (504) Google Scholar, 33Block B.A. Thermogenesis in muscle.Annu. Rev. Physiol. 1994; 56: 535-577Crossref PubMed Scopus (217) Google Scholar]. Therefore, muscle thermogenesis during wheel running may have caused mice to downregulate thermogenesis by brown adipose and other tissues. In support of this idea, while voluntary physical activity at thermoneutrality increased energy expenditure in mice, physical activity below thermoneutrality had no effect on daily energy expenditure [34Virtue S. Even P. Vidal-Puig A. Below thermoneutrality, changes in activity do not drive changes in total daily energy expenditure between groups of mice.Cell Metab. 2012; 16: 665-671Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar]. Mice on wheels at lower ambient temperatures also exhibit a shallower slope between acute running speed and rate of energy expenditure, most likely reflecting the larger contribution of muscle thermogenesis at lower ambient temperatures [27Chappell M.A. Garland Jr., T. Rezende E.L. Gomes F.R. Voluntary running in deer mice: speed, distance, energy costs and temperature effects.J. Exp. Biol. 2004; 207: 3839-3854Crossref PubMed Scopus (81) Google Scholar]. Finally, a study employing high-resolution (one sample every 2 s) indirect calorimetry noted that the resting metabolic rate of mice at 22°C dropped below basal levels for 15–30 min following bouts of motor activity. The authors hypothesized that this was due to muscle thermogenesis during activity, reducing the need for other forms of thermogenesis [35Even P.C. Blais A. Increased cost of motor activity and heat transfer between non-shivering thermogenesis, motor activity, and thermic effect of feeding in mice housed at room temperature – implications in pre-clinical studies.Front. Nutr. 2016; 3: 43Crossref PubMed Scopus (9) Google Scholar]. Since humans operate in an approximate state of thermoneutrality, this aspect of energy expenditure may be less relevant to humans than mice. Although exercise acutely increases energy expenditure, this may be compensated for by a comparable reduction in non-exercise physical activity. Accordingly, we observed a decrease in off-wheel locomotion in mice that were provided with running wheel access, consistent with findings of other researchers [36Copes L.E. Schutz H. Dlugosz E.M. Acosta W. Chappell M.A. Garland Jr., T. Effects of voluntary exercise on spontaneous physical activity and food consumption in mice: results from an artificial selection experiment.Physiol. Behav. 2015; 149: 86-94Crossref PubMed Scopus (50) Google Scholar, 37de Carvalho F.P. Benfato I.D. Moretto T.L. Barthichoto M. de Oliveira C.A. Voluntary running decreases nonexercise activity in lean and diet-induced obese mice.Physiol. Behav. 2016; 165: 249-256Crossref PubMed Scopus (16) Google Scholar]. Muscle efficiency can also increase with exercise repetition and training such that performing the same exercise over time utilizes less energy [21Gibala M.J. Little J.P. van Essen M. Wilkin G.P. Burgomaster K.A. Safdar A. Raha S. Tarnopolsky M.A. Short-term sprint interval versus traditional endurance training: similar initial adaptations in human skeletal muscle and exercise performance.J. Physiol. 2006; 575: 901-911Crossref PubMed Scopus (761) Google Scholar]. While we did not measure the biomechanics or dynamics of how the mice ran on the wheels in this study, it is possible that such adaptations further affected energy expenditure in this study. Our results may relate to why exercise results in modest changes in weight [1Byrne N.M. Wood R.E. Schutz Y. Hills A.P. Does metabolic compensation explain the majority of less-than-expected weight loss in obese adults during a short-term severe diet and exercise intervention?.Int. J. Obes. 2012; 36: 1472-1478Crossref PubMed Scopus (40) Google Scholar, 2Church T.S. Martin C.K. Thompson A.M. Earnest C.P. Mikus C.R. Blair S.N. Changes in weight, waist circumference and compensatory responses with different doses of exercise among sedentary, overweight postmenopausal women.PLoS ONE. 2009; 4: e4515Crossref PubMed Scopus (204) Google Scholar, 3Ross R. Janssen I. Physical activity, total and regional obesity: dose-response considerations.Med. Sci. Sports Exerc. 2001; 33: S521-S527Crossref PubMed Scopus (243) Google Scholar, 4Shaw K. Gennat H. O’Rourke P. Del Mar C. Exercise for overweight or obesity.Cochrane Database Syst. Rev. 2006; : CD003817PubMed Google Scholar]. However, exercise confers many health benefits even in the absence of weight loss, including improvements in glucose regulation, cardiac function, neurological health, and muscle and joint function [12Michigan A. Johnson T.V. Master V.A. Review of the relationship between C-reactive protein and exercise.Mol. Diagn. Ther. 2011; 15: 265-275Crossref PubMed Google Scholar, 13Benatti F.B. Pedersen B.K. 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We therefore believe that physical activity should be encouraged for its overall health benefits, while expectations concerning its role in weight loss should be kept realistic. Understanding the mechanisms governing energy expenditure may lead to a better understanding of the levels of physical activity required to achieve health goals, regardless of changes in body weight. Male C57BL/6 mice (3–6 months old; n = 51) were used in these experiments, and were individually housed with ad libitum access to food and water. All procedures were reviewed and approved by the National Institute of Diabetes and Digestive and Kidney Disease’s Animal Care and Use Committee. Indirect calorimetry chambers (Oxymax/CLAMS, Columbus Instruments) were used to measure energy expenditure through the detection of O2 consumption and CO2 production within each chamber (22°C, 2.5-L volume, flow rate of 0.5 L/min, sampling flow of 0.4 L/min) in 13 min bins. Alternatively, using the assumption that the energy density of fat and lean mass represents 9.4 kcal/g and 1.0 kcal/g, respectively, energy expenditure was estimated using the mass balance method [23Ravussin Y. Gutman R. LeDuc C.A. Leibel R.L. Estimating energy expenditure in mice using an energy balance technique.Int. J. Obes. 2013; 37: 399-403Crossref PubMed Scopus (56) Google Scholar, 24Guo J. Jou W. Gavrilova O. Hall K.D. Persistent diet-induced obesity in male C57BL/6 mice resulting from temporary obesigenic diets.PLoS ONE. 2009; 4: e5370Crossref PubMed Scopus (113) Google Scholar] as follows:Energyexpenditure=metabolizableenergyintake–(Δfatmass+Δleanmass). Raw data for all analyses are provided in Table S1. Measures of physical activity, energy homeostasis, and body composition were independently analyzed in GraphPad Prism or Microsoft Excel using paired t tests or RM ANOVAs (one way or 2 × 5), according to experimental design. Conceptualization, T.J.O., D.M.F., and A.V.K.; Methodology, T.J.O., D.M.F., and A.V.K.; Investigation, T.J.O. and D.M.F.; Data Analysis, T.J.O., D.M.F., J.G., K.D.H., and A.V.K.; Writing, T.J.O., D.M.F., K.D.H., and A.V.K.; Supervision, D.M.F. and A.V.K.; Funding, K.D.H. and A.V.K. This research was supported by the Intramural Research Program of the NIH, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK; grant no. 1ZIADK075096). We would like to thank the Mouse Metabolism Core at the National Institute of Diabetes and Digestive and Kidney Diseases for assistance with indirect calorimetry experiments. We thank members of the A.V.K. lab, Marc Reitman, and Oksana Gavrilova for helpful discussions and insight on the manuscript. Download .pdf (.2 MB) Help with pdf files Document S1. Supplemental Experimental Procedures and Figure S1 Download .xlsx (.22 MB) Help with xlsx files Table S1. Raw Data and Animal Information Used to Create Graphs in Figures 1, 2, 3, and 4" @default.
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