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Critical Importance of Controlling Energy Status to Understand the Effects of "Exercise" on Metabolism

2007; Lippincott Williams & Wilkins; Volume: 36; Issue: 1 Linguagem: Inglês

10.1097/jes.0b013e31815e42c2

1538-3008

Barry Braun, George A. Brooks,

Sports Performance and Training

Editor's Note: For the past 7 years and since Exercise and Sport Sciences Reviews changed to a quarterly journal, readers have had the opportunity to read the News Briefs column. Michael J. Joyner, M.D., FACSM, first News Briefs editor, was well succeeded by George A. Brooks, Ph.D., FACSM, in January 2006. Now, I am pleased to unveil the column Commentary to Accompany, which will replace the News Briefs column. The articles in ESSR continue to offer exciting new concepts and hypotheses based on the author's body of work. The new Commentary is designed to feature one of these articles; each commentary's main focus will be to provide a more global perspective on the significance of the manuscript it accompanies. One or two commentaries will be featured in each issue. We are fortunate to have Dr. Brooks continue working with the journal as the Commentary Editor. We hope you enjoy the first commentary below, which as a transition from the News Briefs column to the commentary format focuses on one topic, and look forward to the commentaries to come. INTRODUCTION Ever read a paper in which the authors conclude that training does X to lipolysis, or that high altitude does Y to energy/substrate partitioning only to read subsequently that the real answers are otherwise? Are such events inevitable in science, or have investigators failed to conduct adequate control trials in the course of their experiments? One of the key concerns in experimental science is to ensure that the outcome of interest is isolated from potentially confounding variables. This concern is often referred to as "internal validity," sometimes shorthanded as "making sure you are measuring what you think you are measuring." In studies involving human exercise, ensuring internal validity leads investigators to include experimental groups that arrive at the laboratory and sit on exercise equipment without actually performing exercise (to control for effects of just being in the laboratory environment and interacting with the investigators), to rigidly maintain consistent environmental conditions (including temperature, humidity, air circulation, and even the quantity and quality of verbal encouragement), and to design creative studies that isolate local effects of muscle contraction from systemic effects of, for example, circulating hormones (e.g., one-legged training studies). Although every investigator who performs experimental studies focused on human exercise is aware that there are interactions between exercise (energy expenditure) and diet (energy intake), there are few studies in which energy status (the relationship between intake and expenditure) is carefully controlled. Because energy status (deficit, balance, or surplus) by itself can have profound effects on metabolism, the internal validity of studies of exercise that do not strictly control energy status may be compromised. In particular, there are many effects of energy deficit that overlap considerably with effects of "exercise." Unless dietary intake rises to match new higher energy expenditure, effects of exercise are likely to be confounded by the attendant energy deficit. It would be impossible, in this limited venue, to provide a comprehensive overview of how short-term energy deficit can confound the interpretation of exercise studies (single bout and training). To illustrate the point, five examples are briefly described below to demonstrate the potential role of energy status in mediating effects often attributed to exercise. Although disrupted menstrual cyclicity (amenorrhea or dysmenorrhea) is relatively common in female athletes, the root cause of the problem was controversial. Initially, most researchers and practitioners assumed that low body fat was the culprit. When that hypothesis was disproved, the general consensus blamed hard exercise training. To address the question in a systematic way, Loucks and colleagues performed definitive studies in which they tested the hypothesis that energy deficit, not exercise itself, explained the disrupted menstrual function. In an elegantly designed experiment in which the energy expended by exercise was either replaced (energy balance) or not replaced (energy deficit), Hilton and Loucks (5) showed that energy imbalance, not the stress of exercise itself, reduced the pulsatility of the reproductive hormones that regulate menstrual function. In this study and their follow-up studies, Loucks and colleagues have shifted the focus of the issue from energy output (exercise) to energy intake (eating behavior) and fundamentally altered the way secondary menstrual dysfunction is treated. For many decades, understanding the protein requirements for athletes and other active individuals has been almost an obsession for nutritionists and exercise biochemists. Research studies aimed at determining whether the stress of exercise training increases protein requirements above the recommended dietary allowance (RDA) have yielded somewhat equivocal results, with nitrogen balance attained at protein intakes approximating the RDA to more than double that value. Part of the reason it has been difficult to hone in on a tight range of values is the critical impact of energy (and in particular, carbohydrate energy) status on protein requirements. It has been known for decades that energy and/or carbohydrate deficit greatly increases protein requirements to provide carbon skeletons for energy and gluconeogenesis. Without compulsive control of dietary intake and expenditure, determining the true impact of endurance or resistance training on protein requirements is impossible. When energy and carbohydrate balance are maintained, the protein needs for the recreational athlete/physically active individual is only slightly higher than the RDA. In serious athletes training several hours per day at high intensities, this need may be somewhat higher (but typically, the increased need is provided by the higher total energy intake in these individuals). In athletes who are not taking in sufficient energy to maintain energy balance, the protein requirements may be increased dramatically. The interactions between energy, carbohydrate, and protein needs were nicely summarized in a review by Tarnopolsky (8). In short, for studies of nitrogen (protein) balance in which energy balance was uncontrolled, the results are totally forgettable. In studies of exercise and insulin sensitivity, the energy expended during the exercise bout is rarely replaced by dietary energy, so subjects are confronted by two variables - exercise and short-term energy deficit. Because short-term energy deficit is well known to enhance insulin sensitivity, it has been difficult to determine how much of the insulin-sensitizing effect of exercise is actually mediated by the energy deficit incurred by not replacing the expended calories. To explicitly address that question, Black et al. (2) imposed daily exercise on previously sedentary subjects for six consecutive days. In one group, the expended energy was carefully replaced to maintain energy balance; in the other group, the energy was not replaced, and subjects incurred a daily energy deficit of 500 kcal. Insulin sensitivity was enhanced by 40% after the short-term training in the deficit group, but this effect was completely absent when energy balance was maintained by feeding back the energy. The story is likely to be even more complex than simple energy status, as a series of studies from the research group led by Jeff Horowitz has shown that replacing the expended energy but withholding carbohydrate has no impact on the exercise-induced enhancement of insulin action (7), reinforcing similar results from studies of glycogen-depleted rats done 20 yr ago by Greg Cartee and associates (3). Hypophagia, energy deficit, and weight loss are commonly observed in humans exposed to hypobaric hypoxia at high altitude. Attempts to understand the impact of acute and acclimatized hypoxia on substrate metabolism have been complicated by independent effects of energy deficit to up-regulate lipolysis and increase reliance on lipid as an oxidizable energy substrate. In a series of studies undertaken to isolate the effects of hypoxia per se from the confounding impact of energy deficit, investigators observed that when energy balance was maintained by rigidly controlling energy intake to match the new higher expenditure, men exposed to high altitude shifted to a greater dependence of glucose, rather than lipid, as compared with those exposed to sea level (6). More recently, researchers have teased apart the interactions between hypoxia and energy deficit by bringing men to high altitude and maintaining either energy balance or energy deficit (1). The hormonal responses to hypoxia are strongly mediated by energy status during the acclimatization process, a finding that may underlie the divergent effects on substrate metabolism. In sum, regard with skepticism results of studies of metabolism at high altitude in which subjects lost 5, 10, or more kilograms of body weight for it is impossible to know the effect of altitude independent of undernutrition. A bout of prior exercise has been shown to reduce postprandial lipemia, but in a study of energy expenditure, diet was not adjusted to replace the energy expended. Therefore, it was possible that the blunting of lipemia after exercise was mediated by the concurrent energy deficit and not by exercise itself. In 2000, Gill and Hardman (4) compared the effects of exercise versus an equivalent level of energy restriction on the triacylglycerol and fatty acid responses to a mixed high-fat meal. They found that energy restriction had only a mild and nonsignificant effect on lipemia, but the response to exercise was much more robust and statistically significant. Unlike the previous four scenarios, in this case, exercise per se is more important than energy imbalance in mediating metabolic outcomes, but without careful control of dietary intake and output, the independent impact of exercise or energy deficit would still be unknown. CONCLUSIONS Seemingly, in a first course on experimental design, students are cautioned to guard against the presence of confounding variables in designing experiments. So why is it that for studies of exercise and environmental physiology, dietary controls are seldom imposed? Perhaps it is because we, exercise physiologists, are so enthusiastic about studying such really cool things like muscle protein synthesis, altitude adaptation, athlete amenorrhea, insulin action, and the management of lipidemia that we forget elementary but elemental controls? Those controls are necessary to understand not only the five phenomena just described but also countless others, such as etiology of the epidemics in obesity and metabolic syndrome.