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W1994137712 abstract "Energy is a concept of universal importance. In relation to body weight regulation, one is so used to consider energy intake, energy expenditure, and energy balance that one forgets that energy is an abstract notion without physiological equivalent. The body's regulatory functions may strive to maintain carbohydrate (CHO), protein and/or fat balances, but not energy balance. The body ignores that 1 g of fat contains more than twice the energy present in 1 g of carbohydrate, an element of information needed to determine the energy balance. In applying this knowledge to consider body weight regulation, one introduces a biologically irrelevant fact. One may learn to be in awe at the body's ability to maintain approximate energy balances over extended periods of an individual's life, as a consequence of the organism's ability to maintain substrate balances, but attempts to understand this as the result of a regulatory process directed at the energy balance itself are doomed to be frustrated. Not surprisingly, failure to be aware of the inappropriate use of the energy and energy balance concepts in considering body weight regulation and obesity has spawned numerous misconceptions ((1)). The intent of this article is to provide direct access to the considerations that pertain to particular notions commonly cited in the context of obesity. Their presentation under separate headings should be helpful, in particular to individuals not necessarily immersed in obesity research who want to understand the meaning of specific terms and concepts. 1. Problems in applying the energy balance concept The energy balance equation is often invoked to frame issues relating to body weight regulation and obesity. The equation states that Energy Balance = Energy Intake — Energy Expenditure which appears to support the statement that obesity is due to a “positive energy balance,” i.e., that energy intake is exceeding energy expenditure. Unfortunately, this seemingly obvious pronouncement sets up several misconceptions ((1)). First, this view confuses past and present, obscuring the fact that obese individuals, like lean subjects, tend to reach a state of approximate energy balance, with similar short-term fluctuations in the energy balance. Thus, one fails to recognize that the really important difference between lean and obese individuals is the degree of adiposity at which, on average, their energy intake tends to adjust itself to their energy expenditure. This varies widely between individuals, in a manner influenced by genetic as well as by environmental conditions. Thus obesity is brought about by a failure of the interactions between body composition and food intake regulation to restrain eating when the body's energy stores are more than adequate for health (Table 1). 2. Problems with the metabolic efficiency concept Weight gains or losses generally do not exceed 1 or 2 kg per year during long periods of an individual's life ((2)), reflecting an error of only 1–2% in the adjustment of food intake to energy expenditure. This corresponds to an average daily difference between energy intake and expenditure in the order of 25–50 kcal. Thus even minor differences between energy intake and expenditure appear to be able, in their cumulative long-term effect, to cause or to prevent the progressive development of obesity. The second misconception promoted by notions based on the energy balance equation is that obesity could therefore be due to unusually low metabolic rates. This impression has been enhanced because rates of energy expenditures per kg body weight or per kg fat-free mass (FFM) appear to be lower in obese than in lean subjects, which is a simple artefact due to a positive intercept in the correlations between energy expenditure and body weight or FFM. Nevertheless it has led to speculations about higher “metabolic efficiency” in obesity, as a way to account for a higher than normal proportion of energy retention. Such a notion, sometimes tossed around without proper definition of “metabolic efficiency” ((3)), should long ago have been dispelled by the realization that total energy expenditure is raised in obesity, due to the increase in lean body mass associated with weight gain and the greater costs associated with moving a heavier body. The utter confusion introduced by the energy efficiency concept becomes apparent when one realizes that the large daily variations in food consumption that occur when food is freely available, cause energy balance to be positive on some days and negative on others. Thus, during period of weight stability, metabolic efficiency would oscillate between positive and negative values over the short term, whereas it is essentially equal to zero over extended periods. 3. The misleading emphasis on the importance of low resting metabolic rates Arguments about the potential long-term impact on body weights of differences in resting energy expenditure, or of small diet– or physical activity-induced increases in energy expenditure, hinge on the assumption that such differences would not be offset by adjustments in energy intake. This is a totally unwarranted assumption, as there is no evidence indicating that average energy intakes in subjects eating at their own discretion are “clamped” at some particular level ((4)). Several facts speak against the notion that minor differences in metabolic efficiency or in resting energy expenditure may be important for body weight regulation. (i) Stature, which is positively correlated with resting and with total energy expenditures, has no impact on adiposity ((5)). (ii) There is no correlation between % body fat and deviations from predicted (or “normal”) basal energy expenditure (Figure 1) ((6)). Adiposity and basal energy expenditure (BEE). (a) % Body fat contents of 433 women whose ages, anthropometric data, and BEE are listed in the dietary reference intake (DRI) database ((45)), plotted against the deviation (expressed in terms of %) from their predicted (i.e., “normal”) daily BEE (as kcal/day) calculated using the multiple regression equation in ((45)). % Body fat contents were predicted from their BMI, using the equation correlating BMI and measurements of body fat by bio-impedance in the National Health and Nutrition Examination Survey (NHANES) III data ((45)). (b) % Body fat contents of 335 men whose ages, anthropometric data, and BEE are listed in the DRI database ((45)), plotted against the deviation (expressed in terms of %) from their predicted (i.e., “normal”) daily BEE (as kcal/day) calculated using the multiple regression equation in ((45)). % Body fat contents were predicted from using the equation correlating BMI and measurements of body fat by bio-impedance in the NHANES III data ((45)). It is generally considered that causes cannot safely be inferred from correlations, especially from cross-sectional correlations. In the case considered here, however, the crucial fact is the lack of correlation. This is much simpler to interpret, as this evidence directly and simply demonstrates that factors other than deviations from predicted resting metabolic rate are overwhelming the possible effect of such deviations in determining the degree of adiposity associated with the steady state of weight maintenance. Various arguments have been made about the potential roles of futile cycles ((3)) and of brown adipose tissue and uncoupling proteins (UCP) in affecting adiposity by raising energy expenditure ((7)). However, their impact on overall energy expenditure in man appears to be small at best. Since differences in basal energy expenditure have no statistically recognizable impact on body fat contents, speculations about the potential significance of UCP and futile cycles need to be made cautiously. Given that long-term CHO balance will be maintained under all circumstances, one should only expect an effect on body fat if the resulting increases in energy expenditure were largely covered by increments in fat oxidation, setting up an effect similar to that of physical activity (see #18 below). At any rate, it is of interest to note that spontaneous food intake regulation is powerful enough to obliterate the impact that meals and foods served in uniform proportions could be expected to exert on fatness among individuals whose energy expenditures differ, for example, due to differences in stature ((5)). 4. Misleading expectations about the importance of “adaptive thermogenesis” Adaptive thermogenesis describes changes in resting energy expenditure which serve, or have the effect of diminishing weight gains or weight losses during periods of overconsumption or starvation, relative to the weight changes which would be expected if changes in resting energy expenditure were solely due to changes in body size and in the thermic effect of food ((8)). This phenomenon has thus been considered to reflect a kind of “metabolic adaptation.” While adaptive thermogenesis has been found to be substantial in some animal models, they are modest in humans, to the point that it has been difficult to establish them unambiguously. The fact that differences in resting energy expenditure have no statistically recognizable impact on adiposity (see Figure 1) argues strongly against the view that differences in adaptive thermogenesis, which occur only occasionally, play a significant role in preventing or promoting the preponderance of obesity. 5. Problem in judging the importance of de novo lipogenesis and of its metabolic costs Several reactions in the fatty acid synthesizing pathway require adenosine triphosphate (ATP), so conversion of glucose into fat requires a substantial investment of energy. If the costs for prior conversion of glucose into glycogen as well as for the transport of fatty acid synthesized in the liver to adipose tissue are also included, the cost for conversion of dietary carbohydrate into fat may be assessed at some 25% ((9)). The net ATP yield, i.e., the total number of ATP generated minus the number of ATP expended for the transport, activation, and remodeling in the metabolic process, was evaluated in refs. (3) and (10). This yield is higher during fatty acid oxidation than during glucose oxidation. The net ATP yield from ingested glucose followed by the oxidation of that amount of fat is thus not much affected by initial conversion of glucose to fat, or by the concomitant occurrence of lipogenesis and oxidation of a matching amount of fat ((10)). Thus, contrary to a still commonly held expectation, dissipation of dietary energy by conversion of glucose into fat cannot explain why high-carbohydrate diets are less conducive to obesity than high-fat diets ((11)). In fact, the issue is essentially moot, mainly because fatty acid synthesis from glucose, estimated at some 10 g/day ((12)) in subjects consuming a Western diet, is of minor quantitative significance and not sufficient to compensate for concomitant fat oxidation even after massive CHO loads ((13)). 6. The irrelevance of the “nutrient-partitioning” concept The concept of nutrient partitioning has been developed in the context of meat production, where the proportions of nutrients consumed retained as muscle or fat is important. It is relevant for periods of rapid growth, but it has also been considered in discussing the problem of obesity, in attempts to understand the differences in degrees of adiposity reached by different individuals ((14)). However, in lean as well as in overweight adults whose weight is relatively stable, essentially all the nutrients consumed over a period of a few days are oxidized, regardless of diet, level of physical activity, and degree of adiposity. Furthermore, the large variations in physical activity, food consumption, and energy balance occurring under free-living conditions cause nutrient balances to vary considerably from day to day. Thus the nutrient-partitioning concept is rather meaningless when applied to adult humans. 7. Failure to recognize the different impacts of energy intake and energy expenditure on energy balance Food intake elicits an increase in energy expenditure, known as the “thermic effect of food” (TEF). It is mainly due to the need to regenerate the ATP used for the absorption, transport and storage of the nutrients consumed ((15)). It is usually considered to amount to about 10% of the food energy consumed when living on a mixed diet. In addition, modest increases or declines in resting energy expenditure occur during periods of excessive or deficient energy intake, which are commonly referred to as adaptive thermogenesis (cf. #4). The sum of the latter plus TEF is often referred to as diet-induced thermogenesis. These changes can only slightly attenuate, but not reverse, the impact of changes in energy intake on the energy balance. Unfortunately, the energy balance equation suggests that energy intake and energy expenditure occupy equivalent roles in determining energy balance, when in fact the factors governing energy intakes influence the energy balance far more powerfully than the factors determining resting energy expenditure. This important fact does not become evident by a simplistic consideration of the energy balance equation. 8. Difficulties in understanding food intake regulation In spite of the multitude of physiological phenomena known to contribute to the regulation of food consumption, variations in daily food intake are very large. The coefficients of variation for intraindividual energy intake were found to average ±23% ((16)). Furthermore, changes in food intake are not closely synchronized with variations in energy expenditure, which can also be substantial ((17)). Evidently, metabolic functions can be readily sustained in spite of large daily deviations from energy balance. That is why evolution was not compelled to develop a precise control over daily food consumption. The physiological mechanisms involved in controlling food intake should therefore be expected to explain only a minor part of the observed variability in daily food intake. This has made it difficult to elucidate the mechanisms involved. Furthermore, there appears to be considerable redundancy in this regulation. Thus, inactivation or stimulation at one control site may lead to temporary disruptions, but weight maintenance generally tends to become re-established subsequently, albeit possibly at a different level. Since most individuals maintain stable body weights during long periods of their lives ((2)), and since changes in resting energy expenditure cannot compensate for changes in intake (cf. #7), it can be inferred that food intake tends to adjust itself remarkably well to energy expenditure over the long term, even though large daily deviations from energy balance occur. Therefore, adjustment of intake to expenditure in humans must obviously be happening over periods of several days. This view is supported by the recent recognition of corrective responses occurring with 3–4-day delays ((18)). 9. Conditions for body weight stability: “settling point” vs. “set point” Although less obvious than the fact that energy intake must be equal to energy expenditure, weight stability also requires that the substrate mixture oxidized be equivalent, on average, to the composition of the nutrient mix consumed. When “substrate balance” is not achieved, changes in body composition occur, which in time are bound to elicit adjustments in food intake ((15),(19)). The contributions made by carbohydrate and by fat to the fuel mix oxidized is reflected in the ratio of CO2 produced to O2 consumed. This ratio is known as the “respiratory quotient” or “RQ.” It varies between the values of 1.0, when CHO is the predominant fuel, and 0.7, when oxidation of fat provides most of the body's energy. The ratio of CO2 produced to O2 consumed during the biological oxidation of a representative sample of the diet consumed is defined as the “food quotient” or “FQ” ((15)). Stable body compositions will only be sustained if the average RQ matches the average FQ of the diet. The composition of the fuel mix oxidized and hence the average RQ are influenced by the size of the body's substrate reserves. The steady state of weight maintenance thus tends to become established for a particular body composition in a given individual living under a particular set of circumstances. This corresponds to a “settling point” ((20)). Such a view accommodates the fact that circumstances cause weight stability to occur for various degrees of adiposity. Thus it seems to fit reality much better than the concept of a “set point” or “ponderostat” ((21)) often invoked to explain weight stability. In fact, such a concept would seem to be utterly inconsistent with the rise in the preponderance of obesity, since set-points would have to be seen as preventing the impact of changing circumstances. It has sometimes been considered that “set-points” are reset for different conditions, but in effect this argument reduces the set-point phenomenon to a settling point. Rapid weight changes take place during growth, as well as sometimes in adults. Such changes reflect the fact that their body composition is still substantially different from that which corresponds to the steady state of weight maintenance. 10. Problems with the application of the RQ/FQ concept An RQ greater than the FQ indicates that CHO makes a greater, and fat a smaller, contribution to the substrate mix oxidized than their relative proportions in the diet ((3)). On the other hand, a RQ/FQ ratio below 1.0 reflects the oxidation of a fuel mix containing a higher proportion of fat than that provided by the diet. While this insight is theoretically valid, the differences between RQ and FQ under conditions of variable nutrient intakes are small and greatly influenced by daily events. Except under tightly controlled conditions, the RQ/FQ ratio cannot be established with sufficient precision to predict whether weight gain or loss would take place. Reports finding no correlation between RQ/FQ data and body weights or body weight changes should therefore not be taken to challenge the validity of the RQ/FQ concept. 11. The “defense of body weight” concept The common tendency of individual body weights to return to their original value after a weight-changing intervention is often explained as the manifestation of a mechanism tending to “defend” a particular body composition. The problem with this concept is that it appears to imply that mechanisms exist to actively drive the fat mass to a particular level, much as one would expect if a set-point mechanism existed ((21)). It fails to take into consideration that before the intervention, body composition for a given individual had already evolved until a steady state of weight maintenance had become established. The body composition, that prevailed before such an intervention will naturally tend to re-establish itself when the disrupting intervention has ceased, not because a given adiposity is “defended” or “targeted,” but because weight maintenance tends to become re-established at the settling point, i.e., at the particular body composition which that individual had previously reached under this set of circumstances ((19)). Discussion of differing interpretation of such concepts as settling point, set point, ponderostat, and defense of body weight, which all appear to provide tenable explanations for common observations, may seem to be futile, until one tries to understand how environmental and dietary factors can influence adiposity and the preponderance of obesity. 12. The different roles played by carbohydrates and fat in energy metabolism Dietary carbohydrates and fats both provide substrates for the regeneration of the ATP expended to sustain the body's functions. Carbohydrates generally contribute 40–60% of dietary energy and daily CHO intakes in adults consuming mixed diets range from 200 g in relatively small and sedentary individuals to >500 g in physically active persons. The body's glycogen reserves may be estimated to vary between 1.0 and 1.5 times the amount of carbohydrate consumed and oxidized during a typical day ((22)). The body's fat content commonly amounts to 10–15 kg, being much larger in obesity. The triglyceride reserve typically ranges from 100,000 to 200,000 kcal in adults and it is thus some 100 times greater than the CHO reserve of 1,000–2,000 kcal present in the form of glycogen. Given its small size in relation to its turnover and the importance of maintaining adequate blood glucose levels, maintenance of appropriate glycogen stores present a considerable metabolic challenge. Evolution was therefore compelled to develop appropriate regulatory features to adjust glucose oxidation to carbohydrate availability, through adjustments of the activity of key enzymes and by hormonal signals, notably those conveyed by insulin and glucagon. Thanks to these, large variations in carbohydrate intake can be accommodated without noticeable stress. Other phenomena cause the oxidation of amino acids to adjust themselves to protein intake, as recognized long ago by monitoring nitrogen balances. On the other hand, the body's large fat stores are hardly affected by daily gains or losses and adjustment of fat oxidation to fat intake has received much lower priority in metabolic regulation. Indeed, consumption of fat has little or no effect on fat oxidation, which declines even following fatty meals ((23))! The rate of fat oxidation varies greatly during the day, depending on nutrient intake and physical activity, but the amount of fat oxidized in a 24-h period is in effect primarily determined by the difference between total energy expenditure and the energy provided by CHO plus protein intakes ((19)). While numerous mechanisms operate to prevent large deviations from CHO and protein balances, no such functions are at work to limit daily fat imbalances. Not surprisingly, deviations from fat balance can be much greater than deviations from CHO and protein (or nitrogen) balances ((24)). It follows that energy balance cannot be expected to be more accurately maintained than fat balance. The roles which CHO and fat play in the body's fuel economy and in body weight regulation are therefore markedly different, another fact that is neglected when only the energy balance is considered ((1)). Over the long term, changes in free fatty acid levels and in insulin sensitivity brought about by gains or losses in the adipose tissue mass influence the average rate of fat oxidation ((19),(25)). Thanks to this long-term or “chronic” influence, body composition will drift toward the degree of adiposity for which the average rate of fat oxidation has become commensurate with fat intake ((19)). Another important consideration needs to be made here, namely that fat oxidation is restrained by high glycogen levels ((26)), so a greater expansion of the fat mass is needed in individuals who maintain relatively high glycogen reserves. 13. Food intake regulation and carbohydrate balance Spontaneous food consumption is increased after periods of food deprivation, and inhibited after deliberate weight gain, but only until the status prevailing under the habitual ad libitum conditions is re-established. This makes it glaringly apparent that food intake regulation does not have maintenance of energy balance as its primary purpose! In addition, it becomes evident that body composition is an important parameter in the regulation of food intake ((19)). Maintenance of appropriate glycogen levels under conditions of ad libitum food intake would be facilitated if, in addition to adjustment of glucose oxidation to carbohydrate intake, food intake were to be regulated in a manner helping to sustain the balance between the use of glucose and the influx of dietary carbohydrate. Making such considerations at a time when the existence of specific glucose receptors in the brain had just been revealed, Mayer ((27)) developed the concept of “glucostatic” regulation of food intake, in which it is presumed that monitoring of blood glucose levels by the brain generates signals for the regulation of food intake by the central nervous system. Indeed, it is now known that transient small declines in blood glucose levels tend to elicit feeding ((28)). However, blood glucose levels vary greatly during the day, and there is much overlap between the values that prevail under different nutritional and metabolic conditions. Subsequently, it was therefore considered that changes in liver glycogen levels ((29)) or in liver substrate oxidation rates ((30)) would be more suitable or more likely to provide appropriate feedback signals to the brain, as such inputs can be based on some integrated parameter of substrate and carbohydrate utilization and availability. Little is known about the mechanisms and signals, that may be involved, though there is a possibility that they could be transmitted to the central nervous system via the autonomous nervous system ((31)). One could also entertain the notion that the rate of change instead of, or in addition to, the size of the body's glycogen stores could provide signals affecting hunger. This would account for the fact that hunger is greatly attenuated after a few days of total starvation and relatively well tolerated on protein-sparing diets ((32)), once the organism has become adapted to low but stable glycogen and blood glucose levels. 14. The difficulty in obtaining experimental evidence about the role of carbohydrate balance in food intake regulation In one of the few studies suitable to examine this issue, Stubbs et al. ((33)) used continuous indirect calorimetry in a respiratory chamber to established 24-h substrate balances in young men eating ad libitum over 7 consecutive days. They observed a negative correlation between 24-h carbohydrate imbalances and subsequent food intakes, which accounted for 5–10% of the variance in the next day's energy balances and hence energy intakes. Considering that most factors influencing food consumption and variations in the daily energy balance occur pretty much at random once a particular lifestyle has become established, even modest, but systematic, regulatory effects have the potential to exert significant long-term “steering effects.” These may be difficult to establish with statistical certainty during the short experimental periods feasible in humans. The situation is similar to casino games, where the small percentage gains programmed for the house would be difficult to characterize in the short run, but lead in time to significant profits. 15. The need to distinguish between the role of carbohydrate balance in food intake regulation and the role of habitual glycogen levels in body weight regulation Regulation of food intake in a manner helping to maintain carbohydrate balance provides means to achieve body weight stability, but only when the situation has been reached for which the composition of the fuel mix oxidized matches, on average, the nutrient distribution in the diet. However, in relation to body weights and health, the mechanisms involved in stabilizing body weights are less important than the factors determining the body fat content for which weight maintenance tends to occur. Glycogen levels are spontaneously maintained at levels sufficient to prevent hypoglycemia and to carry out habitual physical tasks. They also spontaneously remain far below the level at which rapid conversion of carbohydrate into fat is induced in adults consuming mixed diets ((12),(13),(34)). Glycogen levels in adults can be estimated to vary between a lower limit of some 150–200 g and an upper limit of 500–600 g. Glycogen levels are known to be higher on high-carbohydrate than on low-carbohydrate diets ((22)). They are therefore not likely to vary over the entire range when conditions are stable, but to oscillate within a narrower range. Since neither the lower nor the upper limits are specifically determined, the range within which glycogen levels are habitually maintained can differ among individuals and be affected by circumstances as well. Although actual measurements of glycogen levels in human populations are not yet available from which one could gauge the influence of glycogen levels in reducing fat oxidation, this effect can be recognized in experiments performed in respiratory chambers, where changes in glycogen content could be calculated ((26),(33)). When the range within which glycogen levels are habitually maintained rises, daily fat oxidation can be expected to decrease, promoting fat accumulation. Thus, the role which increased habitual glycogen levels will play in promoting obesity in humans needs to be recognized! An attempt was made to assess the scope of this effect in a computer model of human metabolism that reproduces some of the behaviors known to regulate substrate utilization in humans ((35)). Minor upward shifts in habitual glycogen levels led to substantial body weight gains, whereas decline in glycogen levels entrained significant weight losses. The model's behavior thus supports the view that changes in glycogen levels too small to be documented by current means conceivably can explain recent gains in adiposity. 16. Understanding the recent increases in the preponderance of obesity During the past few decades a continuing increase in the prevalence of obesity in the United States has occurred ((36)), even though neither the population gene pool nor the parameters considered to have caused the progressive increase in obesity in affluent societies, such as higher dietary fat content, greater buying power, and decreased physical activity, appear to have changed substantially during this period. However, food diversity and its appetizing qualities ((37)), changes in its energy density and increased portion size, wider choices, and advertising efforts have continued to increas" @default.
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W1994137712 title "Issues and Misconceptions About Obesity" @default.
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