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Physiological Regulation of Body Weight and the Issue of Obesity
Obesity
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Physiological Regulation of Body Weight and the Issue of Obesity Richard E. Keesey, PhD*
The perspective on obesity offered in this article rests on the presumption that an individual's body weight, like body core temperature or body fluid osmolarity, is regulated physiologically at a specified level or "set-point." Evidence supporting this view is reviewed, with emphasis given to the role of energy expenditure in this process. The unique relationship between resting metabolism and the body weight set-point is described and proposed as a basis for assessing one's regulatory status. From this perspective, two forms of animal obesity are characterized and evaluated from the standpoint of whether they represent an instance of regulation at an elevated set-point or onc of regulatory failure. It is concluded that both regulated and unregulated forms of obesity occur in animals. The issue of whether such distinct forms are found among human obese subjects is raised and procedures suitable for assessing this question are discussed. Finally, the implications of such a diagnostic distinction for treatment of the obese are considered.
CONTROL OF ENERGY INTAKE AND EXPENDITURE IN BODY WEIGHT REGULATION In order to establish that a particular physiological condition is, indeed, regulated, it is necessary to demonstrate its active defense in response to challenge. In the case of body weight, this defense should be evidenced by the occurrence of adjustments in food intake and energy expenditure appropriate to maintaining the regulated level or set-point. In the case of intake, where historically most interest has eentered, supporting evidence is abundant. When weight is elevated from the usual level by force feeding, for example, eating is reduced sharply3; if lowered by caloric restriction, intake is elevated. 17 Evidence of a similar control over energy expenditure in defense of a particular body weight is less well documented. Several factors appear to have contributed to the relative neglect of this factor. First, the basic physiological processes fueled by our ingested energy traditionally have been regarded as stable or fixed in their requirements. Resting or "basal" metabolism often is regarded as reflecting the irreducible energy cost of sustaining the body's vital functions. Consistent with this *Professor of Psychology and Nutrition, University of Wisconsin, Madison, Wisconsin
Medical Clinics of North America-Vo!' 73, No. 1, January 1989
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view was the observation by Kleiber14 that the daily resting energy expenditure of animals, ranging in size from small birds and rodents to large mammals, was a fixed function of their "metabolic mass" or body weight raised to the 0.75 power. This is to say that all animals expend energy at comparable rates when expenditure is expressed relative to their metabolic mass (BW75). This constancy is illustrated in Figure 1, where Kleiber's original observations have been replotted to show the resting energy expenditures of various animal species, expressed relative to their body weight raised to the 0.75 power. Preliminary observations indicate that metabolic mass (BW75) also may account for much of the variance in resting energy expenditure between different size members of the same species. Such a conclusion is suggested by observations (Fig. 2) of the resting oxygen energy expenditure of different sized rats of the same strain, sex, and age. Rates of energy expenditure, expressed relative to body weight raised to 0.75 power, again, appear to be essentially the same for rats of varying
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Figure 2. The regularity of daily energy expenditure (kcal), expressed per metabolic body size (BW75), of individual male rats of the same strain and age at the body weight each spontaneously maintains. (Herzog, Hirvonen, and Keesey; unpublished data.)
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sizes. Both between and within animal species, therefore, resting energy needs would appear to be determined by the tissue mass being maintained and, in this sense, fixed. Given the conventional view concerning "basal metabolism" and the (apparently) fixed relationship between energy needs and the mass of metabolically active tissue, it is none too suprising that intake, rather than expenditure, generally has been regarded the key controlling factor in weight regulation. But there are reasons for believing that these assumptions concerning the expenditure of body energy are incorrect and that the primary reliance on intake may be misplaced. First, it now is clear that the relative stability of body weight cannot be accounted for by intake. Changes in intake frequently fail to produce the expected changes in body weight. The weight loss resulting from food restriction, for example, almost invariably is smaller than expected from a consideration of the apparent caloric deficit. Similarly, overconsumption fails to produce weight gains commensurate with the apparent caloric excess. 1 In other circumstances, weight gains are seen in the absence of hyperphagia1B and weight loss is seen with no reduction in intake. 19 Clearly, these outcomes would not occur were the expenditure of energy fixed. Secondly, there now is evidence that the Kleiber equation, while accurately predicting an animal's resting energy expenditure at the body weight it normally maintains, fails to do so when that animal's weight is displaced from this level. When food intake is restricted and weight loss occurs, for example, resting or "basal" metabolism is reduced by an amount significantly exceeding that expected from the loss of metabolically active tissue. We have observed,4 for example, that when the weight of rats was reduced by 15 per cent through caloric restriction, their rate of resting metabolism declined by 25 per cent. This decline in resting energy expenditure, which is disproportionately larger than the loss of body mass, indicates that less energy is required to maintain a gram of tissue in rats in negative energy balance than those in balance. Indeed, expressing resting energy expenditure in deprived rats relative to their metabolic mass (BW75) reveals that their expenditure is only 85 per cent that expected. Comparably larger than expected reductions in resting metabolism have been reported in food-deprived men. 13 Strictly speaking, then, the resting, postabsorptive metabolism of normalweight individuals is not "basal." Rather, when weight is reduced from the level normally maintained, energy needs decline to levels substantially below those usually observed, and substantially below that predicted by the Kleiber equation. In the event of overconsumption and weight gain, there is, in a converse fashion, an exaggerated increase in resting energy expenditure. 22 Just as expenditure declines following weight loss, following weight gain, it rises significantly above that expected from the increase in metabolic mass that has taken place. At least in certain species, this exaggerated heat production can be linked to the activation of a specific thermogenic effector organ, that is, the brown adipose tissue. 21 These adjustments in energy expenditure may be viewed as adaptive, in that they act to resist displacement of body weight from the normal level and to facilitate its restoration to that level if displaced. Furthermore, these metabolic adjustments provide compelling evidence for the physiological regulation of body weight and for the existence of a physiologically preferred weight level or set-point.
ENERGY EXPENDITURE AND THE BODY WEIGHT SET-POINT It would appear from the preceding discussion that Kleiber's empirically derived equation relating resting energy expenditure to body weight is based on animals in energy balance. As such, it should predict accurately the energy expenditure of an animal at its physiologically regulated body weight. But, as noted, the adjustments
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Figure 3. Schematic representation of the effects upon a rat's daily resting energy (kcal), expressed per metabolic body size (BW75), of increasing body weight by overconsumption or reducing it by caloric restriction. Note in both cases that the changes in expenditure are greater than expected from the Kleiber" interspecies relationship between expenditure and metabolic body size (dotted line).
that occur when weight is raised or lowered cause greater increases or decreases in expenditure than this equation would predict. Thus, resting energy expenditure is consonant with the value predicted by Kleiber's equation only when the animal is at its physiologically regulated body weight or set-point. To illustrate this point, the Kleiber function previously depicted in Figure 1 has been redrafted as Figure 3, with arrows representing what could be expected to occur to the resting metabolism of a rat were its weight to be elevated from the normally maintained level by overeating or depressed by dieting. With the compensatory adjustments that come into play when weight is perturbed, the rat's
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Figure 4. Schematic representation of the effects on daily resting energy expenditure (kcal), expressed per metabolic body size (BW 75), of one rat weighing 375 g and another weighing 330 g. While these rats display energy expenditures comparable to other rats while 375 g or 330 g (dotted line), they are hypermetabolic if caused to increase body weight by overconsumption or hypometabolic if caused to lose weight by caloric restriction. Each rat metabolizes normally only when at a specific, although different, body weight, which can be regarded as its set-point.
PHYSIOLOGICAL REGULATIOl\ OF BODY \VEICIIT Al\O TIlE ISSCE OF OBESITY
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expenditure will increase or decrease faster than the normal relationship indicates. As weight declines (to levels closer to those of a mouse), the rat will become hypometabolic; when its weight increases (to levels closer to those of a cat), it will become hypermetabolic. Only when at the body weight normal for a rat will the expenditure of this animal be at a level consistent with the interspecies value predicted at the Kleiber equation. Concluding that a rat metabolizes normally only when at the weight typical for a rat may seem to be simply stating the obvious, but this is not the case when one considers the implications of extending Kleiber's relationship and this line of analysis to different weight individuals of the same species. Consider the resting metabolism of the 10 rats depicted in Figure 4. Note that, depite their weight differences, the resting energy expenditures of these rats are comparable when expressed relative to the metabolic mass (BW7') each maintains. However, if one lowered the weight of the 375-g rat by restricting its intake, the arrows indicate that it no longer would expend energy at the rate of other rats (or other species). Nor could its weight be increased by overfeeding without its energy expenditure rising above the normal level. That is, this male rat expends energy at rates appropriate to its body size when and only when it weighs 375 g. At weights above or below this level, its energy expenditure is greater or less than expected from the maintained body mass. In a similar manner, the rat weighing 330 g expends energy normally at this particular weight, but would become hyper- or hypometabolic were its weight to be elevated by overconsumption or depressed by dieting. It should follow from this discussion that the resting energy expenditure of an individual is consonant with the value predicted by Kleiber's rule only when at his or her physiologically regulated body weight or set-point. We therefore can say that an individual's body weight set-point is that particular weight at which his or her energy expenditure is congruent with the interspecies Kleiber value. At any time, there should be only one weight at which this will occur. But this specified weight or set-point can change. It changes over the individual's life span and can be altered by dietary and surgical interventions. [2 Still, at any particular point in time, there is but one body weight for each individual at which he or she expends energy at the "normal" rate. It is proposed that this weight be regarded as the setpoint for that individual.
OBESITY AND BODY WEIGHT REGULATION Many regard obesity as a consequence of regulatory failure. It often is assumed to result from the absence of the internal controls on food intake that serve to maintain weight and body energy stores at a normal level. It also has been proposed that a reduced rate of energy expenditure further contributes to the excess accumulation of adipose tissue. 9 The possibility recently has been raised that obesity may be neither a problem of an uncontrolled intake nor of a lowered expenditure. Instead, it is suggested that obesity can be a condition of regulation at an elevated set-point. 10 According to this proposal, some obese individuals control both intake and expenditure normally but do so in such a manner as to maintain body weight and adiposity at abnormally high levels. That is, what characterizes this form of obesity is an energy regulating system that is set to be in stasis only at a high level of adiposity. The rationale and procedures previously discussed for evaluating an individual's set-point should be applicable in assessing whether or not obesity is, indeed, a physiologically regulated phenomenon. Assessing the rate of energy expenditure in obese individuals at the body weights they maintain should provide one critical piece of information on this point. Information concerning whether or not adjust-
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Time (weeks) Figure 5. Body weight of rats fed either a high-fat or regular laboratory diet for 17 weeks. Prior to the end of this period, the weight of half the high-fat fed rats and half the rats fed a regular diet was reduced by restricting their intake. (Corbett and Keesey; unpublished data.)
ments in energy expenditure are made when an obese individual is displaced from his elevated body weight should provide a second. In the section that follows, an attempt is made to apply these procedures to an analysis of the fundamental disorder underlying obesity in animals. Animal models of obesity contribute much to the ways in which we conceptualize and deal with this condition in humans. Two rodent models that have played a significant role in this regard are used here to illustrate the application of these concepts. The two, dietary obesity and hypothalamic obesity, are both produced experimentally and both are characterized by excessive adiposity and adipose hypercellularity. But, as the following section will show, they differ radically in the degree to which their obese condition can be said to be physiologically regulated. Consideration of this issue begins by examining the features of rats made obese by dietary means. Diet-induced Obesity As previously noted, rats induced to overconsume by palatable diets typically display increased rates of energy expenditure that tend to resist or attenuate the weight gain that the excess calories otherwise would produce. Even so, maintenance on such diets can, and many times does, lead to marked obesity. 24 Furthermore, under certain circumstances, the obesity is irreversible in that it persists even after the animal has been returned to a regular diet. 20 In a recent experiment,4 rats were maintained on a palatable high-fat diet for a period of 6 months. As seen in Figure 5, their weight increased steadily above that of rats fed a standard diet. By the end of the experiment, they weighed 26 per cent more than controls. Subsequent carcass analyses revealed that they had accumulated more than twice the normal amount of body fat over this period. Significantly, they also had increased (by 47 per cent) their number of filled adipocytes. Toward the end of the experiment, the intake of half the dietary obese and
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Body Weight (g) Figure 6. The resting energy expenditure (kcal), expressed per metabolic body size (BW 75) of rats fed either a standard laboratory diet or a high-fat diet for 17 weeks. At the body weights the two diet groups spontaneously maintained, their expenditures were the same (dotted line). Restricting intake so as to produce a loss caused the sharp decline in expenditure indicated by the arrows. The expenditure of the restricted high-fat rats declines to a level below that of nonrestricted rats fed a regular diet despite their weighing over 50 g more. (Data from Corbett SW, Stern JS, Keesey RE: Energy expenditure in rats with dietinduced obesity. Am J Clin Nutr 44:173-180, 1986.)
half the control rats was restricted so as to lower their weight from the maintained level (see Fig. 5). The resting energy expenditure of all rats then was assessed, either at their spontaneously maintained body weight or at the somewhat reduced levels produced by the caloric restriction. These results are seen in Figure 6. Note that the resting rate of energy expenditure of the unrestricted obese rats was not elevated, but normal, for the metabolic mass they now were maintaining (see Fig. 6). That is, energy expenditure in these rats (per metabolic mass) was the same as that of normal weight rats. The physiological conditions responsible for producing the hypermetabolic response initially seen following diet-induced weight gain evidently do not persist after some time. Equally interesting are the results obtained from the calorically restricted obese and control rats. The ensuing weight loss produced the expected decline in resting metabolism in the normal weight rats. But the same adjustment to weight loss is shown by the obese rats as well. Furthermore, the actual daily energy expenditure of the weight-reduced obese rats dropped below that of the normal weight rats despite the fact they still weighed 53 g more. The normal rates of resting metabolism at the elevated body weights the dietary obese rats maintain and the adaptive decline in resting metabolism that they display with caloric privation and weight loss, suggest that prolonged maintenance on the high-fat diet has caused the body weight set-point to be elevated. It thus appears that dietary factors contribute to the life span changes in set-point noted earlier. Such a view is consistent with the observation that dietary obesity often is irreversible. It also is consistent with certain internal changes that have been noted in animals maintained on weight-promoting diets. Among these are increases in adipocyte number, which can be detected some weeks after exposure to such diets. 5 Another is the pattern of change in tissue norepinephrine (NE) turnover rates following exposure to weight-promoting diets. 16 Although initially elevated, NE turnover rates decline following continued exposure to such diets,
Days Postlesion Figure 7. The body weight of rats following lesions of the ventromedial hypothalamus. (U npublished data.)
and return to near normal levels in several months. Whether the changes in these systems simply co-vary with other internal adjustments crucial to altering the setpoint or, themselves, are responsible for this regulatory adjustment is not presently known. Hypothalamic Obesity Perhaps the most widely studied form of animal obesity is that produced by experimental destruction of the ventromedial portion of the hypothalamus (V~lH). Animals with such lesions initially are hyperphagic and increase their weight at a high rate. In time, however, the hyperphagia abates and body weight subsequently is maintained at an elevated level (Fig. 7). Like dietary obese rats, their large accumulation of total body fat (which may increase several fold) is associated with an increase in the number of filled adipocytes. 26 Despite their maintenance of a relatively stable body weight, however, hypothalamic obese rats do not display the responses appropriate to the defense of an elevated set-point. First, intake is not controlled properly in a defense of their high body weight. If challenged by unpalatable or low-calorie diets, for example, the weight of VMH -lesioned rats declines to the level of nonlesioned rats. 29 Or, if such diet~ are presented from the time of the lesion on, neither hyperphagia nor the usual obesity is expressed. 6 . 25 Recent observations of the energy expenditure of obese V~IH-lesioned rats reveal further regulatory deficiencies. First, their resting energy expenditure, while higher in absolute amount than that of normal weight rats, is substantially lower than expected from their metabolic mass (BW75). Second, they fail to display the expected adjustment in resting metabolism when their weight is reduced from the maintained level. Displayed in Figure 8 are the rates of resting energy expenditure of both nonlesioned control and VMH-lesioned obese rats at the body weights each normally maintains and after having had their body weights reduced by caloric restriction to 90 or 80 per cent of that level. In spite of very substantial weight
PHYSIOLOGICAL RECCLATIO:-.J OF BODY \VEIl;HT AI\]) THE ISSCE OF OBESITY
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Figure 8. The resting oxygen consumption (ml per minute) of hypo thalamic (VMH) obese rats and normal weight (sham) rats. Testing of the VMH and sham rats was conducted both at the body weights each spontaneously maintained and following diet-induced weight loss. The sham rats display the expected drop in resting energy expenditure upon being displaced from their maintained body weight. Obese VMH rats fail to display this adaptive reduction in expenditure despite weight losses sometimes more than twice as large (Vilberg and Keesey; in preparation.)
losses, the resting energy expenditure of the V.\1H-Iesioned rat displays little or no change. No evidence is seen of the adaptive reduction in resting metabolism seen in control rats whose weight was reduced similarly, suggesting the absence of a metabolic defense of body weight in V.\1H-Iesioned rats. Animal Obesities: Regulated and Unregulated Forms The preceding observations suggest that, in the dietary obese rat, the set-point for body weight over time, has been elevated. Both the normal rate of resting metabolism at an elevated body weight and the adjustments in resting metabolism that operate to sustain this obesity support such a conclusion. VMH-Iesioned rats, on the other hand, display neither a resting energy expenditure normal for the metabolic mass they maintain nor the metabolic adjustments appropriate to the defense of a particular body weight. Among these two animal models of obesity, therefore, one provides an example of regulation of an elevated set-point that
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apparently is normal in all essential respects. The other is one in which ncither the pattern of energy expenditure while obese nor the metabolic response to weight perturbation are consistent with regulation at an elevated set-point. The obesity in the former is regulated; in the latter regulation is lacking. PROPOSED CLINICAL APPLICATIONS OF THE BODY MASS-ENERGY EXPENDITURE RELATIONSHIP The preceding conclusions rest, as previously noted, on two assumptions concerning the relationship of body weight to resting metabolism. One is that the interspecific relationship previously established between energy expenditure and body mass (for example, Kleiber l4 ) also applies to different sized members of the same species. The second specifies that this relationship applies to individuals in energy stasis, that is, at their regulated body weight or set-point. A corollary assumption is that, when not at set-point, this relationship fails to hold because of adaptive regulatory adjustments in energy expenditure that occur independent of changes in body mass. Although these assumptions by and large are supported by the animal studies, at issue is whether this approach would be useful in the clinical evaluation of energy status in humans and, if so, how it could be applied. Two possible applications are proposed here. The first is to use the body mass-energy expenditure relationship to specify the set-point of individual patients. Ordinarily, a person's "expected" or "ideal" body weight is derived from tables such as those provided by the Metropolitan Life Insurance Company (1983), representing a population estimate of the mean weight of all individuals having the same height and body type. Yet, all that has been examined thus far indicates that considerable natural variation exists between individuals in maintained and, presumably, regulated weight. Thus, the "ideal" weight from such tables, to varying degrees, will be substantially below the regulated value for many people and, to a similar extent, above for many others. It should, in theory, be possible with humans, just as it is with rats, to use resting energy expenditure as an index of whether one is either at set-point or displaced from this regulated level. Fundamental to such an evaluation is a precise specialization of the relationship between body mass and energy expenditure in different sized persons in energy homeostasis. In animals, the Kleiber equation appears to serve adequately but in humans, equations relating body mass to expenditure more commonly derive from the classic observations of Harris and Benedict. 8 Resting energy expenditures predicted from the Harris and Benedict data, however, are not always sufficiently precise. "Errors" are sometimes on the order of ± 14 per cent,21 approaching the magnitude of the regulatory adjustment in resting energy expenditure seen when overconsumption and weight gain, or caloric restriction and weight loss, occur. Still, it is possible that, with currently available equipment, improved technique, and longer sample periods, the variance in estimates of resting metabolism in individuals can be reduced substantially. It is useful to note, for example, that the contributions of the regulatory adjustments to resting metabolism generally have not been appreciated or considered in prior attempts to quantify the relationship of resting metabolism to body mass. Thus, while it may be unrealistic to expect the precision of measurement one can achieve in laboratory animals having the same age, sex, energy status, and so on, an appreciation of the influence of such factors in humans, and an effort to minimize their involvement, very well could provide the accuracy of prediction necessary for this application. A second proposal is to use whole body metabolic response to weight change as a basis for characterizing the obesity of individuals as being essentially regulated
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or unregulated in character. In the same way that dietary obese and hypothalamic obese rats can be characterized and differentiated on the basis of their adjustments in resting metabolism in response to the change in body weight, it is suggested that obese humans may be so distinguished. There are indications in the literature that a distinction of this sort may be valid clinically. First, many obese individuals do display metabolic adjustments appropriate to the defense of an elevated body weight. The participation of an active regulatory response is indicated, for example, by findings of a 17 per cent decline in the resting metabolism of dietary obese patients following a weight decline of only 3 per cent. 2 That these adaptive responses are sustained chronically is indicated by a recent report l5 that obese patients successful in maintaining a weight loss for up to 6 years continue to display reduced levels of resting metabolism. Yet, apparently not all obese display this metabolic defense of body weight (Welle et aP'). Of particular interest in this regard are the observations by Garrow7 of the resting metabolic rate of 26 individual patients before and after diet-reduced weight loss. Although a majority of these persons displayed a disproportionately larger drop in resting energy expenditure than in weight, the remainder displayed a decline in resting metabolism roughly equivalent to that expected from the decline in body mass. That is, their obesity did not appear to be defended physiologically. Thus, the distinctions drawn between regulated and unregulated obe si ties in animals, based on their patterns of energy expenditure, well may have its counterpart among the human obese. Presuming the validity of such a distinction, how could these different forms be identified and treated? Observing the effects of weight gain or loss on resting metabolic rate should reveal whether physiologic adjustments that resist weight changes are present or absent. Changes in metabolism that passively follow weight change suggest a regulatory dysfunction and also indicate a treatment strategy. Because conventional therapies such as dieting and/or behavior modification of eating habits probably are not resisted physiologically, they well may be effective in weight-loss programs. A different approach is needed for an individual whose obesity appears to be regulated. Such a person displays energy-conserving metabolic adaptations that resist weight change and, in all likelihood, greatly diminish the chanees of achieving significant weight loss or of sustaining losses that do occur. To sustain their weight loss, these patients must make a life-long commitment to diets that provide a daily ealoric intake that probably is inadequate to satisfy their hunger and possibly is less than that consumed by persons of normal weight. For such individuals, the hope is that research eventually may reveal a means for reducing the body weight setpoint. Evidence is growing that various neuroanatomic, physiologic, and pharmacologie manipulations are capable of lowering the level of regulated body weight. 11 Although these methods are not suitable for clinical use, their discovery should intensifY the search for safe and effective ways of causing obese individuals to achieve normal energy balance at lower body weights.
SUMMARY The relationship described here between resting energy expenditure and the body weight set-point provides a framework for assessing an animal's regulatory status. Procedures based on this relationship have been used to evaluate the status of rats whose obesity was either of dietary or hypothalamic origin. In dietary obese rats, the body weight set-point appears to have elevated. Their normal rate of energy expenditure at an elevated weight, as well as their active adjustments of expenditure in defense of their obesity, supports this conclusion. Hypothalamic
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obese rats, in contrast, neither expend energy at a rate normal for their body mass nor display the adjustments in expenditure appropriate to defending their obesity. From these observations, a distinction is drawn between regulated and unregulated forms of obesitv. It is sugg~sted that weight disorders in humans, particularly obesity, may be amenable to similar sorts of analysis and categorization, eventually leading to the development of therapies appropriate to the specific type or form indicated.
REFERENCES 1. Apfelbaum M, Bostsarron I. Lacatis D: Effect of caloric restriction and excessive intake on energy expenditure. Am J Clin Nutr 24:140.5-1409, 1971 2. Bray CA: Effect of caloric restriction on energy expenditure in obese patients. Lancet 2:397-398, 1969 3. Colm C, Joseph D: Influence of body weight and body fat on appetite of "normal" lean and obese rats. Yale J Bioi 34:598-607, 1962 4. Corbett SW, Stern JS, Keesey HE: Energy expenditure in rats with diet-induced obesity. Am J Clin "Iutr 44:173-180, 1986 5. Faust IM, Johnson PH, Stern JS, et al: Diet-induced adipocyte number increase in adult rats: A new model of obesity. Am J Physiol 235:E279-E286, 1978 6. Ferguson NBL, Keesey HE: Effect of a quinine-adulterated diet upon body weight maintenance in male rats with ventromedial hypothalamic lesions. J Comp Physiol Psvchol 89:478-488, 1975 7. Carr~w JS: Energy Balance and Obesity in Man. Elsevier, North-Holland Biomedical Press, 1970 8. Harris JA, Benedict FC: A Biometric Study of Basal Metabolism in Man. Washington, DC, Carnegie Institute of Washington, 1919, No 279 9. James WPT, Trayhurn P: Thermogenesis and obesity. Br Med Bull 37:43-48, 1981 10. Keesey HE: A set-point theory of obesity. In Brownell KD, Foreyt JP (eds): Handbook of Eating Disorders: Physiology, psychology, and treatment of obesity, anorexia, and bulimia. New York, Basic Books, 1981, pp 63-87 11. Keesey HE, Powley TL: The regulation of body weight. Annu Hev Psychol 37:109-133, 1986 12. Keesey HE, Boyle PD, Kemnitz JW, et al: The role of the lateral hypo thalamus in determining the body weight set-point. In Novin D, Wyrwicka W, Bray CA (eds): Hunger: Basic mechanisms and clinical implications. New York, Haven Press, 1976, pp 243-255 13. Keys A, Brozek I. Henschel A: The Biology of Human Starvation. Minneapolis, University of Minneapolis Press, 1950 14. Kleiber M: Body size and metabolic rate. Physiol Hev 15:511-541, 1947 15. Leibel HL, Hirsch J: Diminished energy requirements in reduced-obese patients. Metabolism 33:164-170, 1984 16. Levin BE, Triscari I. Sullivan AC: Altered sympathetic activity during development of diet-induced obesity in the rat. Am J Physiol 244:H347-H355, 1983 17. Levitsky DA: Feeding patterns of rats in response to fasts and changes in environmental conditions. Physiol Behav 5:291-300, 1970 18. Levitsky DA, Faust I, Classman M: The ingestion of food and the recovery of body weight following Elsting in the naive rat. Physiol Behav 17:575-580, 1976 19. Obarzanek E, Levitsky DA: Weight gain through overeating and return to normal without undereating. Fed Proc 43:1057, 1984 20. Holls BJ, Howe EA, Turner HC: Persistent obesity in rats following a period of consumption of a mixed high-energy diet. J Physiol (London) 298:415-427, 1980 21. Hothwell NJ, Stock MJ: A role for brown adipose tissue in diet-reduced thermogenesis. Nature 281:31-35, 1979 22. Hothwell NI. Stock MJ: Energy expenditure of 'cafeteria'-fed rats determined from measurements of energy balance and indirect calorimetry. J Physiol 328:371-377, 1982 23. Hoza AM, Shizgal HM: The Harris Benedict equation re-evaluated: Hesting energy requirements and the body cell mass. Am J Clin Nutr 40:168-182, 1984
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24. Sclafani A: Dietary obesity. In Stunkard A] (ed): Obesity. Philadelphia, WB Saunders, 1980, pp 166~ 181 25. Sclafani A, Springer D, Kluge L: Effects of quinine-adulterated diets on the food intake and body weight of obese and nonobese hypothalamic hyperphagic rats. Physiol Behav 15:631~640, 1976 26. Stern IS, Keesey RE: The effect of ventromedial hypothalamic lesions on adipose cell number in the rat. Nutr Rep Int 23:295~301, 1981 27. Trayhurn PL, Thurlby PL, lames WPT: A defective response to cold in the obese (obob) mouse and the obese Zucker (bfa) rat. Proc :\Jutr Soc 35:133A, 1976 28. Welle SL, Amatruda JM, Forbes GB, et al: Resting metabolic rates of obese women after rapid weight loss. ] Clin Endocrinol Metab 59:41~44, 1984 29. Weingarten HP, Chang P, Jarvie KR: Reactivity of normal and VMH-Iesioned rats to quinine-adulterated foods: l\egative evidence for negative finickiness. Behav l\eurol 97:221~233, 1983 Universitv of Wisconsin 1202 We;t J ohnson Street Madison, WI 53706
0025--7125/89 $0.00
+ .20
Physiological Regulation of Body Weight and the Issue of Obesity Richard E. Keesey, PhD*
The perspective on obesity offered in this article rests on the presumption that an individual's body weight, like body core temperature or body fluid osmolarity, is regulated physiologically at a specified level or "set-point." Evidence supporting this view is reviewed, with emphasis given to the role of energy expenditure in this process. The unique relationship between resting metabolism and the body weight set-point is described and proposed as a basis for assessing one's regulatory status. From this perspective, two forms of animal obesity are characterized and evaluated from the standpoint of whether they represent an instance of regulation at an elevated set-point or onc of regulatory failure. It is concluded that both regulated and unregulated forms of obesity occur in animals. The issue of whether such distinct forms are found among human obese subjects is raised and procedures suitable for assessing this question are discussed. Finally, the implications of such a diagnostic distinction for treatment of the obese are considered.
CONTROL OF ENERGY INTAKE AND EXPENDITURE IN BODY WEIGHT REGULATION In order to establish that a particular physiological condition is, indeed, regulated, it is necessary to demonstrate its active defense in response to challenge. In the case of body weight, this defense should be evidenced by the occurrence of adjustments in food intake and energy expenditure appropriate to maintaining the regulated level or set-point. In the case of intake, where historically most interest has eentered, supporting evidence is abundant. When weight is elevated from the usual level by force feeding, for example, eating is reduced sharply3; if lowered by caloric restriction, intake is elevated. 17 Evidence of a similar control over energy expenditure in defense of a particular body weight is less well documented. Several factors appear to have contributed to the relative neglect of this factor. First, the basic physiological processes fueled by our ingested energy traditionally have been regarded as stable or fixed in their requirements. Resting or "basal" metabolism often is regarded as reflecting the irreducible energy cost of sustaining the body's vital functions. Consistent with this *Professor of Psychology and Nutrition, University of Wisconsin, Madison, Wisconsin
Medical Clinics of North America-Vo!' 73, No. 1, January 1989
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view was the observation by Kleiber14 that the daily resting energy expenditure of animals, ranging in size from small birds and rodents to large mammals, was a fixed function of their "metabolic mass" or body weight raised to the 0.75 power. This is to say that all animals expend energy at comparable rates when expenditure is expressed relative to their metabolic mass (BW75). This constancy is illustrated in Figure 1, where Kleiber's original observations have been replotted to show the resting energy expenditures of various animal species, expressed relative to their body weight raised to the 0.75 power. Preliminary observations indicate that metabolic mass (BW75) also may account for much of the variance in resting energy expenditure between different size members of the same species. Such a conclusion is suggested by observations (Fig. 2) of the resting oxygen energy expenditure of different sized rats of the same strain, sex, and age. Rates of energy expenditure, expressed relative to body weight raised to 0.75 power, again, appear to be essentially the same for rats of varying
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Figure 2. The regularity of daily energy expenditure (kcal), expressed per metabolic body size (BW75), of individual male rats of the same strain and age at the body weight each spontaneously maintains. (Herzog, Hirvonen, and Keesey; unpublished data.)
PHYSIOLOGICAL REGULATION OF BODY WEIGHT AND THE ISSUE OF OBESITY
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sizes. Both between and within animal species, therefore, resting energy needs would appear to be determined by the tissue mass being maintained and, in this sense, fixed. Given the conventional view concerning "basal metabolism" and the (apparently) fixed relationship between energy needs and the mass of metabolically active tissue, it is none too suprising that intake, rather than expenditure, generally has been regarded the key controlling factor in weight regulation. But there are reasons for believing that these assumptions concerning the expenditure of body energy are incorrect and that the primary reliance on intake may be misplaced. First, it now is clear that the relative stability of body weight cannot be accounted for by intake. Changes in intake frequently fail to produce the expected changes in body weight. The weight loss resulting from food restriction, for example, almost invariably is smaller than expected from a consideration of the apparent caloric deficit. Similarly, overconsumption fails to produce weight gains commensurate with the apparent caloric excess. 1 In other circumstances, weight gains are seen in the absence of hyperphagia1B and weight loss is seen with no reduction in intake. 19 Clearly, these outcomes would not occur were the expenditure of energy fixed. Secondly, there now is evidence that the Kleiber equation, while accurately predicting an animal's resting energy expenditure at the body weight it normally maintains, fails to do so when that animal's weight is displaced from this level. When food intake is restricted and weight loss occurs, for example, resting or "basal" metabolism is reduced by an amount significantly exceeding that expected from the loss of metabolically active tissue. We have observed,4 for example, that when the weight of rats was reduced by 15 per cent through caloric restriction, their rate of resting metabolism declined by 25 per cent. This decline in resting energy expenditure, which is disproportionately larger than the loss of body mass, indicates that less energy is required to maintain a gram of tissue in rats in negative energy balance than those in balance. Indeed, expressing resting energy expenditure in deprived rats relative to their metabolic mass (BW75) reveals that their expenditure is only 85 per cent that expected. Comparably larger than expected reductions in resting metabolism have been reported in food-deprived men. 13 Strictly speaking, then, the resting, postabsorptive metabolism of normalweight individuals is not "basal." Rather, when weight is reduced from the level normally maintained, energy needs decline to levels substantially below those usually observed, and substantially below that predicted by the Kleiber equation. In the event of overconsumption and weight gain, there is, in a converse fashion, an exaggerated increase in resting energy expenditure. 22 Just as expenditure declines following weight loss, following weight gain, it rises significantly above that expected from the increase in metabolic mass that has taken place. At least in certain species, this exaggerated heat production can be linked to the activation of a specific thermogenic effector organ, that is, the brown adipose tissue. 21 These adjustments in energy expenditure may be viewed as adaptive, in that they act to resist displacement of body weight from the normal level and to facilitate its restoration to that level if displaced. Furthermore, these metabolic adjustments provide compelling evidence for the physiological regulation of body weight and for the existence of a physiologically preferred weight level or set-point.
ENERGY EXPENDITURE AND THE BODY WEIGHT SET-POINT It would appear from the preceding discussion that Kleiber's empirically derived equation relating resting energy expenditure to body weight is based on animals in energy balance. As such, it should predict accurately the energy expenditure of an animal at its physiologically regulated body weight. But, as noted, the adjustments
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Figure 3. Schematic representation of the effects upon a rat's daily resting energy (kcal), expressed per metabolic body size (BW75), of increasing body weight by overconsumption or reducing it by caloric restriction. Note in both cases that the changes in expenditure are greater than expected from the Kleiber" interspecies relationship between expenditure and metabolic body size (dotted line).
that occur when weight is raised or lowered cause greater increases or decreases in expenditure than this equation would predict. Thus, resting energy expenditure is consonant with the value predicted by Kleiber's equation only when the animal is at its physiologically regulated body weight or set-point. To illustrate this point, the Kleiber function previously depicted in Figure 1 has been redrafted as Figure 3, with arrows representing what could be expected to occur to the resting metabolism of a rat were its weight to be elevated from the normally maintained level by overeating or depressed by dieting. With the compensatory adjustments that come into play when weight is perturbed, the rat's
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Figure 4. Schematic representation of the effects on daily resting energy expenditure (kcal), expressed per metabolic body size (BW 75), of one rat weighing 375 g and another weighing 330 g. While these rats display energy expenditures comparable to other rats while 375 g or 330 g (dotted line), they are hypermetabolic if caused to increase body weight by overconsumption or hypometabolic if caused to lose weight by caloric restriction. Each rat metabolizes normally only when at a specific, although different, body weight, which can be regarded as its set-point.
PHYSIOLOGICAL REGULATIOl\ OF BODY \VEICIIT Al\O TIlE ISSCE OF OBESITY
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expenditure will increase or decrease faster than the normal relationship indicates. As weight declines (to levels closer to those of a mouse), the rat will become hypometabolic; when its weight increases (to levels closer to those of a cat), it will become hypermetabolic. Only when at the body weight normal for a rat will the expenditure of this animal be at a level consistent with the interspecies value predicted at the Kleiber equation. Concluding that a rat metabolizes normally only when at the weight typical for a rat may seem to be simply stating the obvious, but this is not the case when one considers the implications of extending Kleiber's relationship and this line of analysis to different weight individuals of the same species. Consider the resting metabolism of the 10 rats depicted in Figure 4. Note that, depite their weight differences, the resting energy expenditures of these rats are comparable when expressed relative to the metabolic mass (BW7') each maintains. However, if one lowered the weight of the 375-g rat by restricting its intake, the arrows indicate that it no longer would expend energy at the rate of other rats (or other species). Nor could its weight be increased by overfeeding without its energy expenditure rising above the normal level. That is, this male rat expends energy at rates appropriate to its body size when and only when it weighs 375 g. At weights above or below this level, its energy expenditure is greater or less than expected from the maintained body mass. In a similar manner, the rat weighing 330 g expends energy normally at this particular weight, but would become hyper- or hypometabolic were its weight to be elevated by overconsumption or depressed by dieting. It should follow from this discussion that the resting energy expenditure of an individual is consonant with the value predicted by Kleiber's rule only when at his or her physiologically regulated body weight or set-point. We therefore can say that an individual's body weight set-point is that particular weight at which his or her energy expenditure is congruent with the interspecies Kleiber value. At any time, there should be only one weight at which this will occur. But this specified weight or set-point can change. It changes over the individual's life span and can be altered by dietary and surgical interventions. [2 Still, at any particular point in time, there is but one body weight for each individual at which he or she expends energy at the "normal" rate. It is proposed that this weight be regarded as the setpoint for that individual.
OBESITY AND BODY WEIGHT REGULATION Many regard obesity as a consequence of regulatory failure. It often is assumed to result from the absence of the internal controls on food intake that serve to maintain weight and body energy stores at a normal level. It also has been proposed that a reduced rate of energy expenditure further contributes to the excess accumulation of adipose tissue. 9 The possibility recently has been raised that obesity may be neither a problem of an uncontrolled intake nor of a lowered expenditure. Instead, it is suggested that obesity can be a condition of regulation at an elevated set-point. 10 According to this proposal, some obese individuals control both intake and expenditure normally but do so in such a manner as to maintain body weight and adiposity at abnormally high levels. That is, what characterizes this form of obesity is an energy regulating system that is set to be in stasis only at a high level of adiposity. The rationale and procedures previously discussed for evaluating an individual's set-point should be applicable in assessing whether or not obesity is, indeed, a physiologically regulated phenomenon. Assessing the rate of energy expenditure in obese individuals at the body weights they maintain should provide one critical piece of information on this point. Information concerning whether or not adjust-
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Time (weeks) Figure 5. Body weight of rats fed either a high-fat or regular laboratory diet for 17 weeks. Prior to the end of this period, the weight of half the high-fat fed rats and half the rats fed a regular diet was reduced by restricting their intake. (Corbett and Keesey; unpublished data.)
ments in energy expenditure are made when an obese individual is displaced from his elevated body weight should provide a second. In the section that follows, an attempt is made to apply these procedures to an analysis of the fundamental disorder underlying obesity in animals. Animal models of obesity contribute much to the ways in which we conceptualize and deal with this condition in humans. Two rodent models that have played a significant role in this regard are used here to illustrate the application of these concepts. The two, dietary obesity and hypothalamic obesity, are both produced experimentally and both are characterized by excessive adiposity and adipose hypercellularity. But, as the following section will show, they differ radically in the degree to which their obese condition can be said to be physiologically regulated. Consideration of this issue begins by examining the features of rats made obese by dietary means. Diet-induced Obesity As previously noted, rats induced to overconsume by palatable diets typically display increased rates of energy expenditure that tend to resist or attenuate the weight gain that the excess calories otherwise would produce. Even so, maintenance on such diets can, and many times does, lead to marked obesity. 24 Furthermore, under certain circumstances, the obesity is irreversible in that it persists even after the animal has been returned to a regular diet. 20 In a recent experiment,4 rats were maintained on a palatable high-fat diet for a period of 6 months. As seen in Figure 5, their weight increased steadily above that of rats fed a standard diet. By the end of the experiment, they weighed 26 per cent more than controls. Subsequent carcass analyses revealed that they had accumulated more than twice the normal amount of body fat over this period. Significantly, they also had increased (by 47 per cent) their number of filled adipocytes. Toward the end of the experiment, the intake of half the dietary obese and
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half the control rats was restricted so as to lower their weight from the maintained level (see Fig. 5). The resting energy expenditure of all rats then was assessed, either at their spontaneously maintained body weight or at the somewhat reduced levels produced by the caloric restriction. These results are seen in Figure 6. Note that the resting rate of energy expenditure of the unrestricted obese rats was not elevated, but normal, for the metabolic mass they now were maintaining (see Fig. 6). That is, energy expenditure in these rats (per metabolic mass) was the same as that of normal weight rats. The physiological conditions responsible for producing the hypermetabolic response initially seen following diet-induced weight gain evidently do not persist after some time. Equally interesting are the results obtained from the calorically restricted obese and control rats. The ensuing weight loss produced the expected decline in resting metabolism in the normal weight rats. But the same adjustment to weight loss is shown by the obese rats as well. Furthermore, the actual daily energy expenditure of the weight-reduced obese rats dropped below that of the normal weight rats despite the fact they still weighed 53 g more. The normal rates of resting metabolism at the elevated body weights the dietary obese rats maintain and the adaptive decline in resting metabolism that they display with caloric privation and weight loss, suggest that prolonged maintenance on the high-fat diet has caused the body weight set-point to be elevated. It thus appears that dietary factors contribute to the life span changes in set-point noted earlier. Such a view is consistent with the observation that dietary obesity often is irreversible. It also is consistent with certain internal changes that have been noted in animals maintained on weight-promoting diets. Among these are increases in adipocyte number, which can be detected some weeks after exposure to such diets. 5 Another is the pattern of change in tissue norepinephrine (NE) turnover rates following exposure to weight-promoting diets. 16 Although initially elevated, NE turnover rates decline following continued exposure to such diets,
Days Postlesion Figure 7. The body weight of rats following lesions of the ventromedial hypothalamus. (U npublished data.)
and return to near normal levels in several months. Whether the changes in these systems simply co-vary with other internal adjustments crucial to altering the setpoint or, themselves, are responsible for this regulatory adjustment is not presently known. Hypothalamic Obesity Perhaps the most widely studied form of animal obesity is that produced by experimental destruction of the ventromedial portion of the hypothalamus (V~lH). Animals with such lesions initially are hyperphagic and increase their weight at a high rate. In time, however, the hyperphagia abates and body weight subsequently is maintained at an elevated level (Fig. 7). Like dietary obese rats, their large accumulation of total body fat (which may increase several fold) is associated with an increase in the number of filled adipocytes. 26 Despite their maintenance of a relatively stable body weight, however, hypothalamic obese rats do not display the responses appropriate to the defense of an elevated set-point. First, intake is not controlled properly in a defense of their high body weight. If challenged by unpalatable or low-calorie diets, for example, the weight of VMH -lesioned rats declines to the level of nonlesioned rats. 29 Or, if such diet~ are presented from the time of the lesion on, neither hyperphagia nor the usual obesity is expressed. 6 . 25 Recent observations of the energy expenditure of obese V~IH-lesioned rats reveal further regulatory deficiencies. First, their resting energy expenditure, while higher in absolute amount than that of normal weight rats, is substantially lower than expected from their metabolic mass (BW75). Second, they fail to display the expected adjustment in resting metabolism when their weight is reduced from the maintained level. Displayed in Figure 8 are the rates of resting energy expenditure of both nonlesioned control and VMH-lesioned obese rats at the body weights each normally maintains and after having had their body weights reduced by caloric restriction to 90 or 80 per cent of that level. In spite of very substantial weight
PHYSIOLOGICAL RECCLATIO:-.J OF BODY \VEIl;HT AI\]) THE ISSCE OF OBESITY
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Figure 8. The resting oxygen consumption (ml per minute) of hypo thalamic (VMH) obese rats and normal weight (sham) rats. Testing of the VMH and sham rats was conducted both at the body weights each spontaneously maintained and following diet-induced weight loss. The sham rats display the expected drop in resting energy expenditure upon being displaced from their maintained body weight. Obese VMH rats fail to display this adaptive reduction in expenditure despite weight losses sometimes more than twice as large (Vilberg and Keesey; in preparation.)
losses, the resting energy expenditure of the V.\1H-Iesioned rat displays little or no change. No evidence is seen of the adaptive reduction in resting metabolism seen in control rats whose weight was reduced similarly, suggesting the absence of a metabolic defense of body weight in V.\1H-Iesioned rats. Animal Obesities: Regulated and Unregulated Forms The preceding observations suggest that, in the dietary obese rat, the set-point for body weight over time, has been elevated. Both the normal rate of resting metabolism at an elevated body weight and the adjustments in resting metabolism that operate to sustain this obesity support such a conclusion. VMH-Iesioned rats, on the other hand, display neither a resting energy expenditure normal for the metabolic mass they maintain nor the metabolic adjustments appropriate to the defense of a particular body weight. Among these two animal models of obesity, therefore, one provides an example of regulation of an elevated set-point that
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apparently is normal in all essential respects. The other is one in which ncither the pattern of energy expenditure while obese nor the metabolic response to weight perturbation are consistent with regulation at an elevated set-point. The obesity in the former is regulated; in the latter regulation is lacking. PROPOSED CLINICAL APPLICATIONS OF THE BODY MASS-ENERGY EXPENDITURE RELATIONSHIP The preceding conclusions rest, as previously noted, on two assumptions concerning the relationship of body weight to resting metabolism. One is that the interspecific relationship previously established between energy expenditure and body mass (for example, Kleiber l4 ) also applies to different sized members of the same species. The second specifies that this relationship applies to individuals in energy stasis, that is, at their regulated body weight or set-point. A corollary assumption is that, when not at set-point, this relationship fails to hold because of adaptive regulatory adjustments in energy expenditure that occur independent of changes in body mass. Although these assumptions by and large are supported by the animal studies, at issue is whether this approach would be useful in the clinical evaluation of energy status in humans and, if so, how it could be applied. Two possible applications are proposed here. The first is to use the body mass-energy expenditure relationship to specify the set-point of individual patients. Ordinarily, a person's "expected" or "ideal" body weight is derived from tables such as those provided by the Metropolitan Life Insurance Company (1983), representing a population estimate of the mean weight of all individuals having the same height and body type. Yet, all that has been examined thus far indicates that considerable natural variation exists between individuals in maintained and, presumably, regulated weight. Thus, the "ideal" weight from such tables, to varying degrees, will be substantially below the regulated value for many people and, to a similar extent, above for many others. It should, in theory, be possible with humans, just as it is with rats, to use resting energy expenditure as an index of whether one is either at set-point or displaced from this regulated level. Fundamental to such an evaluation is a precise specialization of the relationship between body mass and energy expenditure in different sized persons in energy homeostasis. In animals, the Kleiber equation appears to serve adequately but in humans, equations relating body mass to expenditure more commonly derive from the classic observations of Harris and Benedict. 8 Resting energy expenditures predicted from the Harris and Benedict data, however, are not always sufficiently precise. "Errors" are sometimes on the order of ± 14 per cent,21 approaching the magnitude of the regulatory adjustment in resting energy expenditure seen when overconsumption and weight gain, or caloric restriction and weight loss, occur. Still, it is possible that, with currently available equipment, improved technique, and longer sample periods, the variance in estimates of resting metabolism in individuals can be reduced substantially. It is useful to note, for example, that the contributions of the regulatory adjustments to resting metabolism generally have not been appreciated or considered in prior attempts to quantify the relationship of resting metabolism to body mass. Thus, while it may be unrealistic to expect the precision of measurement one can achieve in laboratory animals having the same age, sex, energy status, and so on, an appreciation of the influence of such factors in humans, and an effort to minimize their involvement, very well could provide the accuracy of prediction necessary for this application. A second proposal is to use whole body metabolic response to weight change as a basis for characterizing the obesity of individuals as being essentially regulated
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or unregulated in character. In the same way that dietary obese and hypothalamic obese rats can be characterized and differentiated on the basis of their adjustments in resting metabolism in response to the change in body weight, it is suggested that obese humans may be so distinguished. There are indications in the literature that a distinction of this sort may be valid clinically. First, many obese individuals do display metabolic adjustments appropriate to the defense of an elevated body weight. The participation of an active regulatory response is indicated, for example, by findings of a 17 per cent decline in the resting metabolism of dietary obese patients following a weight decline of only 3 per cent. 2 That these adaptive responses are sustained chronically is indicated by a recent report l5 that obese patients successful in maintaining a weight loss for up to 6 years continue to display reduced levels of resting metabolism. Yet, apparently not all obese display this metabolic defense of body weight (Welle et aP'). Of particular interest in this regard are the observations by Garrow7 of the resting metabolic rate of 26 individual patients before and after diet-reduced weight loss. Although a majority of these persons displayed a disproportionately larger drop in resting energy expenditure than in weight, the remainder displayed a decline in resting metabolism roughly equivalent to that expected from the decline in body mass. That is, their obesity did not appear to be defended physiologically. Thus, the distinctions drawn between regulated and unregulated obe si ties in animals, based on their patterns of energy expenditure, well may have its counterpart among the human obese. Presuming the validity of such a distinction, how could these different forms be identified and treated? Observing the effects of weight gain or loss on resting metabolic rate should reveal whether physiologic adjustments that resist weight changes are present or absent. Changes in metabolism that passively follow weight change suggest a regulatory dysfunction and also indicate a treatment strategy. Because conventional therapies such as dieting and/or behavior modification of eating habits probably are not resisted physiologically, they well may be effective in weight-loss programs. A different approach is needed for an individual whose obesity appears to be regulated. Such a person displays energy-conserving metabolic adaptations that resist weight change and, in all likelihood, greatly diminish the chanees of achieving significant weight loss or of sustaining losses that do occur. To sustain their weight loss, these patients must make a life-long commitment to diets that provide a daily ealoric intake that probably is inadequate to satisfy their hunger and possibly is less than that consumed by persons of normal weight. For such individuals, the hope is that research eventually may reveal a means for reducing the body weight setpoint. Evidence is growing that various neuroanatomic, physiologic, and pharmacologie manipulations are capable of lowering the level of regulated body weight. 11 Although these methods are not suitable for clinical use, their discovery should intensifY the search for safe and effective ways of causing obese individuals to achieve normal energy balance at lower body weights.
SUMMARY The relationship described here between resting energy expenditure and the body weight set-point provides a framework for assessing an animal's regulatory status. Procedures based on this relationship have been used to evaluate the status of rats whose obesity was either of dietary or hypothalamic origin. In dietary obese rats, the body weight set-point appears to have elevated. Their normal rate of energy expenditure at an elevated weight, as well as their active adjustments of expenditure in defense of their obesity, supports this conclusion. Hypothalamic
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obese rats, in contrast, neither expend energy at a rate normal for their body mass nor display the adjustments in expenditure appropriate to defending their obesity. From these observations, a distinction is drawn between regulated and unregulated forms of obesitv. It is sugg~sted that weight disorders in humans, particularly obesity, may be amenable to similar sorts of analysis and categorization, eventually leading to the development of therapies appropriate to the specific type or form indicated.
REFERENCES 1. Apfelbaum M, Bostsarron I. Lacatis D: Effect of caloric restriction and excessive intake on energy expenditure. Am J Clin Nutr 24:140.5-1409, 1971 2. Bray CA: Effect of caloric restriction on energy expenditure in obese patients. Lancet 2:397-398, 1969 3. Colm C, Joseph D: Influence of body weight and body fat on appetite of "normal" lean and obese rats. Yale J Bioi 34:598-607, 1962 4. Corbett SW, Stern JS, Keesey HE: Energy expenditure in rats with diet-induced obesity. Am J Clin "Iutr 44:173-180, 1986 5. Faust IM, Johnson PH, Stern JS, et al: Diet-induced adipocyte number increase in adult rats: A new model of obesity. Am J Physiol 235:E279-E286, 1978 6. Ferguson NBL, Keesey HE: Effect of a quinine-adulterated diet upon body weight maintenance in male rats with ventromedial hypothalamic lesions. J Comp Physiol Psvchol 89:478-488, 1975 7. Carr~w JS: Energy Balance and Obesity in Man. Elsevier, North-Holland Biomedical Press, 1970 8. Harris JA, Benedict FC: A Biometric Study of Basal Metabolism in Man. Washington, DC, Carnegie Institute of Washington, 1919, No 279 9. James WPT, Trayhurn P: Thermogenesis and obesity. Br Med Bull 37:43-48, 1981 10. Keesey HE: A set-point theory of obesity. In Brownell KD, Foreyt JP (eds): Handbook of Eating Disorders: Physiology, psychology, and treatment of obesity, anorexia, and bulimia. New York, Basic Books, 1981, pp 63-87 11. Keesey HE, Powley TL: The regulation of body weight. Annu Hev Psychol 37:109-133, 1986 12. Keesey HE, Boyle PD, Kemnitz JW, et al: The role of the lateral hypo thalamus in determining the body weight set-point. In Novin D, Wyrwicka W, Bray CA (eds): Hunger: Basic mechanisms and clinical implications. New York, Haven Press, 1976, pp 243-255 13. Keys A, Brozek I. Henschel A: The Biology of Human Starvation. Minneapolis, University of Minneapolis Press, 1950 14. Kleiber M: Body size and metabolic rate. Physiol Hev 15:511-541, 1947 15. Leibel HL, Hirsch J: Diminished energy requirements in reduced-obese patients. Metabolism 33:164-170, 1984 16. Levin BE, Triscari I. Sullivan AC: Altered sympathetic activity during development of diet-induced obesity in the rat. Am J Physiol 244:H347-H355, 1983 17. Levitsky DA: Feeding patterns of rats in response to fasts and changes in environmental conditions. Physiol Behav 5:291-300, 1970 18. Levitsky DA, Faust I, Classman M: The ingestion of food and the recovery of body weight following Elsting in the naive rat. Physiol Behav 17:575-580, 1976 19. Obarzanek E, Levitsky DA: Weight gain through overeating and return to normal without undereating. Fed Proc 43:1057, 1984 20. Holls BJ, Howe EA, Turner HC: Persistent obesity in rats following a period of consumption of a mixed high-energy diet. J Physiol (London) 298:415-427, 1980 21. Hothwell NJ, Stock MJ: A role for brown adipose tissue in diet-reduced thermogenesis. Nature 281:31-35, 1979 22. Hothwell NI. Stock MJ: Energy expenditure of 'cafeteria'-fed rats determined from measurements of energy balance and indirect calorimetry. J Physiol 328:371-377, 1982 23. Hoza AM, Shizgal HM: The Harris Benedict equation re-evaluated: Hesting energy requirements and the body cell mass. Am J Clin Nutr 40:168-182, 1984
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24. Sclafani A: Dietary obesity. In Stunkard A] (ed): Obesity. Philadelphia, WB Saunders, 1980, pp 166~ 181 25. Sclafani A, Springer D, Kluge L: Effects of quinine-adulterated diets on the food intake and body weight of obese and nonobese hypothalamic hyperphagic rats. Physiol Behav 15:631~640, 1976 26. Stern IS, Keesey RE: The effect of ventromedial hypothalamic lesions on adipose cell number in the rat. Nutr Rep Int 23:295~301, 1981 27. Trayhurn PL, Thurlby PL, lames WPT: A defective response to cold in the obese (obob) mouse and the obese Zucker (bfa) rat. Proc :\Jutr Soc 35:133A, 1976 28. Welle SL, Amatruda JM, Forbes GB, et al: Resting metabolic rates of obese women after rapid weight loss. ] Clin Endocrinol Metab 59:41~44, 1984 29. Weingarten HP, Chang P, Jarvie KR: Reactivity of normal and VMH-Iesioned rats to quinine-adulterated foods: l\egative evidence for negative finickiness. Behav l\eurol 97:221~233, 1983 Universitv of Wisconsin 1202 We;t J ohnson Street Madison, WI 53706