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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:233-238.)
© 1997 American Heart Association, Inc.

Articles

Regulation of Body Adiposity and the Problem of Obesity

Michael W. Schwartz; John D. Brunzell

the Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington, and Puget Sound Veterans Affairs Medical Center (M.W.S.), Seattle, Wash.

	Abstract

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The hypothesis that body adiposity is homeostatically regulated is the focus of an intensive research effort, and support for this concept is rapidly growing. While generating optimism about the future of obesity treatment, these advances also bear on our current approach to the obese patient. The observation that body adiposity appears to be subject to regulation in obese as well as lean individuals suggests that common forms of obesity may result from a primary disorder of the weight-regulatory system. As a result, voluntary efforts to lower body adiposity activate compensatory responses that limit weight loss and facilitate weight regain. The use of weight-reduction strategies based on caloric restriction, therefore, effectively pits the will of the obese individual against his or her own intrinsic weight-regulatory system. Until more effective approaches to weight reduction are available, we suggest that clinical intervention should focus on patient education and strategies to limit weight gain or modestly lower weight. Since the combination of a low-fat diet with an exercise program appears to reduce the level at which body weight is regulated without active caloric restriction, this approach may be appropriate for many obese individuals.

Key Words: body weight regulation • adipose tissue • obesity • weight loss • atherosclerosis • leptin

	Introduction

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The enormous economic and health cost of obesity¹ places it among the most pressing national health care problems. Although defined as abnormally elevated body fat content, obesity is more often expressed in terms of an elevated ratio of weight to height, or body mass index. By the latter criterion, the prevalence of "overweight" is increasing in the United States, affecting some 31% of men and 35% of women (body mass index >27 kg/m², reflecting 124% and 120% of desirable weight for men and women, respectively).² In view of the increased risk for cardiovascular disease conferred by obesity, sustained weight reduction seems an appropriate objective for affected individuals,^{3 4 5} as it clearly improves the cardiovascular risk profile.⁶ This benefit occurs with decreased body fat achieved by caloric restriction⁷ or through endurance training.⁸ However, while most methods for weight reduction are effective in the short term, long-term outcomes have generally been disappointing. Previously ascribed to a lack of willpower, a large and rapidly growing body of literature has begun to clarify the biological basis for the failure to sustain diet-induced weight loss. The conclusion drawn from these studies is that body adiposity is homeostatically regulated and that a reduction of adipose stores in humans and in experimental animals, be they lean or obese, activates compensatory responses that restore weight toward its regulated level.^{9 10 11 12 13 14}

Despite broad acceptance in the scientific community of the concept that body adiposity is regulated, its importance is less widely recognized among health care providers. Fortunately, this gap between basic science and clinical practice appears to be narrowing as a result of the discovery of the "ob" gene and the hormone it encodes, known as "leptin."¹⁵ Leptin is secreted by adipocytes in proportion to adiposity and is required for normal weight regulation, since mice homozygous for mutations of this gene locus (ob/ob) overeat and develop a severe form of obesity.¹⁶ Combined with evidence that systemic administration of leptin to ob/ob mice normalizes food intake and body weight,^{17 18 19} leptin appears to be essential for the negative feedback regulation of body adiposity. While scientists have argued for many years that obesity can result from a disorder of the weight-regulating system,²⁰ the surge of interest generated by the discovery of the ob gene has helped to galvanize a consensus that body adiposity is regulated and has generated optimism that breakthroughs in the pathophysiology and treatment of obesity may be within our reach.

For the present, however, the concept that body weight is regulated raises important questions about our clinical approach to the obese patient. Is recovery of lost weight the expected consequence of a normal biological process, even among those with abnormally elevated body adiposity? Available data, portrayed in the Figure, suggest this to be the case.^{21 22 23} What, then, are realistic goals for weight reduction? For which patients is transient weight loss an appropriate objective? What alternatives to caloric restriction should be considered? Is it possible to lower the level of body adiposity that is regulated? These questions provide the focus for this commentary.

View larger version (17K): [in this window] [in a new window]   Figure 1. After obese subjects lost weight by caloric restriction, follow-up for over 9 years was associated with the return of weight to pre–weight-loss levels in 95% of individuals. The 102 subjects were predominantly men (93%) who underwent severe caloric restriction or therapeutic starvation for morbid obesity, resulting in a mean weight loss of 28.6 kg over a minimum of 8 weeks. Of this group, only 7 remained below their initial weight for the entire follow-up period. A unique aspect of this study is the length of follow-up and the notable fact that no better outcome has been established by other studies conducted for varying times of follow-up.22 Modified from Drenick and Johnson.23

	Physiological Aspects of the Body Weight–Regulating System

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Early studies by Keys et al,²⁴ Mayer and Thomas,²⁵ Kennedy,⁹ and others provided evidence that the level of body adiposity (the body's primary source of stored fuel) is a homeostatically regulated variable analogous to the level of plasma osmolarity, blood pressure, blood sugar, or arterial oxygen tension. Subsequent studies established that body adiposity is maintained within narrow limits in virtually all mammals by a homeostatic process that can be activated in response to deviations in body adiposity from the regulated level.^{12 13 14} While many details of this regulatory process remain uncertain, the key elements appear to be analogous to those of other homeostatic control systems in which the central nervous system (CNS) plays a critical role. Just as a change in arterial PO₂ activates CNS-controlled effector mechanisms (eg, ventilatory rate) to counter changes in this regulated variable, a change in body adiposity elicits counterregulatory responses comprised of alterations in the drive to consume food,²⁶ complemented by changes in energy expenditure.^{27 28 29 30 31} As a result, compensation occurs in response to a deviation from the regulated level of body adiposity such that adipose stores return to values that approximate preintervention levels. Importantly, counterregulation occurs over months to years, rather than seconds to minutes, a feature that distinguishes body adiposity from most other homeostatically regulated variables. Moreover, this regulation can be demonstrated in virtually all individuals, regardless of the level of body adiposity. Thus, just as essential hypertension reflects blood pressure regulation that occurs at an abnormally elevated level, obesity appears to result from regulation of an elevated level of adiposity rather than from the absence of regulation. Although feeding is a complex behavior influenced over the short term by an almost limitless number of internal and external factors, over long time intervals, energy intake (and perhaps energy expenditure and efficiency of storage) is modified so as to maintain body adiposity within its regulated range in obese as well as lean individuals.

The biological regulation of fat stores has been popularized by the notion of a "set point" of body adiposity. Set point theory reflects an engineering feedback control model and proposes that afferent information regarding the size of the regulated variable (adipose stores) is analyzed within a central controller (the brain) and compared with an internal reference value of the level of the regulated variable to be defended (the set point). According to this model, a deviation of the perceived level of adiposity from the set point triggers the activation of efferent responses (a change in caloric intake and/or expenditure) that restore adiposity to its defended level. Accordingly, defects in either afferent signaling or efferent responses could lead to defense of an elevated level of adiposity, as occurs in the obese.²⁸ The set point model becomes problematic, however, when applied to conditions that appear to change the regulated level of adiposity. To explain the apparent increase in the defended level of adiposity associated with consumption of a highly palatable, high-fat diet, for example, it is necessary to invoke a change in the set point. How could a change in diet composition alter the brain's adiposity set point?

An alternative model that accounts for the observation that the regulated level of adiposity can change proposes a simpler negative feedback control system.¹⁴ Rather than invoking an internal set point, this model is based on the concept that CNS effector systems capable of strongly influencing energy intake and expenditure are sensitive to negative feedback signals generated in proportion to the level of adipose mass. Candidate negative feedback signals include leptin and insulin, both of which appear to act in the CNS to reduce food intake.^{12 14 17 18 19 32} Rather than being major determinants of caloric intake during each meal, these negative feedback signals may act by modifying the CNS response to the many factors capable of influencing food consumption over the short term that are not generated in proportion to the level of adiposity (eg, emotional factors, voluntary decisions regarding meal size, and palatability of the food). Thus, in response to a novel input such as a new, highly palatable diet, body adiposity is predicted to increase due to the tendency to increase caloric intake, thereby increasing the level of negative feedback signals until they are sufficient to offset the new stimulus to feeding. At this point, a new steady state will be established in which body adiposity is regulated at an elevated level, with the extent of this change depending on both the degree to which the novel diet stimulates food intake and on the robustness with which negative feedback signals are generated by the change in adiposity. Individual differences in responsiveness may lead to substantial weight gain in some, while in others, the change in adiposity may be undetectable. According to this model, therefore, body adiposity is regulated homeostatically but is not "set" or predetermined, since the regulated level can change in response to novel inputs.¹⁴ This model provides an explanation for how body adiposity can be at once regulated and yet subject to change.

The observation that body adiposity increases with advancing age³³ could be interpreted as evidence against homeostatic regulation of body energy stores. However, counterregulation in response to a deviation from the regulated level of adiposity can be demonstrated across all age groups (although the robustness of the response may be compromised in the elderly).³⁴ The effect of aging on body fat content, therefore, may reflect a gradual change in the level at which adiposity is regulated, analogous to the effect of aging on the regulation of blood pressure and blood sugar.^{35 36}

	The Medical Risks of Obesity

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Several longitudinal, population-based studies have established that obesity increases the risk of developing type II diabetes, hypertension, and hyperlipidemia, resulting in an excess of cardiovascular disease.^{3 37 38} The degree of cardiovascular disease risk depends more on the site of excess fat deposition than on the level of adiposity per se. The "android" pattern of excess central intra-abdominal fat characteristic of obese men is associated with hypertension, hyperlipidemia, glucose intolerance, and cardiovascular disease (referred to variously as the "insulin-resistance syndrome," the "central obesity syndrome," the "metabolic syndrome," or "syndrome X").^{39 40} In contrast, the "gynoid" pattern of excess subcutaneous fat distributed about the hips and thighs is more characteristic of women and is less strongly associated with these problems. Population-based observational studies⁴¹ indicate that most of the excess cardiovascular mortality associated with obesity is confined to those with central obesity, which, by computerized tomography, reflects an accumulation of fat within the abdominal cavity.⁴² Conversely, women with a gynoid pattern of fat distribution do not suffer excess cardiovascular morbidity or mortality.⁴³ This increase of cardiovascular risk with obesity has a major impact on premature cardiovascular disease⁴⁴ that can be demonstrated prospectively in older women⁴³ and men.⁴⁵ In the absence of other risk factors, therefore, cardiovascular risk reduction resulting from long-term weight loss may be limited to those with excess intra-abdominal fat, since the association between gynoid obesity and cardiovascular disease remains uncertain.

	Mechanisms of Obesity-Associated Cardiovascular Disease

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A growing database supports the following model, proposed to explain adverse consequences of intra-abdominal fat on the cardiovascular system.⁴⁶ The initial adverse effects of an increase in intra-abdominal fat content are proposed to be increased circulating free fatty acids, accompanied by the development of insulin resistance. This combination increases the secretion of hepatic apoB in VLDL and also stimulates hepatic lipase activity, resulting in the dyslipidemia of central obesity: hypertriglyceridemia with generation of small, dense LDL and reduced buoyant HDL₂ cholesterol. The predisposition to atherogenesis conferred by this change in lipid profile is exacerbated further by the impaired glucose tolerance resulting from insulin resistance, leading to frank hyperglycemia in those individuals genetically predisposed to type II diabetes. Finally, the association of this metabolic syndrome with increased arterial blood pressure (via an unidentified mechanism) accelerates atherogenesis further.

	Risks and Benefits of Weight-Reduction Therapy

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Risks
Early studies of very-low-calorie diets demonstrated that a marked reduction of body weight was associated with an increased risk of fatal arrhythmias. Subsequent adjustments in the quality and content of protein in the diet and in patient monitoring have eliminated this risk,⁴⁷ and nonsurgical weight reduction can currently be undertaken with few short-term adverse effects. Surgical interventions (gastric bypass and gastric stapling procedures) are associated with considerable short- and long-term risks ranging from wound dehiscence to malabsorption^{48 49 50} and are therefore usually reserved for patients at high risk from morbid obesity and associated medical conditions.

Regardless of the method used, achieving successful weight loss does not preclude subsequent adverse effects of therapy. The risk of cholelithiasis is estimated to be 10% to 25% during the first few months after initiating a very-low-calorie diet in obese subjects⁵¹ and is related to the rate of weight loss in a dose-dependent manner.⁵² In addition, many individuals report lethargy and most experience increased hunger after weight reduction.²¹ Although not widely recognized as a consequence of weight reduction, a behavioral abnormality of food intake ("binge eating") was reported in over 40% of subjects in one study.⁵³ This finding raises the possibility that the increased drive to eat elicited as a counterregulatory response to reduced fat stores can precipitate binge eating in some individuals.

An additional concern is the epidemiological associations of both weight loss and weight cycling (repeated cycles of weight loss and regain) with increased mortality.^{54 55 56 57} Data from several large, population-based studies have demonstrated that both marked weight loss and weight cycling are associated with a 40% to 60% increase in the risk of cardiovascular and total mortality. Such studies do not establish causality and are potentially confounded by the epidemiological association between weight loss and illness. Nonetheless, these studies raise concern that weight loss may have adverse effects in some individuals. Since benefit is unlikely to occur if weight is regained, any potential harm must be considered carefully. Finally, the less quantifiable risk to self-esteem must be considered in the obese patient who, after successful weight-reduction therapy, experiences weight regain. This unwelcome outcome would no doubt be softened if the patient were informed about the regulated nature of body adiposity.

Benefits
Several studies have demonstrated that weight-loss therapy can have a beneficial impact on cardiovascular risk factors of hypertension, hyperlipidemia, glucose intolerance, and diabetes, in addition to other benefits.⁶ While weight reduction unquestionably improves the cardiovascular risk profile, it is not clear that this improvement can be translated into reduced cardiovascular risk. This uncertainty stems from a lack of interventions available to achieve sustained weight loss and hence a lack of any randomized intervention trial testing the hypothesis that a reduction in risk factors confers protection from excess morbidity or mortality associated with obesity. On the basis of the assumption that long-term weight reduction is an attainable goal that will reduce the incidence of related diseases, consensus panels of the National Institutes of Health⁴ and the American Medical Association⁵ recommended that the diagnosis of obesity be considered an indication for weight-reduction therapy. In contrast, more recent recommendations from both the American Heart Association⁵⁸ and the American Diabetes Association⁵⁹ advocate a low-fat diet combined with a prudent exercise program for obese patients rather than caloric restriction. These recommendations can be implemented indefinitely and are aimed at achieving modest weight reduction or limiting weight gain. Similarly, The Institute of Medicine recently recommended that although weight lost through caloric restriction may eventually be regained, even a minor reduction of weight may be beneficial in obese patients with hypertension, hyperlipidemia, or diabetes if it can be sustained.⁶⁰ Is it possible to lower the regulated level of adiposity without the use of active caloric restriction?

	Dietary Fat Content, Exercise, and Body Weight Regulation

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As discussed above, the level of a biological variable such as body fat content need not be fixed or unchangeable to be subject to regulation. A variety of stimuli can influence the regulated level of adiposity, including both intrinsic (eg, a change in emotional state or metabolic rate) and extrinsic (eg, the palatability and caloric density of the diet and the level of exercise) factors. While the impact that these factors have on body weight is limited by the negative feedback response to a change in adiposity, and such counterregulation may be incomplete. Thus, lifelong consumption of a highly palatable, high-fat diet may contribute to the increasing prevalence of obesity in the United States,⁶¹ a phenomenon particularly evident in immigrant populations from societies accustomed to a lower dietary fat content.⁴² A corollary to this hypothesis is that a lifelong reduction in the fat content of diets consumed by those at highest risk could lower both the incidence of obesity and the maximal weight achieved in obese individuals. Evidence of modest but sustained weight reduction during ad libitum consumption of a low-fat diet has been reported by several investigators,^{62 63 64 65 66 67} and cross-sectional studies report an association between dietary fat content and body adiposity.^{68 69} These studies support the hypothesis that fat content of the diet is a factor that influences the regulated level of body weight. Similarly, an increased level of physical activity has the potential to modestly reduce the regulated level of adiposity if sustained over long time intervals.²² These observations suggest that many obese individuals may benefit from consumption of a low-fat diet in combination with increased exercise and underscore the need for prospective trials to investigate the impact of these lifestyle changes on the natural history of obesity.

	Pharmacotherapy for Obesity

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Recognition of obesity as a chronic illness has led to the concept that obesity requires chronic treatment, including the use of drugs. A number of obstacles have limited the use of drugs in the management of obesity,⁷⁰ and persistent concerns regarding long-term efficacy and side effects must be overcome before pharmacotherapy can be recommended to most obese individuals.

Among the best-studied drugs for the treatment of obesity are the -adrenergic agonist phentermine and the serotonergic agent fenfluramine (composed of a racemic mixture of the active dextro- isomer dexfenfluramine and the inactive levo- isomer). Both phentermine and fenfluramine have been shown to promote weight loss, and their use in combination for intervals of up to 3 years was investigated by Weintraub et al.⁷¹ Moderately obese patients receiving 15 mg phentermine and 60 mg fenfluramine combined with diet, exercise, and behavior modification lost 16% of their initial weight by 34 weeks of treatment (significantly more than did the placebo control group), and one third of the treated patients remained at least 10% below their starting weight at the end of the trial. However, since 40% of 121 enrollees discontinued the trial before its conclusion, only 20% of the initial treatment group retained at least 10% weight loss after 3 years. These data suggest that long-term drug treatment of obesity is feasible, although sustained loss of >10% of initial weight occurs in only a minority of patients.

Concerns related to side effects represent a second limitation to pharmacotherapy of obesity.⁷² In general, these side effects are not severe (although pulmonary artery hypertension has been reported in rare instances with fenfluramine), and abuse potential is low among drugs currently under investigation. Dry mouth is the most common adverse effect (reported in 23% of patients taking either phentermine or fenfluramine), and CNS side effects such as fatigue, insomnia, and memory impairment are also common (5% to 10%).⁷² Moreover, the expected decrease in blood pressure did not occur with the phentermine-fenfluramine combination, suggesting that beneficial effects of weight loss on blood pressure may be offset by the adrenergic action of phentermine. An additional concern is that the acute withdrawal of fenfluramine may precipitate episodes of depression.⁷¹ As our understanding of basic mechanisms underlying body weight regulation increases, the development of more effective, better-tolerated therapeutic alternatives will likely follow.

	Recommendations for the Physician

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How might this information modify the clinical approach to the obese patient? As a first step, we believe that physicians should inform their obese patients that body adiposity is regulated by a biological process and engage them in a discussion of the risks, benefit, and likely outcome of available treatment options. Weight-loss methods that employ caloric restriction should be compared with strategies designed to achieve more modest weight-reduction goals or to minimize further weight gain (eg, low-fat diet and/or exercise programs). Those patients encouraged to use caloric restriction should be informed that long-term, sustained weight loss is an infrequent outcome and that transient weight loss is of uncertain benefit to long-term health. We believe that avoiding unrealistic expectations for long-term weight loss will promote the well-being of the obese patient and support the patient-physician relationship.

A second point for physicians to consider is that the indications for weight loss are influenced by factors additional to the degree of obesity per se. Body fat distribution and the presence or absence of comorbid illnesses are factors that strongly influence the health risk associated with obesity and should therefore be considered in the clinical decision-making process. Measurement of the waist-to-hip ratio provides an estimate of intra-abdominal fat content, although this method is limited in its ability to estimate risk of lipoprotein disturbance compared with more precise methods, such as CAT scanning.⁷³ Our approach is to assess body habitus visually to identify those in whom significant accumulation of intra-abdominal fat is likely. These individuals are then screened for the presence of hypertension, hyperglycemia, and dyslipidemia, and if additional risk factors are present, a dialogue regarding the importance of controlling body weight is initiated and various treatment options are discussed. Obese individuals with a "gynoid" pattern of fat deposition that do not have additional risk factors for coronary artery disease are less likely to benefit from weight reduction than those with an "android" pattern. The rationale for caloric restriction in such individuals may therefore be called into question. The potential health benefit conferred by transient weight reduction is most likely to be realized in obese individuals with comorbid conditions such as type II diabetes, hypertension, hyperlipidemia, and coronary artery disease. Moreover, since obesity increases the risk of developing these comorbidities, careful surveillance for and rapid treatment of these disorders is warranted for all obese patients.

	Summary

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The consumption of a meal is a voluntary act over which we exert conscious control, from which we derive pleasure, and in which we all have occasionally overindulged. It seems intuitively obvious, therefore, that obesity should reflect a behavioral rather than a physiological disorder. This perception is sanctioned by cultural standards of attractiveness that emphasize "thinness" and by an aversion to obese individuals,^{21 11} a combination that fosters a climate in which the individuals are often held accountable for their level of adiposity. Physicians advising their obese patients to reduce their weight without acknowledging the regulated nature of body adiposity may inadvertently further this belief. Moreover, this approach leaves obese patients vulnerable to a sense of guilt or personal weakness if lost weight is regained, because they feel they failed to meet an important challenge. Until it is possible to intervene effectively in the biological processes regulating body weight, perhaps it is time for the medical community to reassess its approach to the problem of obesity. We suggest that most obese patients will benefit more from interventions aimed at modest weight reduction and/or maintenance of weight stability (such as low-fat diets and exercise programs) than from the use of caloric restriction.

	Acknowledgments

 
This work was supported by the Career Development and Merit Review Programs of the Department of Veterans Affairs and by National Institutes of Health grants DK02456 and NS32273. We are grateful to Daniel Porte Jr, MD; Theodore B. Schwartz, MD; Jerry Palmer, MD; and Francis Wood, MD for their insightful suggestions.

	Footnotes

 
Reprint requests to Michael W. Schwartz, MD, Metabolism (151), Puget Sound VA Medical Center, 1660 S Columbian Way, Seattle, WA 98108. E-mail mschwart@u.washington.edu.

Received March 31, 1996; revision received June 11, 1996;

	References

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1. Wolf AM, Colditz GA. Social and economic effects of body weight in the United States. Am J Clin Nutr. 1996;63:466S-469S.[Abstract/Free Full Text]
2. Kuczmarski RJ. Prevalence of overweight and weight gain in the United States. Am J Clin Nutr. 1992;55(suppl):495S-502S.
3. Van Itallie TB. Health implications of overweight and obesity in the United States. Ann Intern Med. 1985;103:983-988.
4. National Institutes of Health Consensus Development Conference Statement. Health implications of obesity. Ann Intern Med. 1985;1073-1077.
5. Council on Scientific Affairs. Treatment of obesity in adults. JAMA. 1988;260:2547-2551.[Abstract]
6. Wing RR, Jeffery RW, Burton LR, Thorson C, Kuller LH, Folsom AR. Change in waist-hip ratio with weight loss and its association with change in cardiovascular risk factors. Am J Clin Nutr. 1992;55:1086-1092.[Abstract/Free Full Text]
7. Wood PD, Stefanic ML, Dreon DM. Changes in plasma lipids and lipoproteins in overweight men during weight loss through dieting as compared with exercise. N Engl J Med. 1988;319:1173-1179.[Abstract]
8. Schwartz RS, Cain KC, Shuman WP. Effect at endurance training on lipoprotein profiles in young and older men. Metabolism. 1992;41:649-654.[Medline] [Order article via Infotrieve]
9. Kennedy GC. The role of depot fat in the hypothalamic control of food intake in the rat. Proc R Soc Lond B Biol Sci. 1953;140:579-592.
10. Keesey RE, Powley TL. The regulation of body weight. Annu Rev Psychol. 1986;37:109-133.[Medline] [Order article via Infotrieve]
11. Garner DM, Wooley SC. Confronting the failure of behavioral and dietary treatments for obesity. Clin Psychol Rev. 1991;11:729-780.
12. Woods SC, Porte DJ, Bobbioni E, Ionescu E, Sauter JF, Rohner-Jeanrenaud F, . Insulin: its relationship to the central nervous system and to the control of food intake and body weight. Am J Clin Nutr. 1985;42:1063-1071.[Abstract/Free Full Text]
13. Stallone DD, Stunkard AJ. The regulation of body weight: evidence and clinical implications. Ann Behav Med. 1991;13:220-230.
14. Kaiyala KJ, Woods SC, Schwartz MW. A new model for the regulation of energy balance by the central nervous system. Am J Clin Nutr. 1995;62(suppl):1123S-1134S.
15. Zhang Y, Proenca R, Maffie M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372:425-432.[Medline] [Order article via Infotrieve]
16. Coleman DL. Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice. Diabetologia. 1978;14:141-148.[Medline] [Order article via Infotrieve]
17. Campfield LA, Smith FJ, Gulsez Y, Devos R, Burn P. Mouse ob protein: evidence for a peripheral signal linking adiposity and central neural networks. Science. 1995;269:546-549.[Abstract/Free Full Text]
18. Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, Boone T, . Effects of the obese gene product on body weight regulation in ob/ob mice. Science. 1995;269:540-543.[Abstract/Free Full Text]
19. Halaas JL, Gajiwala KS, Maffel M, Cohen SL, Chait BT, Rabinowitz D. Weight-reducing effects of the plasma protein encoded by the obese gene. Science. 1995;269:543-546.[Abstract/Free Full Text]
20. Bray GA, York DA, Fisler JS. Experimental obesity: a homeostatic failure due to defective nutrient stimulation of the sympathetic nervous system. Vitam Horm. 1989;45:1-125.[Medline] [Order article via Infotrieve]
21. Bennett W. Dietary treatment of obesity. Ann N Y Acad Sci. 1987;499:250-263.[Abstract]
22. Safer DJ. Diet, behavior modification, and exercise: a review of obesity treatments from a long-term perspective. South Med J. 1991;84:1470-1474.[Medline] [Order article via Infotrieve]
23. Drenick EJ, Johnson D. Weight reduction by fasting and semistarvation in morbid obesity: long-term follow-up. Int J Obes. 1978;2:123-132.[Medline] [Order article via Infotrieve]
24. Keys BA, Henschel A, Mickelson O, Taylor HL. The Biology of Human Starvation. The University of Minnesota Press; 1950.
25. Mayer J, Thomas DW. Regulation of food intake and obesity. Science. 1967;156:328-337.[Abstract/Free Full Text]
26. Drewnowski A, Brunzell JD, Sande K, Iverius PH, Greenwood MRC. Sweet tooth reconsidered: taste responsiveness in human obesity. Physiol Behav. 1985;35:617-622.[Medline] [Order article via Infotrieve]
27. Weigle DS, Sande KJ, Iverus PH, Monsen ER, Brunzell JD. Weight loss leads to marked decrease in non-resting energy expenditure in ambulatory human subjects. Metabolism. 1988;37:930-936.[Medline] [Order article via Infotrieve]
28. Leibel RL, Rosenbaum M, Hirsch J. Changes in energy expenditure resulting from altered body weight. N Engl J Med. 1995;332:621-628.[Abstract/Free Full Text]
29. Schwartz RS, Brunzell JD. Increase of adipose tissue lipoprotein lipase activity with weight loss. J Clin Invest. 1981;67:1425-1430.
30. Ong JM, Kern PA. Effect of feeding and obesity on lipoprotein lipase activity, immunoreactive protein, and messenger RNA levels in human adipose tissue. J Clin Invest. 1989;84:305-311.
31. Kern PA, Ong JM, Saffari B, Carty J. The effects of weight loss on the activity and expression of adipose-tissue lipoprotein lipase in very obese humans. N Engl J Med. 1990;322:1053-1059.[Abstract]
32. Schwartz MW, Figlewicz DP, Baskin DG, Woods SC, Porte D Jr. Insulin in the brain: a hormonal regulator of energy balance. Endocr Rev. 1992;13:387-414.[Medline] [Order article via Infotrieve]
33. Andres R, Elahi D, Tobin JD, Muller DC, Brant L. Impact of age on weight goals. Ann Intern Med. 1985;103:1030-1033.
34. Roberts SB, Fuss P, Heyman MB, Evans WJ, Tsay R, Rasmussen H. Control of food intake in older men. JAMA. 1994;272:1601-1606.[Abstract]
35. Folkow B, Svanborg A. Physiology of cardiovascular aging. Physiol Rev. 1993;73:725-764.[Free Full Text]
36. Kahn SE, Larson VG, Beard JC, Cain KC, Fellingham GW, Schwartz RS. Effect of exercise on insulin action, glucose tolerance, and insulin secretion in aging. Am J Physiol. 1990;258:E937-E943.[Abstract/Free Full Text]
37. Bray GA. Complications of obesity. Ann Intern Med. 1985;103:1052-1062.
38. Kannel WB, D'Agostino RB, Cobb JL. Effect of weight on cardiovascular disease. Am J Clin Nutr. 1996;63:419S-422S.[Abstract/Free Full Text]
39. Bouchard C, Bray GA, Hubbard VS. Basic and clinical aspects of regional fat distribution. Am J Clin Nutr. 1990;52:946-950.[Free Full Text]
40. Kissebah AH, Vydelingum N, Murray R, Evans DJ, Hartz AJ, Kalkhoff RK, . Relation of body fat distribution to metabolic complications of obesity. J Clin Endocrinol Metab. 1982;54:254-260.[Abstract]
41. Kannel WB, Cupples LA, Ramaswami R, Stokes J, Kreger BE, Higgins M. Regional obesity and risk of cardiovascular disease: the Framingham study. J Clin Epidemiol. 1991;44:183-190.[Medline] [Order article via Infotrieve]
42. Fujimoto WY, Abbata SL, Kahn SE, Hokanson JE, Brunzell JD. The visceral adiposity syndrome in Japanese-American men. Obes Res. 1994;2:364-371.[Medline] [Order article via Infotrieve]
43. Lapidus L, Bengtsson C, Larsson B, Pennert K, Rybo E, Sjostrom L. Distribution of adipose tissue and risk of cardiovascular disease and death: a 12 year follow up of participants in the population study of women in Gothenburg, Sweden. Br Med J. 1984;289:1257-1261.
44. Larsson B, Bjorntorp P, Tibblin G. The health consequences of obesity. Int J Obes. 1981;5:97-116.[Medline] [Order article via Infotrieve]
45. Larsson B, Svardsudd K, Welin L, Wilhelmsen L, Bjorntorp P, Tibblin G. Abdominal adipose tissue distribution, obesity, and risk of cardiovascular disease and death: 13-year follow-up of participants in the study of men born in 1913. Br Med J. 1984;288:1401-1404.
46. Brunzell JD, Nevin DN, Schwartz RS, Austin MA, Fujimoto WY. Overview: low density lipoprotein subclass phenotype B as a biochemical marker of visceral obesity and insulin resistance. In: Bray GA, Ryan DH, eds. Molecular and Genetic Aspects of Obesity. Louisiana State University Press: Baton Rouge, La/London, UK; 1996;5:355-363. Pennington Center Nutritional Series.
47. Wadden TA, Van Itallie TB, Blackburn GL. Responsible and irresponsible use of very-low-calorie diets in the treatment of obesity. JAMA. 1990;263:83-85.[Medline] [Order article via Infotrieve]
48. Adibi SA, Stanko RT. Perspectives on gastrointestinal surgery for treatment of morbid obesity: the lesson learned. Gastroenterology. 1984;87:1381-1391.[Medline] [Order article via Infotrieve]
49. National Institutes of Health Consensus Development Conference Statement. Gastrointestinal surgery for severe obesity. Am J Clin Nutr. 1992;55:615S-619S.[Abstract/Free Full Text]
50. Desaive C. A critical review of a personal series of 1000 gastroplasties. Int J Obes Relat Metab Disord. 1995;19:S56-S60.
51. Everhart J. Contributions of obesity and weight loss to gallstone disease. Ann Intern Med. 1993;119:1029-1035.[Abstract/Free Full Text]
52. Shiffman ML, Kaplan GD, Brinkman-Kaplan V, Vickers FF. Prophylaxis against gallstone formation with ursodeoxycholic acid in patients participating in a very-low-calorie diet program. Ann Intern Med. 1995;122:899-905.[Abstract/Free Full Text]
53. Marcus MD, Wing RR, Lamparski DM. Binge eating among the obese. Ann Behav Med. 1985;9:23-27.
54. Pamuk ER, Williamson DF, Serdula MK, Madans J, Byers TE. Weight loss and mortality in adults. Ann Intern Med. 1994;119:744-748.
55. Andres R, Muller DC, Sorkin JD. Body weight changes and all-cause mortality: a review. Ann Intern Med. 1993;119:737-743.[Abstract/Free Full Text]
56. Lissner L, Odell PM, D'Agostino RB, Stokes J III, Kreger BE, Belanger AJ, . Variability of body weight and health outcomes in the Framingham population. N Engl J Med. 1991;324:1839-1844.[Abstract]
57. Blair SN, Shaten J, Brownell K, Collins G, Lissner L. Body weight change, all-cause mortality, and cause-specific mortality in the multiple risk factor intervention trial. Ann Intern Med. 1993;119:749-757.[Abstract/Free Full Text]
58. Chait A, Brunzell JD, Denke MA, Eisenberg D, Ernst ND, Franklin FA. Rationale for the diet-heart statement of the American Heart Association: report of the Nutrition Committee. Circulation. 1993;88:3008-3029.[Free Full Text]
59. Nutrition recommendations and principles for people with diabetes mellitus. Diabetes Care. 1994;17:519-522. Position Statement.[Abstract]
60. Thomas PR and the Institute of Medicine Committee to Develop Criteria for Evaluating the Outcomes of Approaches to Prevent and Treat Obesity. Weighing the Options: Criteria for Evaluating Weight Management Programs. Washington, DC: National Academy Press; 1995.
61. Kuczmarski R, Flegal K, Campbell S, Johnson C. Increasing prevalence of overweight among US adults: the national health and nutrition examination surveys, 1960 to 1991. JAMA. 1994;272:205-211.[Abstract]
62. Kendall A, Levitsky DA, Strupp BJ, Lissner L. Weight loss on a low-fat diet: consequence of the imprecision of the control of food intake in humans. Am J Clin Nutr. 1991;53:1124-1129.[Abstract/Free Full Text]
63. Schaefer EJ, Lichtenstein AH, Lamon-Fava S, McNamara JR, Schaefer MM, Rasmussen H, . Body weight and low-density lipoprotein cholesterol changes after consumption of a low-fat ad libitum diet. JAMA. 1995;274:1450-1455.[Abstract]
64. Lichtenstein AH, Ausman LM, Carrasco W, Jenner JL, Ordovas JM, Schaefer EJ. Short-term consumption of a low-fat diet beneficially affects plasma lipid concentrations only when accompanied by weight loss: hypercholesterolemia, low-fat diet, and plasma lipids. Arterioscler Thromb. 1994;14:1751-1760.[Abstract/Free Full Text]
65. Lissner L, Levitsky DA, Strupp BJ, Kalkwarf HJ, Roe DA. Dietary fat and the regulation of energy intake in human subjects. Am J Clin Nutr. 1987;46:886-892.[Abstract/Free Full Text]
66. Sheppard L, Kristal AR, Kushi LH. Weight loss in women participating in a randomized trial of low-fat diets. Am J Clin Nutr. 1991;54:821-828.[Abstract/Free Full Text]
67. Prewitt TE, Schmeisser D, Bowen PE, Aye P, Dolecek TA, Langenberg P, . Changes in body weight, body composition and energy intake in women fed high- and low-fat diets. Am J Clin Nutr. 1991;54:304-310.[Abstract/Free Full Text]
68. Kasim SE, Martino S, Kim P, Khilnani S, Boomer A, Depper J, . Dietary and anthropometric determinants of plasma lipoproteins during a long-term low-fat diet in healthy women. Am J Clin Nutr. 1993;57:146-153.[Abstract/Free Full Text]
69. Astrup A, Buemann B, Western P, Toubro S, Raben A, Christensen NJ. Obesity as an adaptation to a high-fat diet: evidence from a cross-sectional study. Am J Clin Nutr. 1994;59:350-355.[Abstract/Free Full Text]
70. Bray GA. Barriers to treatment of obesity. Ann Intern Med. 1991;115:152-153.
71. Weintraub M, Sundareson PR, Schuster B, . Long-term weight control study I-VI. Pharmacol Ther. 1992;51:581-646.
72. Spitz A, Heymsfield S, Blank RC. Drug therapy for obesity: clinical considerations. Endocr Pract. 1995;1:274-279.
73. Pouliot MC, Despres JP, Moorjani S, Tremblay A, Lupien PJ, Nadeau A. Computed tomography–measured trunk fat and plasma lipoprotein levels in nonobese women. Metabolism. 1989;38:1244-1250.[Medline] [Order article via Infotrieve]

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