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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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Key Words: body weight regulation adipose tissue obesity weight loss atherosclerosis leptin
| Introduction |
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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.
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| Physiological Aspects of the Body WeightRegulating System |
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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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| Mechanisms of Obesity-Associated Cardiovascular Disease |
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| Risks and Benefits of Weight-Reduction Therapy |
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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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| Pharmacotherapy for Obesity |
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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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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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| Acknowledgments |
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| Footnotes |
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Received March 31, 1996;
revision received June 11, 1996;
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