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Articles  |   February 2008
Addressing Overweight and Obesity: Evolving to a Medical Consensus
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Cardiovascular Disorders / Endocrinology / Gastroenterology / Hypertension/Kidney Disease / Pediatrics / Preventive Medicine / Diabetes
Articles   |   February 2008
Addressing Overweight and Obesity: Evolving to a Medical Consensus
The Journal of the American Osteopathic Association, February 2008, Vol. 108, S2-S15. doi:
The Journal of the American Osteopathic Association, February 2008, Vol. 108, S2-S15. doi:
Abstract

Rising rates of obesity and the resultant increase in associated cardiometabolic morbidity and mortality provided impetus for a roundtable discussion by an expert panel of physicians, physician assistants, and other scientists. Panel members reached a consensus concluding that obesity itself, as defined by waist circumference and the presence of comorbidities, is a disease that should be recognized and addressed with appropriate therapy. Their consensus is based on discussion including evidence that supports obesity, particularly central obesity, best measured by waist circumference, as a risk factor for cardiometabolic diseases. Waist circumferences greater than 102 cm (>40 inches) for men and greater than 88 cm (>35 inches) for women portend high risk. The expert panel endorses three levels of options for management: lifestyle modification, pharmacotherapy, and surgery. Panel members recommend the use of antiobesity agents and acknowledge that the benefits outweigh the risks associated with surgical procedures for obesity. They also point to the need to develop risk stratification guidelines for intervention targeting obesity as a disease.

Approximately a third of the adult population of the United States is overweight, defined as a body mass index (BMI) of 25 to 29.9. This statistic, although higher than in other countries, has remained stable for almost 50 years. 
When obesity, as defined by a BMI of greater than or equal to 30, is added into the mix, however, the statistics become much more disturbing. Rates of obesity more than doubled between 1960 and 2004 across gender, age, educational levels, and smoking status. Obesity now affects another third of American adults; together, overweight and obesity have an impact on the lives of more than two thirds of American adults.1-3 
This increase in prevalence is not just an adult phenomenon. During recent decades, the percentage of overweight children and adolescents has also grown, from 4% and 6.1%, respectively, between 1971 and 1974, to 18.8% and 17.4%, respectively, between 2003 and 2004.1 A variety of factors contributes to these findings, including greater availability and larger portions of food, along with a decline in physical activity.4 Racial differences also affect the prevalence of overweight among children aged 6 to 11 years, with African Americans and Latinos more likely to be overweight. In the adolescent group, Latinos and Asian/Pacific Islanders are more likely to be overweight.5 
As Figure 1 shows, obesity increases the risk for many chronic diseases and decreases life expectancy.6-8 There has been particular interest in abdominal obesity as a risk factor for the development of diabetes9,10 and heart disease,11 the latter being the leading cause of death in the United States.1 
In an epidemiologic study of more than half a million adults aged 50 to 71 years, Adams and associates12 reported that people who were overweight at age 50 years had a 20% to 40% higher mortality risk than did people with BMIs between 23.5 and 24.9 at the same age. In addition, people who were obese had a two to three times greater risk of death than those in the normal weight group. 
Figure 1.
Medical complications of obesity. (Sources: US Department of Health and Human Services. The Surgeon General's Call to Action to Prevent and Decrease Overweight and Obesity. Rockville, Md: US Department of Health and Human Services, Public Health Service, Office of the Surgeon General; 2001. Fontaine KR, Redden DT, Wang C, Westfall AO, Allison DB. Years of life lost due to obesity. JAMA. 2003;289:187-193. Malnick SDH, Knobler H. The medical complications of obesity. QJ Med.) 2006;99:565-579.
Figure 1.
Medical complications of obesity. (Sources: US Department of Health and Human Services. The Surgeon General's Call to Action to Prevent and Decrease Overweight and Obesity. Rockville, Md: US Department of Health and Human Services, Public Health Service, Office of the Surgeon General; 2001. Fontaine KR, Redden DT, Wang C, Westfall AO, Allison DB. Years of life lost due to obesity. JAMA. 2003;289:187-193. Malnick SDH, Knobler H. The medical complications of obesity. QJ Med.) 2006;99:565-579.
Increasingly, diseases such as type 2 diabetes mellitus, hyperinsulinemia, dyslipidemia, and hypertension are being seen in obese children and adolescents. Furthermore, obese children often become obese adults. Unfortunately, adults who were overweight as children continue to have greater morbidity and mortality, even if they lose weight as adults.13 
The impact of obesity goes beyond increased morbidity and mortality, however. Obesity has a profound economic effect on our society. Finkelstein and colleagues14 estimated medical spending by payers (ie, the uninsured, privately insured, Medicaid, and Medicare) that could be attributed to overweight and obesity, as measured by BMI in adults. Although the increase in medical spending associated with overweight was significant only for out-of-pocket expenses, the increase associated with obesity, 37.4%, was significant for all payers (P<.05). 
Looking at the data in another way, 5.3% of adult medical expenditures in the United States were attributable to obesity. Because the analysis used self-reported data, the authors thought that the findings actually reflected underreporting of overweight and obesity, which may have resulted in lower obesity-related expenditures than actually occur in our society. Moreover, the analysis did not include medical spending for children. 
Clearly, the issue of overweight and obesity must be addressed. In 2001, it prompted a call to action by the surgeon general of the US Public Health Service to increase recognition of the problem, promote healthful eating, develop culturally appropriate interventions, and encourage environmental changes.6 Lifestyle modification has typically been recommended for overweight and obese people, but one need only look at maps showing prevalence of diabetes (Figure 2) and obesity (Figure 3) in the United States15-17 to recognize that management has been inadequate, with severe consequences. Is obesity more than an issue, or is it a disease in and of itself? 
This question was at the heart of an expert roundtable, comprising representatives of the American Osteopathic Association, the American College of Osteopathic Internists, the American College of Osteopathic Family Physicians, the American Academy of Physician Assistants, and The Diabetes Consortium, Inc, which met on June 26 and 27, 2007, in Arlington, Virginia. The charge of the panel was to come to consensus on two questions: 
  • Is obesity a disease?
  • If obesity is a disease, is treatment of patients for obesity warranted?
Question 1: Is Obesity a Disease?
It would be true but simplistic to say that obesity is the result of too much to eat and too little exercise for the panel members to understand that genetic, metabolic, and environmental factors all contribute to making a person obese. The panel discussed whether these factors warrant the label of “disease.” According to Dorland's Illustrated Medical Dictionary,18 a disease is 

any deviation from or interruption of the normal structure or function of any part, organ, or system (or combination thereof) of the body that is manifested by a characteristic set of symptoms and signs and whose etiology, pathology, and prognosis may be known or unknown.

 
The expert panel evaluated the evidence that supports the definition of obesity as a disease and, after considerable debate, agreed that obesity is a disease. The panel's reasoning is based on the following information. 
Applying the Definition of Disease
Found mainly in the subcutaneous region and around viscera, white adipose tissue (WAT), the predominant type of adipose tissue, is a pleiotropic organ. Until recently, it had been thought of as a storage site for triglycerides and as a provider of insulation. WAT is now recognized as a complex, dynamic, active endocrine organ that is involved in such processes as energy homeostasis, metabolic control, immunity, inflammation, coagulation, and angiogenesis through the secretion of bioactive peptides, known as adipokines. Figure 4 lists some of the proteins produced by WAT, including their actions. WAT also expresses receptors through which it responds to hormonal and central nervous system signals.19-23 
Figure 2.
Trends in prevalence of diabetes (includes gestational diabetes) in US adults. (Source: Centers for Disease Control and Prevention. Diabetes and Gestational Diabetes Trends Among Adults in the United States. Available at: www.cdc.gov/diabetes/statistics/maps. Accessed January 31, 2008.
Figure 2.
Trends in prevalence of diabetes (includes gestational diabetes) in US adults. (Source: Centers for Disease Control and Prevention. Diabetes and Gestational Diabetes Trends Among Adults in the United States. Available at: www.cdc.gov/diabetes/statistics/maps. Accessed January 31, 2008.
In people who are obese, adipocytes, particularly visceral adipocytes, increase in size and sometimes increase in number, resulting in added weight or mass. In addition, there is increased production of most adipokines and free fatty acids (FFAs), beginning an inflammatory process that has been implicated in the development of insulin resistance and endothelial dysfunction, and eventual diabetes and/or atherosclerosis.19,24,25 Both added mass and adipokine production represent deviations from the normal structure and function of WAT. A discussion of the role of several key adipokines follows.20,23 
Key Adipokines and Cardiometabolic Risk
  • Leptin—Leptin was the first adipokine to be identified and is involved in the regulation of feeding and energy expenditure. In murine and human models of leptin deficiency, overeating and obesity result. Therefore, leptin was originally viewed as an antiobesity hormone.22,26
    In one small study,27 overeating and obesity were suppressed with injections of recombinant human leptin in leptin-deficient humans, but leptin deficiency is exceedingly rare. It is now recognized that leptin signals energy sufficiency and, with starvation, leptin levels decrease, thereby increasing appetite and decreasing energy expenditure.
    In obesity, leptin levels are high, and a state of leptin resistance develops. Leptin has other cardiometabolic effects as well, suppressing insulin synthesis and secretion, and increasing insulin sensitivity.28 A significant association (P<.0001) between leptin and C-reactive protein (CRP), a predictor of atherosclerosis, has been reported.29 High levels of CRP as a measure of inflammation signal high levels of leptin, and vice versa. Although leptin and CRP act in independent and different ways, together they may produce added or synergistic risk.29
  • Adiponectin—Another adipokine, adiponectin, is a key regulator of lipid and glucose metabolism. Its antidiabetes actions—increasing insulin sensitivity and enhancing insulin action, and suppressing glucose production and decreasing serum glucose levels—have been studied.30,31 Adiponectin also has anti-inflammatory and antiatherogenic activity—stimulating the oxidation of FFAs.32 In obese people and those with type 2 diabetes mellitus, plasma adiponectin levels decrease, resulting from insulin resistance, hyperinsulinemia, or both.33
    Decreased plasma adiponectin levels have been associated with low high-density lipoprotein cholesterol (HDL-C) and high triglyceride levels. Whether low adiponectin levels directly cause these lipid changes and thus increase cardiometabolic risk, is unknown.34
  • Interleukin 6—A proinflammatory adipokine in itself, interleukin 6 (IL-6) also acts by increasing the levels of other adipokines with atherogenic effects. Plasminogen activator inhibitor 1 (PAI-1) is one of the adipokines that is induced by IL-6.35 Its actions will be discussed in the next bulleted section.
    Interleukin-6 also stimulates the production of CRP.25 Both CRP and IL-6 are determinants of risk of the development of diabetes.36 As demonstrated with in vitro and animal models, IL-6 may also support angiogenesis during adipose tissue growth.37 Interleukin-6 is increased in obese people.
  • Plasminogen Activator Inhibitor 1— Another adipokine that is increased in obese people, PAI-1 is produced during the early phase of inflammation. It contributes to the maintenance of vascular hemostasis by inhibiting the breakdown of fibrin clots by plasmin.21,25,38 Thus, the increased PAI-1 can lead to hypercoagulation and atherogenesis in patients with visceral obesity and diabetes.39 Angiotensin II (Ang II) stimulates the release of PAI-1 by adipocytes. In insulin resistance, increased PAI-1 is associated with greater risk of cardiac events.38
  • Tumor Necrosis Factor αTumor necrosis factor α (TNF-α) is a proinflammatory cytokine that regulates the production and action of other cytokines, such as PAI-1. It is thought to alter insulin signaling and mediate decreased insulin sensitivity in the liver and muscle.21,38,40 Elevated in obese people, TNF-α contributes to hypertriglyceridemia and insulin resistance.40
    Tumor necrosis factor α is increased in patients with diabetes, even in the absence of obesity and marked hyperglycemia, demonstrating the importance of inflammation as part of the diabetic and atherosclerotic process and supporting reports that patients with diabetes are at increased cardiovascular risk.41
  • Angiotensinogen—Angiotensinogen (AGT) is the precursor to Ang II, which is a vasoconstrictive, proatherogenic peptide.25 The increased release of AGT correlates with hypertension, a cardiometabolic risk factor.
Figure 3.
Trends in prevalence of obesity in US adults. (Source: Centers for Disease Control and Prevention. US Obesity Trends 1985-2006. Available at: ww.cdc.gov/nccdphp/dnpa/obesity/trend/maps/. Accessed January 31, 2008.)
Figure 3.
Trends in prevalence of obesity in US adults. (Source: Centers for Disease Control and Prevention. US Obesity Trends 1985-2006. Available at: ww.cdc.gov/nccdphp/dnpa/obesity/trend/maps/. Accessed January 31, 2008.)
Although the primary source of AGT is the liver, AGT produced in WAT may increase circulating levels of the peptide in obese people, raising their risk of hypertension.42 It has been speculated that the adipose tissue renin-angiotensin system may also contribute to the development of insulin resistance.43 
Atherosclerosis and Type 2 Diabetes Mellitus
Fueled by obesity and excess adipokine production, insulin resistance may progress to diabetes if pancreatic beta-cells fail to meet the demand for insulin, and endothelial dysfunction may progress to atherosclerosis in a parallel, yet intertwined manner.25 Adipokines secreted by WAT have positive, as in the case of adiponectin, or negative, as with TNF-α and IL-6, cardiometabolic effects. Some adipokines with negative effects attract and activate macrophages, which may generate an even greater proinflammatory effect.44,45 
Figure 4.
Cardiometabolic actions of key adipokines produced by white adipose tissue. (Sources: Ahima RS. Adipose tissue as an endocrine organ. Obesity. 2006;14(suppl 5): 242S-249S. Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab. 2004;89:2548-2556. Ronti T, Lupattelli G, Mannarino E. The endocrine function of adipose tissue: an update. Clin Endocrinol. 2006;64:355-365. Hutley L, Prins JB. Fat as an endocrine organ: relationship to the metabolic syndrome. Am J Med Sci. 2005;330:280-289.)
Figure 4.
Cardiometabolic actions of key adipokines produced by white adipose tissue. (Sources: Ahima RS. Adipose tissue as an endocrine organ. Obesity. 2006;14(suppl 5): 242S-249S. Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab. 2004;89:2548-2556. Ronti T, Lupattelli G, Mannarino E. The endocrine function of adipose tissue: an update. Clin Endocrinol. 2006;64:355-365. Hutley L, Prins JB. Fat as an endocrine organ: relationship to the metabolic syndrome. Am J Med Sci. 2005;330:280-289.)
Circulating FFAs increase glucose production and decrease the ability of insulin to inhibit gluconeogenesis. The release of FFAs combined with insulin resistance contributes to hypertriglyceridemia, reduction in HDL-C levels, elevation of non–HDL-C levels, and changes in low-density lipoprotein cholesterol (LDL-C) composition to increase the number of small dense LDL. 
Decreases in insulin activity lead to impaired fasting glucose or glucose intolerance.46 In turn, glucose intolerance is associated with increased left ventricular mass and wall thickness.47 Obesity is linked to both vascular dysfunction and vessel wall elasticity. Insulin resistance leads to endothelial dysfunction, and both are exacerbated by inflammation.48 
Other Pathways Linking Obesity and Cardiometabolic Risk
Although adipokines play a significant role in obesity, other body systems have been implicated as well. Gut hormones, including cholecystokinin, glucagon-like peptide 1, peptide YY, and ghrelin help regulate appetite, as does the pancreatic hormone insulin. In the brain, the serotonin and norepinephrine systems, as well as many regions of the hypothalamus, also influence hunger and satiety.49 
The endocannabinoid system, an endogenous system with cannabinoid-type receptors in the brain, adipose tissue, muscle, liver, gastrointestinal tract, and pancreas, is particularly intriguing, because it presents multiple pathways for linking obesity and cardiometabolic dysfunction.50-53 
Endocannabinoids are known to regulate feeding and body weight by stimulating cannabinoid type 1 (CB1) receptors. In mouse models, fasting increases endocannabinoid levels in the brain.54 The endocannabinoids have been shown to stimulate eating, possibly under the control of leptin, the previously discussed adipokine. It is also well established that marijuana, or cannabis, acts at CB1 receptors to stimulate appetite.55 
In another pathway that modulates feeding, starvation of mice raised levels of anandamide in the small intestine sevenfold, without raising levels in the brain or stomach.56 Other animal models have identified a role of endocannabinoids in fat metabolism and the regulation of hepatic lipogenesis and subsequent development of diet-induced obesity and fatty liver.57 
Blockade of CB1 receptors reduces body weight and waist circumference by decreasing appetite and reducing lipogenesis in WAT.58 Of course, multiple pathways of action yield multiple opportunities for blockade. When rimonabant, a CB1-antagonist, was administered in a murine model, it increased adiponectin mRNA levels in healthy animals, but not in CB1-receptor knockout mice.59 
Blockade of CB1 receptors has beneficial effects on cardiometabolic parameters as well. Administration of rimonabant activated thermogenesis, elicited hypophagia, and increased glucose uptake in an animal model.60 Fasting glycemia and leptin levels were improved in mice fed a high-fat diet and given rimonabant.61 Analogously, triglyceride values and LDL-C levels were significantly decreased (P<.001), and adiponectin levels raised in diet-induced obese animals given rimonabant.62 
With actions that promote weight loss and address components that produce cardiometabolic dysfunction, the endocannabinoid system warrants further study. 
Why Obesity Is a Disease
In people with abdominal obesity, the increased size, and possibly number, of fat cells promotes enhanced secretion of adipokines. Secretion of adipokines leads to insulin resistance, atherogenic dyslipidemia, thrombosis, and reduced adiponectin. Thus begins the progression to diabetes and cardiovascular disease. Obesity produces other end-organ dysfunction as well, including nonalcoholic fatty liver disease,24 hypertension,24 endothelial dysfunction,24 proteinuria,63 pulmonary hypertension,64 muscle insulin resistance,23 pancreatic insufficiency,24 gallbladder disease,24 some cancers,24 and osteoarthritis.24 
Many clinicians and researchers have speculated about the possibility of genetic components that predispose people to the development of obesity. Epidemiologic studies have found that rates of overweight and obesity in the United States are generally higher in racial-ethnic minority populations, including African Americans, Mexican Americans, Pacific Islander Americans, and Native Americans. Prevalence is highest among non-Hispanic black women, and in Mexican American women and men.65 In general, men are more likely to be overweight and have more abdominal obesity.66 Eventually, genetic explanations may be found for these gender-specific and ethnic variations in prevalence. Clearly, many genes are important in the etiology of obesity and visceral adiposity and, in the future, genome scans may be used to identify genetic determinants of susceptibility67 and resistance. 
Having reviewed the supporting evidence, the expert panel reached agreement on the concept of obesity as a disease, as suggested by the following: 

Obesity is a disease that is characterized by increased fat cell size and increased adipokine release, with multiorgan involvement that increases the risk of diabetes and cardiovascular disease. Genetic predisposition triggered by metabolic and endocrine abnormalities of and in adipocytes eventually leads to end-organ dysfunction, including diabetes, coronary heart disease, hypertension, dyslipidemia, stroke, endothelial dysfunction, some cancers, nonalcoholic fatty liver disease, proteinuria, pulmonary hypertension, muscle insulin resistance, pancreatic insufficiency, gallbladder disease, and osteoarthritis.

 
How Should Obesity Be Measured?
Having reached consensus that obesity is indeed a disease, the panel turned to another pressing issue. Throughout the years, researchers studying the effects of obesity have used magnetic resonance imaging and computed tomography to determine abdominal adiposity. Although these are two valid measurements, cost precludes their routine use. Surrogate markers—BMI and waist circumference—are therefore more commonly used to quantify obesity. The BMI has been the gold standard to gauge obesity, but healthcare providers have noted that given two overweight or obese patients with the same BMI, one patient may have few metabolic risk factors while the other may show a full spectrum of cardiometabolic risk. Furthermore, a description based on BMI may classify athletes and obese patients as the same, though their body composition is clearly different. 
These concerns about measurement led to considerable debate about the appropriate clinical recommendation that the roundtable participants should make. It is now recognized that abdominal obesity increases cardiometabolic risk and that waist circumference measurement correlates well with the amount of visceral fat.68 A joint consensus statement, with which the current panel concurs, was issued in 2007 by Shaping America's Health: Association for Weight Management and Obesity Prevention; NAASO: The Obesity Society (formerly known as the North American Association for the Study of Obesity); the American Society for Nutrition; and the American Diabetes Association.69 It asserts the following: 
  • Waist circumference can be reliably measured in clinical practice.
  • Waist circumference has incremental predictive value above that of BMI in determining the risk of diabetes, coronary heart disease, and mortality.
  • Waist circumference measurement may identify “metabolically obese, lean” patients who might benefit from changes in lifestyle, and “metabolically normal, obese” patients who might not require aggressive therapy. Body mass index–specific cutoffs for waist circumference should be established to better describe cardiovascular risk.
  • Waist circumference should be measured around the patient's bare midriff at the level of the posterior superior iliac spine, following exhalation, while the patient stands without shoes, feet touching, and arms hanging. The measuring tape should be of a material that cannot be stretched and should be applied with enough tension to conform to the body. Currently held high-risk waist circumference measurements are greater than 102 cm (>40 inches) for men, and greater than 88 cm (>35 inches) for women.65
Obtaining waist circumference as a measurement of obesity is a simple process that can be done by any staff person in the physician's practice, though training is required. Furthermore, it is a low-cost process and does not impose undue demands on a physician's time. This panel believes it provides valuable information in determining which patients are at risk and guiding physicians in evaluating other components of cardiometabolic risk; however, risk stratification guidelines for intervention should be developed. 
Should Emerging Markers of Cardiovascular Risk Be Measured?
When obesity is present, physicians will often assess for other factors that increase cardiovascular risk: smoking, hypertension, elevated total cholesterol, LDL-C, and blood glucose levels. Additional risk factors have been identified more recently, including elevated triglyceride values; reduced levels of HDL-C,70 increased markers of inflammation, such as high-sensitivity CRP, serum amyloid A, white blood cell count, fibrinogen,71 decreased adiponectin,72 elevated measures of insulin resistance lipoprotein-associated phospholipase A2.73,74 
The expert panel recommends that physicians make the assessments listed in Figure 5 after obesity is determined by waist circumference measurement. 
Figure 5.
Assessments that expert panel recommends be done after evaluating for obesity by measuring waist circumference.
Figure 5.
Assessments that expert panel recommends be done after evaluating for obesity by measuring waist circumference.
Question 2: If Obesity Is a Disease, Is Treatment of Patients for Obesity Warranted?
The expert panel recognized the need to address the cardiometabolic risk associated with obesity and reflected on the lack of agreement in the medical community as to the suitable approach to such risk. Current strategies to reduce cardiometabolic risks produce two different schools of thought. 
The first tactic, and perhaps the most commonly used one, is to manage risk through recognized efficacious treatment of the patient for the risk components—dyslipidemia, hypertension, and hyperglycemia. Thus, patients can be given agents that will reduce their cholesterol levels, decrease their blood pressure, and lower their blood glucose levels. Of course, that means patients will often require more than one agent to treat them for a given condition and, if several diseases are present, many medications. With polypharmacy comes issues of drug interaction, medication management, and adherence, all of which are beyond the scope of this consensus statement. 
The other option is to recognize and treat patients for the underlying disease; in this case, obesity. The benefits of treating patients for overweight and obesity have been enumerated70 and include: 
  • improved quality of life, including appearance and self-esteem
  • improved exercise tolerance
  • reduced LDL-C and triglyceride levels
  • increased HDL-C level
  • reduced risk of diabetes, some cancers, accidents, and chronic lung disease
  • reduced blood pressure
  • greater longevity75,76
  • reduced cost of care14
The treatment of patients for obesity itself remains an area of debate; however; this panel recognizes that effective management may demand more than lifestyle modification alone. As a disease, obesity merits attention as a target for medical intervention. What are our therapeutic options? According to joint guidelines from the National Institutes of Health (NIH), the National Heart, Lung, and Blood Institute (NHLBI), and NAASO: The Obesity Society,77 three levels of treatment options should be recommended to patients based on BMI and the presence of comorbidities: lifestyle modification, pharmacotherapy, and surgery. 
Lifestyle Modification
Physicians should assess a patient's readiness to participate in a structured program of weight loss.65 By evaluating the patient's motivation for weight loss, history of previous attempts, support system, understanding of the disease and its implications, and commitment to all aspects of a program, the physician and patient can begin to set reasonable goals.65 
The American Heart Association (AHA) and the American Diabetes Association report that even moderate weight loss of 7% to 10% of body weight in 1 year in an obese patient reduces the cardiovascular risk factors associated with type 2 diabetes mellitus and improves hyperglycemia.78 Therefore, initial treatment should be directed at achieving up to a 10% reduction in weight. Such weight loss will improve the patient's lipid profile, insulin sensitivity, and susceptibility to thrombosis. Moreover, it will reduce inflammatory markers and enhance endothelial function, thereby decreasing the risk of coronary heart disease.68 
Lifestyle modification forms the cornerstone of the treatment of patients for obesity. It should be encouraged for all people, starting with those who have BMIs that range from 25 to 26.9, who also present with comorbidities. The importance of early identification of overweight and obesity, and the development of prevention and treatment programs, cannot be overemphasized. 
Dietary changes include a moderate reduction in calories, along with education about food composition, labeling, preparation, and portion size. The NIH guidelines recommend a diet low in calories, fats, and carbohydrates to achieve weight loss.65 
Physical activity is another important lifestyle modification. Regular exercise modifies the lipid profile, reducing the levels of very low-density lipoprotein cholesterol (VLDL-C) and, in some cases, LDL-C levels, and raising HDL-C levels. Activity also has positive effects on blood pressure, insulin resistance, and cardiovascular function.79 Physical activity should be maintained for 30 to 45 minutes, 3 to 5 days per week. 
The AHA and NHLBI joint goals for physical activity80 go even further, preferring 60 or more minutes, 5 days a week or daily. Recommended activities that healthcare providers should encourage include moderate-intensity aerobic activity, accompanied by increased movement in daily life. Suggested supplemental daily activities include pedometer step tracking, walking breaks at work, and gardening. Furthermore, the AHA and NHLBI statement advises that resistance training twice weekly be a part of the regimen. Patients who are at high risk should be evaluated medically before initiating an exercise program. 
Adherence to changes in diet and physical activity may be reinforced through a behavioral management program. No specific behavioral management strategy appears to be superior to the others, so a long-term combination of self-monitoring, stress management, stimulus control, problem solving, contingency management, cognitive restructuring, and social support should be employed.65 In many cases, however, lifestyle changes are inadequate to make substantial changes. When that is the case, medical management of obesity should be considered. 
Pharmacotherapy Options
According to joint NIH, NHLBI, and NAASO guidelines,77 pharmacotherapy may be considered for those with a BMI of 27 through 29.9 and comorbidities, and for anyone exceeding that range whether or not they have any obesity-related risk factors. Pharmacotherapy should be considered when weight goals are difficult to achieve or maintain through lifestyle modification alone and should always be used to augment the effects of lifestyle changes. 
Medications should be chosen based on patient assessment and should be administered long term, as short-term use is not considered an effective treatment strategy. In a study of 224 obese adults, the combination of a comprehensive program of group lifestyle modification counseling and pharmacotherapy approximately doubled the weight-loss effects of either intervention alone.81 
Several weight-loss drugs are approved for treatment of patients who are obese, but only two have been approved for long-term use: sibutramine hydrochloride monohydrate and orlistat. Other agents have been used off-label, but our consensus is that off-label use should not be encouraged. Each of the approved agents, along with dietary changes, produces a modest weight loss at 1 year. In meta-analyses, weight loss with sibutramine was approximately 4.45 kg, and orlistat produced a 2.75-kg weight loss.77,82 
  • Sibutramine—Sibutramine works by inhibiting the reuptake of norepinephrine and serotonin in nerve terminals and weakly inhibiting dopamine reuptake.83 One long-term clinical trial with this agent, the Sibutramine Trial of Obesity Reduction and Maintenance (STORM),84 evaluated the effect of sibutramine on weight maintenance after weight loss. Patients who had lost more than 5% of their weight during a 6-month period taking sibutramine combined with a reduced-calorie diet were randomly assigned to an 18-month trial of sibutramine hydrochloride monohydrate (up to 20 mg/d) or placebo (control group).
    Although high dropout rates occurred in both the active treatment and control groups, 43% of patients taking sibutramine maintained 80% or more of their original weight loss, compared with 16% of patients in the control group (P<.001).84 The initial weight loss resulted in improvements in triglyceride, VLDLC, insulin, C-peptide, and uric acid levels, but not blood pressure, changes that persisted in those patients taking sibutramine. Furthermore, in the second year, the patients treated with sibutramine had significant improvement in HDL-C levels (P<.001). Side effects associated with sibutramine included modest increases in heart rate and blood pressure; the latter effect may be a concern in patients with hypertension.
    The Sibutramine Cardiovascular Outcome Trial (SCOUT),85,86 currently under way, will measure cardiovascular outcomes in more than 10,000 patients with baseline cardiovascular disease, hypertension, or diabetes. Preliminary findings from the single-blind, 6-week lead-in period included significant decreases in body weight (P<.001) and waist circumference (P<.001). There were significant decreases in systolic and diastolic blood pressure (P<.001), but two consecutive increases greater than 10 mm Hg in blood pressure were seen in 4.7% of patients. Pulse rates increased by 1.5 beats per minute (bpm), with increases of greater than or equal to 10 bpm seen in 3.5% of patients.
  • Orlistat—Orlistat binds to gastrointestinal lipases in the gut, thereby inhibiting fat absorption.83 In a 4-year clinical trial (XENical in the Prevention of Diabetes in Obese Subjects [XENDOS]) study,87 3305 patients were randomly assigned to lifestyle modification plus orlistat or placebo. The primary end-points were time to diabetes and reduction in body weight. More than half of the patients in the orlistat-treated group completed the trial, compared with 34% in the control group (P<.0001).
    Diabetes risk was reduced by 37.3% with orlistat treatment in those with abnormal glucose tolerance at baseline (P=.0032) and mean weight loss was significantly higher (P<.001). The group receiving orlistat had a higher incidence of gastrointestinal problems and a significant decrease in the absorption of fat-soluble vitamins (vitamin A [P<.05]; 25-hydroxyvitamin D [P<.001]; vitamin E [P<.001]; and vitamin K1 [P<.001), though each remained within its reference range.87
    The effects of orlistat plus diet on cardiovascular risk factors in 126 patients with the metabolic syndrome and diabetes have been studied in an open-label, prospective, multicenter, 6-month trial.88 Orlistat treatment produced significant changes in weight (P=.0001), waist circumference (P<.0001), fasting blood glucose (P<.0001), HbA1C (P<.0001), systolic blood pressure (P=.024), total cholesterol (P<.0001), LDL-C (P<.034), and homeostasis model assessment (HOMA) index (P<.022).
  • Other Antiobesity Agents in Development—Other weight-loss agents are on the horizon, including rimonabant, a selective CB1 antagonist. Rimonabant has been shown to improve the cardiometabolic risk-factor profile independent of weight-loss pathways.89
Investigatory agents that are not as far along in development include those that target central nervous system (CNS) pathways and block appetite stimulation signals or stimulate appetite suppression signals, or those that target peripheral signals to the CNS and block or mimic signals that stimulate or suppress food intake.49 
Sometimes, however, lifestyle modification and pharmaceutical interventions are insufficient and other options become necessary. 
Bariatric Surgery
Joint NIH, NHLBI, and NAASO guidelines77 recommend that weight-loss surgery be considered as an option in high-risk obese patients for whom other less-invasive measures have been unsuccessful. Surgery should be offered to carefully selected patients whose BMI is greater than or equal to 40 or those with comorbid conditions and a BMI greater than or equal to 35. 
Not surprisingly, the number of surgeries is on the rise. Several types of surgical operations are in use including gastric banding, gastric bypass, gastroplasty, biliopancreatic diversion, and duodenal switch. Descriptions of the most common procedures follow.90 
  • Gastric Banding—The laparoscopic adjustable gastric band, placed around the upper part of the stomach, is a restrictive operation that controls the rate of emptying of the stomach pouch and the amount of food that can be consumed at one time.
  • Gastric Bypass—The Roux-en-Y gastric bypass, which can be done laparoscopically, reduces stomach capacity through the creation of a small stomach pouch. In addition, it bypasses part of the small intestine. The laparoscopic adjustable gastric band and Roux-en-Y gastric bypass are, by far, the most commonly done procedures.
  • Biliopancreatic Diversion—For use in certain circumstances, the biliopancreatic diversion procedure removes part of the stomach and bypasses part of the small intestine. A duodenal switch may be part of the procedure. These procedures limit the amount of food that the patient can eat and alter the passage of food through the digestive tract to restrict food absorption more dramatically.
    A meta-analysis comprising 22,094 patients who underwent bariatric procedures91 found that in the majority of patients, surgery reversed, eliminated, or ameliorated morbidity associated with obesity. Diabetes resolved in more than three quarters of all patients and resolved or improved in 86%; hyperlipidemia improved in at least 70%; hypertension was resolved in 61.7% and resolved or improved in 78.5%. Sleep apnea also improved in more than 80% of patients. Although not measured, longevity is expected to increase as a result of these improvements.
  • Benefits Versus Risks—The Swedish Obese Subjects Study75 compared 2010 patients up to 15 years after gastric surgery with 2037 obese patients who were treated conventionally, defined as comprising lifestyle intervention, behavioral modification, or no treatment at all. Patients who had undergone surgical procedures had greater weight loss, lower caloric intake, and were more physically active. Although not all risk factors improved with surgery, improvements were seen in rates of diabetes, hypertriglyceridemia, and hyperuricemia, as well as in HDL-C levels and hypertension. Rates of recovery from hypercholesterolemia were not different between groups. Mortality after an average of 10.9 years of follow-up was reduced by 29% in the group that underwent surgery.
As described, the benefits of bariatric procedures are considerable; however, complication rates associated with surgery are always a concern for both physicians and patients. A multicenter audit92 reviewed data from 1144 bariatric surgery cases, the majority of which were gastric bypass procedures. Restrictive procedures had a complication rate of 3.2%, a 30-day readmission rate of 4.3%, and no 30-day mortality. Gastric bypass procedures had a 16% overall complication rate, 30-day readmission rate of 6.6%, and a 30-day mortality rate of 0.4%. 
Roadblocks to Success
Although the recognition and management of overweight and obesity have improved, significant problems limit the ability of the obese person to lose weight.93 The panel discussed many patient-driven, medical provider/system-driven, and economic roadblocks that keep patients from controlling their obesity. At the forefront of the dialogue were patient issues confronted in clinical practice. Healthcare providers reported that their patients have eating habits that have become ingrained, some of which are the result of cultural and family dynamics. 
Further, there is a lack of education about appropriate food portions, the dangers of obesity, and the role and types of physical activity. Patients, the physicians thought, often had unrealistic expectations of what could be accomplished through diet and exercise, evidenced in a quick-fix mentality. This mentality, along with the lack of a support system, creates an environment of frustration when attempts at weight management fail. 
These patient-driven problems are complicated by societal attitudes. Body images presented in the media are virtually unachievable. Food labeling could be improved. The health policy changes in schools have produced a physically inactive population and resulted in vending machine contracts that are aimed at enriching the providers and schools without adequate concern for the nutrition of children and have distorted consumption patterns. 
Moreover, a culture of consumption and entitlement is promoted in advertising campaigns that reward a hard day with a calorie-dense meal at a fast-food restaurant. Patients often feel a lack of personal responsibility for their obesity. 
It is difficult, too, for physicians to find the time to counsel patients and provide the support that is needed in an obesity-management program. Furthermore, there is a lack of incentive to do so, as these services often are not reimbursed. Medical professionals may also be unaware of the best and simplest ways to diagnose obesity and treat patients for obesity, or they may believe that treatment is ineffective. 
Combine these patient-, societal-, and physician-associated factors with some economic realities and it becomes a recipe for failure. Life is busy, and it is difficult for patients to make the time for healthy choices in food and exercise. Healthy food is expensive, and a fast-food choice may be a question of expediency. Healthy food products and weight-management programs may be unavailable or unaffordable in some areas of the United States. Medication or surgery may not be an option for an uninsured or underinsured patient. 
Frontiers for the Future
Panel participants identified several opportunities for the future of obesity management. They include the suggestions presented in Figure 6. 
Members of the represented organizations looked to the success of smoking cessation programs as a model for controlling a modifiable risk factor and decreasing preventable disease and death. They pointed to the key elements of the antismoking strategies, which are delineated in the report of the surgeon general of the US Public Health Service on reducing tobacco use.94 Plans for the management of nicotine addiction combined educational, self-help, and behavioral intervention strategies; clinical and pharmacologic interventions; and public health programs developed for the media, worksite, community, and government. In addition, the enforcement of tobacco-control policies and the development of clean air laws were important policy decisions. 
It may be possible to improve prevention of obesity through better regulation of school meal programs, vending machines, and food labeling.95 The use of economic incentives or, in the case of tobacco control, disincentives, can be applied to food as well, with subsidies for more healthful food choices. 
Figure 6.
Opportunities for future management of obesity suggested by the members of the expert panel participating in this roundtable discussion.
Figure 6.
Opportunities for future management of obesity suggested by the members of the expert panel participating in this roundtable discussion.
The panel also identified a strong need for the further development of agents for the treatment of patients for obesity. The metabolic pathways of obesity represent a particularly intriguing potential target for pharmaceutical intervention. New weight-loss drugs in late-stage development include rimonabant, CP 945598, and taranabant, all CB1-receptor antagonists; lorcaserin, a serotonin 5-HT2C-receptor agonist; a combination of bupropion (a norepinephrine and dopamine reuptake inhibitor) and zonisamide (an antiseizure agent); and cetilistat, a gastrointestinal lipase inhibitor. Research is ongoing for other cannabinoid antagonists and lipase inhibitors as well as agents that affect neuropeptide Y, leptin, ghrelin, cholecystokinin glucagon-like peptide-1, lipid oxidation, and the CNS. 
Conclusions
Based on the evidence presented during this 2-day session, the expert panel concluded that obesity is a disease and prepared the following statement: 

Obesity, as defined by waist circumference, is a disease for which patients should be treated by a multifaceted approach that must include lifestyle modification and may include medical or surgical intervention.

 
The panel further stated that lifestyle interventions and counseling are demanding of both the patient's and the physician's time and require a commitment to change from the patient. Furthermore, lifestyle interventions have been shown to be of limited effectiveness when used alone. Moreover, expectations associated with such interventions often are unrealistic. 
Inasmuch as the combination of lifestyle changes and medical treatment works together to produce greater weight loss, the panel recommended consideration of using antiobesity agents. Adherence to all elements of a weight-loss program should be monitored, and the patient should be counseled about how much weight can be lost, what adverse effects are possible, and how to manage plateaus. 
Panel members agreed that surgical intervention prolongs life.75,76 They thought, too, that the benefits of surgery in terms of improvements in diabetes, lipid levels, other cardiometabolic parameters, and quality of life, greatly outweigh the risks associated with these procedures. Patients for whom surgery is recommended should be assessed for their willingness to adhere to the lifestyle changes needed to maintain the effects of this treatment choice. 
 A Consensus Report of the American Osteopathic Association, the American College of Osteopathic Internists, the American College of Osteopathic Family Physicians, the American Academy of Physician Assistants, and The Diabetes Consortium, Inc
 
 Address correspondence to Frederick A. Schaller, DO, Vice Dean, Touro University Nevada College of Osteopathic Medicine, 874 American Pacific Dr, Henderson, NV 89014.
 
 Dr Schaller has no relevant financial interests.
 
The authors wish to thank The Diabetes Consortium, Sonia Schursky, MD, and Susan Terner for their assistance in the preparation of this manuscript. All authors have provided editorial support for the development of this manuscript and have participated in developing the content of this manuscript, including preparing and reviewing the draft versions and approving the final version. Financial support for this initiative is made possible through an independent educational grant from sanofi-aventis. 
Centers for Disease Control and Prevention. Health, United States, 2006 With Chartbook on Trends in the Health of Americans. Hyattsville, MD: National Center for Health Statistics; 2006. Available at: www.cdc.gov/nchs/data/hus/hus06.pdf. Accessed January 31, 2008.
Mokdad AH, Ford ES, Bowman BA, Dietz WH, Vinicor F, Bales VS, et al. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA. 2003;289:76-79. Available at: http://jama.ama-assn.org/cgi/content/full/289/1/76. Accessed January 23, 2008.
Ogden CL, Yanovski SZ, Carroll MD, Flegal KM. The epidemiology of obesity. Gastroenterology. 2007;132:2087-2102.
Kimm SY, Glynn NW, Kriska AM, Barton BA, Kronsberg SS, Daniels SR, et al. Decline in physical activity in black girls and white girls during adolescence. N Engl J Med. 2002;347(10):709-715. Available at: http://content.nejm.org/cgi/content/abstract/347/10/709. Accessed January 23, 2008.
Haas JS, Lee LB, Kaplan CP, Sonneborn D, Phillips KA, Liang SY. The association of race, socioeconomic status, and health insurance status with the prevalence of overweight among children and adolescents. Am J Public Health. 2003;93:2105-2110. Available at: http://www.ajph.org/cgi/content/full/93/12/2105. Accessed January 23, 2008.
US Department of Health and Human Services. The Surgeon General's Call to Action to Prevent and Decrease Overweight and Obesity. Rockville, Md: US Department of Health and Human Services, Public Health Service, Office of the Surgeon General; 2001. Available at: http://www.surgeon-general.gov/topics/obesity/calltoaction/CalltoAction.pdf. Accessed January 28, 2008.
Fontaine KR, Redden DT, Wang C, Westfall AO, Allison DB. Years of life lost due to obesity. JAMA. 2003;289:187-193. Available at: http://jama.amaassn.org/cgi/content/full/289/2/187. Accessed January 23, 2008.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Statistics Related to Obesity and Overweight. Bethesda, Md: National Institutes of Health; June(2007). . NIH Publication No. 96-4158.
Colditz GA, Willett WC, Rotnitzky A, Manson JE. Weight gain as a risk factor for clinical diabetes mellitus in women. Ann Intern Med. 1995;122:481-486. Available at: http://www.annals.org/cgi/content/full/122/7/481. Accessed January 23, 2008.
Chan JM, Rimm EB, Colditz GA, Stampfer MJ, Willett WC. Obesity, fat distribution, and weight gain as risk factors for clinical diabetes in men. Diabetes Care. 1994;17:961-969.
Dagenais GR, Yi Q, Mann JF, Bosch J, Pogue J, Yusuf S. Prognostic impact of body weight and abdominal obesity in women and men with cardiovascular disease. Am Heart J. 2005;149:54-60.
Adams KF, Schatzkin A, Harris TB, Kipnis V, Mouw T, Ballard-Barbash R, et al. Overweight, obesity, and mortality in a large prospective cohort of persons 50 to 71 years old. N Engl J Med. 2006;355:763-778. Available at: http://content.nejm.org/cgi/content/abstract/355/8/763. Accessed January 28, 2008.
Deckelbaum RJ, Williams CL. Childhood obesity: the health issue[review]. Obesity Res. 2001;9 (suppl 4):239S-243S. Available at: http://www.obesityresearch.org/cgi/content/full/9/suppl_4/S239. Accessed January 28, 2008.
Finkelstein EA, Fiebelkorn IC, Wang G. National medical spending attributable to overweight and obesity: how much, and who's paying? Health Aff (Millwood). 2003;suppl Web exclusives: W3-219-226. Available at: http://content.healthaffairs.org/cgi/content/full/hlthaff.w3.219v1/DC1. Accessed January 28, 2008.
Centers for Disease Control and Prevention. US Obesity Trends 1985-2006. Available at: www.cdc.gov/nccdphp/dnpa/obesity/trend/maps/. Accessed January 31, 2008.
Centers for Disease Control and Prevention. Diabetes and Gestational Diabetes Trends Among Adults in the United States. Available at: www.cdc.gov/diabetes/statistics/maps. Accessed January 31, 2008.
Centers for Disease Control and Prevention. Behavioral Risk Factor Surveillance System. Available at: http://apps.nccd.cdc.gov/gisbrfss/select_question.aspx. Accessed October 5, 2007.
Dorland's Illustrated Medical Dictionary. 31st ed. Philadelphia, Pa: WB Saunders Co; 2007.
Ahima RS. Adipose tissue as an endocrine organ. Obesity (Silver Spring). 2006;14(suppl 5):242S-249S. Available at: http://www.obesityresearch.org/cgi/content/full/14/suppl_5/242S. Accessed January 28, 2008.
Jackson MB, Ahima RS. Neuroendocrine and metabolic effects of adipocyte-derived hormones [review]. Clin Sci (Lond). 2006;110:143-152. Available at: http://www.clinsci.org/cs/110/0143/cs1100143.htm. Accessed January 28, 2008.
Trayhurn P, Wood IS. Adipokines: inflammation and the pleiotropic role of white adipose tissue [review]. Br J Nutr. 2004;92:347-355. Available at: http://journals.cambridge.org/action/display-Fulltext?type=6&fid=915808&jid=&volumeId=&issueId=03&aid=915804&fulltextType=RA&fileId=S0007114504001795. Accessed January 28, 2008.
Kershaw EE, Flier JS. Adipose tissue as an endocrine organ [review]. J Clin Endocrinol Metab. 2004;89:2548-2556. Available at: http://jcem.endojournals.org/cgi/content/full/89/6/2548. Accessed January 28, 2008.
Greenberg AS, Obin MS. Obesity and the role of adipose tissue in inflammation and metabolism [review]. Am J Clin Nutr. 2006;83(suppl):461S-465S. Available at: http://www.ajcn.org/cgi/content/full/83/2/461S. Accessed January 28, 2008.
Bray GA. Medical consequences of obesity [review]. J Clin Endocrinol Metab. 2004;89:2583-2589. Available at: http://jcem.endojournals.org/cgi/content/full/89/6/2583. Accessed January 2008.
Lyon CJ, Law RE, Hsueh WA. Minireview: adiposity, inflammation, and atherogenesis. Endocrinology. 2003;144:2195-2200. Available at: http://endo.endojournals.org/cgi/content/full/144/6/2195. Accessed January 28, 2008.
Flier JS. Obesity wars: molecular progress confronts an expanding epidemic. Cell. 2004;116:337-350.
Farooqi IS, Matarese G, Lord GM, Lawrence E, Agwu C, Sanna V, et al. Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J Clin Invest. 2002;110:1093-1103.
Huerta MG. Adiponectin and leptin: potential tools in the differential diagnosis of pediatric diabetes? Rev Endocr Metab Disord. 2006;7:187-196.
Shamsuzzaman ASM, Winnicki M, Wolk R, Svatikova A, Phillips BG, Davison DE, et al. Independent association between plasma leptin and C-reactive protein in healthy humans. Circulation. 2004;109:2181-2185. Available at: http://circ.ahajournals.org/cgi/content/full/109/18/2181. Accessed January 28, 2008.
Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med. 2002;8:1288-1295. Available at: http://www.nature.com/nm/journal/v8/n11/full/nm788.html. Accessed January 28, 2008.
Berg AH, Combs TP, Du X, Brownlee M, Scherer PE. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med. 2001;7:947-953. Available at: http://www.nature.com/nm/journal/v7/n8/full/nm0801_947.html. Accessed January 28, 2008.
Fruebis J, Tsao TS, Javorschi S, Ebbets-Reed D, Erickson MRS, Yen FT, et al. Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc Natl Acad Sci USA. 2001;98:2005-2010. http://www.pnas.org/cgi/content/full/98/4/2005. Accessed January 28, 2008.
Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, et al. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab. 2001;86:1930-1935. Available at: http://jcem.endojournals.org/cgi/content/full/86/5/1930. Accessed January 28, 2008.
Matsubara M, Maruoka S, Katayose S. Decreased plasma adiponectin concentrations in women with dyslipidemia. J Clin Endocrinol Metab. 2002;87:2764-2769. Available at: http://jcem.endojournals.org/cgi/content/full/87/6/2764. Accessed January 28, 2008.
Rega G, Kaun C, Weiss TW, Demyanets S, Zorn G, Kastl SP, et al. Inflammatory cytokines interleukin-6 and oncostatin M induce plasminogen activator inhibitor-1 in human adipose tissue. Circulation. 2005;111:1938-1945. Available at: Accessed http://circ.ahajournals.org/cgi/content/full/111/15/1938. January 28, 2008.
Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA. 2001;286:327-334. Available at: http://jama.amaassn.org/cgi/content/full/286/3/327. Accessed January 28, 2008.
Rega G, Kaun C, Demyanets S, Pfaffenberger S; Rychli K, Hohensinner PJ, et al. Vascular endothelial growth factor is induced by the inflammatory cytokines interleukin-6 and oncostatin M in human adipose tissue in vitro and in murine adipose tissue in vivo. Arterioscler Thromb Vasc Biol. 2007;27:1587-1595. Available at: http://atvb.ahajournals.org/cgi/content/full/27/7/1587. Accessed January 28, 2008.
Summers LK. Adipose tissue metabolism, diabetes and vascular disease—lessons from in vivo studies. Diabetes Vasc Dis Res. 2006;3(1):12-21. Available at: Accessed http://www.dvdres.com/pdf/2397/Vol3_Num1_May_2006_p12-21.pdf. January 28, 2008.
Kozek E, Katra B, Malecki M, Sieradzki J. Visceral obesity and hemostatic profile in patients with type 2 diabetes: the effect of gender and metabolic compensation. Rev Diabet Stud. 2004;1(3):122-128. Available at: http://www.socbdr.org/content/e4/e887/volRdsVolumes888/issRdsIssues1034/chpRdsChapters1092/strRdsArticles1093/index_en.html?showfulltext=1. Accessed January 28, 2008.
Rondinone CM. Adipocyte-derived hormones, cytokines, and mediators. Endocrine. 2006;29(1):81-90.
Pereira FO, Frode TS, Medeiros YS. Evaluation of tumour necrosis factor alpha, interleukin-2 soluble receptor, nitric oxide metabolites, and lipids as inflammatory markers in type 2 diabetes mellitus. Mediators Inflamm. 2006;2006(1):39062 .
Ronti T, Lupattelli G, Mannarino E. The endocrine function of adipose tissue: an update {review]. Clin Endocrinol (Oxf). 2006;64:355-365.
Engeli S, Schling P, Gorzelniak K, Boschmann M, Janke J, Ailhaud G, et al. The adipose-tissue renin-angiotensin-aldosterone system: role in the metabolic syndrome? [review]. Int J Biochem Cell Biol. 2003;35:807-825.
Roth J, Qiang X, Marbán SL, Redelt H, Lowell BC. The obesity pandemic: where have we been and where are we going? Obesity Res. 2004;12 (suppl 2):88S-101S. Available at: http://www.obesityresearch.org/cgi/content/full/12/suppl_2/88S. Accessed January 28, 2008.
Ahima RS. Metabolic actions of adipocyte hormones: focus on adiponectin. Obesity (Silver Spring). 2006;14(suppl 1):9S-15S. Available at: http://www.obesityresearch.org/cgi/content/full/14/suppl_1/9S. Accessed January 28, 2008.
Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005;365(9468):1415-1428.
Rutter MK, Parise H, Benjamin EJ, Levy D, Larson MG, Meigs JB, et al. Impact of glucose intolerance and insulin resistance on cardiac structure and function: sex-related differences in the Framingham Heart Study. Circulation. 2003;107:448-454. Available at: http://circ.ahajournals.org/cgi/content/full/107/3/448. Accessed January 28, 2008.
Singhal A. Endothelial dysfunction: role in obesity-related disorders and the early origins of CVD. Proc Nutr Soc. 2005;64(1):15-22. Available at: http://journals.cambridge.org/action/displayFulltext?type=6&fid=902356&jid=&volumeId=&issueId=01&aid=902352&fulltextType=MR&fileId=S0029665105000030. Accessed January 29, 2008.
Jensen MD. Potential role of new therapies in modifying cardiovascular risk in overweight patients with metabolic risk factors. Obesity (Silver Spring). 2006;14(suppl 3):143S-149S. Available at: http://www.obesityresearch.org/cgi/content/full/14/suppl_3/143S. Accessed January 28, 2008.
Blüher M, Engeli S, Klöting N, Berndt J, Fasshauer M, Bátkai S,et al. Dysregulation of the peripheral and adipose tissue endocannabinoid system in human abdominal obesity. Diabetes. 2006;55:3053-3060. Available at: http://diabetes.diabetesjournals.org/cgi/content/full/55/11/3053. Accessed January 28, 2008.
Fride E. The endogenous cannabinoid system: a new player in the brain-gut-adipose axis. Cannabinoids. 2007;2(2):5-12. Available at: http://209.85.173.104/search?q=cache:ZrNDaX64094J:www.cannabis-med.org/english/journal/en_2007_02_1.pdf+The+endogenous+cannabinoid+system:+a+new+player+in+the+brain-gut-adipose+axis&hl=en&ct=clnk&cd=1&gl=us. Accessed January 28, 2008.
Bátkai S, Pacher P, Osei-Hyiaman D, Radaeva, S, Liu J, Harvey-White J, et al. Endocannabinoids acting at cannabinoid-1 receptors regulate cardiovascular function in hypertension. Circulation. 2004;110(14):1996-2002. Available at: http://circ.ahajournals.org/cgi/content/full/110/14/1996. Accessed January 28, 2008.
Cota D. CB1 receptors: emerging evidence for central and peripheral mechanisms that regulate energy balance, metabolism, and cardiovascular health. Diabetes Metab Res Rev. 2007;23:507-517.
Kirkham TC, Williams CM, Fezza F, Di Marzo V. Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation of eating by 2-arachidonoyl glycerol. Br J Pharmacol. 2002;136:550-557. Available at: http://www.nature.com/bjp/journal/v136/n4/full/0704767a.html. Accessed January 28, 2008.
Iverson L. Cannabis and the brain. Brain. 2003;126:1252-1270. Available at: http://brain.oxfordjournals.org/cgi/content/full/126/6/1252. Accessed January 28, 2008.
Gómez R, Navarro M, Ferrer B, et al. A peripheral mechanism for CB1 cannabinoid receptor-dependent modulation of feeding. J Neurosci. 2002;22:9612-9617. Available at: http://www.jneurosci.org/cgi/content/full/22/21/9612. Accessed January 28, 2008.
Osei-Hyiaman D, DePetrillo M, Pacher P, Liu J, Radaeva S, Bátkai S, et al. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest. 2005;115:1298-1305.
Horvath TL. Endocannabinoids and the regulation of body fat: the smoke is clearing. J Clin Invest. 2003;112:323-326. Available at: http://www.jci.org/articles/view/19376. Accessed January 28, 2008.
Bensaid M, Gary-Bobo M, Esclangon A, Maffrand JP, Le Fur G, Oury-Donat F, et al. The cannabinoid CB1 receptor antagonist SR141716 increases Acrp30 mRNA expression in adipose tissue of obese fa/fa rats and in cultured adipocyte cells. Mol Pharmacol. 2003;63:908-914. Available at: http://molpharm.aspetjournals.org/cgi/content/full/63/4/908. Accessed January 28, 2008.
Liu YL, Connoley IP, Wilson CA, Stock MJ. Effects of the cannabinoid CB1 receptor antagonist SR141716 on oxygen consumption and soleus muscle glucose uptake in Lepob/Lepob mice. Int J Obes. 2005;29:183-187.
Ravinet Trillou C, Delgorge C, Menet C, Arnone M, Soubrié P. CB1 cannabinoid receptor knockout in mice leads to leanness, resistance to diet-induced obesity and enhanced leptin sensitivity. Int J Obes Relat Metab Disord. 2004;28(4):640-648.
Poirier B, Bidouard JP, Cadrouvele C, Marniquet X, Staels B, O'Connor SE, et al. The anti-obesity effect of rimonabant is associated with an improved serum lipid profile. Diabetes Obes Metab. 2005;7 (1):65-72.
Matsumoto H, Nakao T, Okada T, Nagaoka Y, Iwasawa H, Tomaru R, et al. Insulin resistance contributes to obesity-related proteinuria. Intern Med. 2005;44:548-553. Available at: http://www.jstage.jst.go.jp/article/internalmedicine/44/6/548/_pdf. Accessed January 28, 2008.
Blankfield RP, Hudgel DW, Tapolyai AA, Zyzanski SJ. Bilateral leg edema, obesity, pulmonary hypertension, and obstructive sleep apnea. Arch Intern Med. 2000;160:2357-2362. Available at: http://archinte.ama-assn.org/cgi/content/full/160/15/2357. Accessed January 28, 2008.
Pi-Sunyer FX, Becker DM, Bouchard C, et al. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults: The Evidence Report. Bethesda, Md: National Institutes of Health; 1998. NIH Publication No. 98-4083.
Bouchard C, Després JP, Mauriége P. Genetic and nongenetic determinants of regional fat distribution. Endocr Rev. 1993;14(1):72-93. Available at: http://edrv.endojournals.org/cgi/reprint/14/1/72. Accessed January 28, 2008.
Challis BG, Yeo GSH. Past, present and future strategies to study the genetics of body weight regulation. Brief Funct Genomic Proteomic. 2002;1:290-304. Available at: http://bfgp.oxfordjournals.org/cgi/reprint/1/3/290. Accessed January 28, 2008.
Després JP, Lemieux I, Purd'homme D. Treatment of obesity: need to focus on high risk abdominally obese patients. BMJ. 2001;322:716-720. Available at: http://www.bmj.com/cgi/content/full/322/7288/716. Accessed January 28, 2008.
Klein S, Allison DB, Heymsfield SB, Kelley DE, Leibel RL, Nonas C, et al. Waist circumference and cardiometabolic risk: a consensus statement from Shaping America's Health: Association for Weight Management and Obesity Prevention; NAASO, the Obesity Society; the American Society for Nutrition; and the American Diabetes Association. Diabetes Care. 2007;30:1647-1652. Available at: http://care.diabetesjournals.org/cgi/content/full/30/6/1647. Accessed January 28, 2008.
Assmann G, Carmena R, Cullen P, Fruchart J-C, Jossa F, Lewis B, et al. Coronary heart disease: reducing the risk: a worldwide view. International Task Force for the Prevention of Coronary Heart Disease. Circulation. 1999;100:1930-1938. Available at: http://circ.ahajournals.org/cgi/content/full/100/18/1930. Accessed January 28, 2008.
Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO 3rd, Criqui M, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003;107:499-511. Available at: http://circ.ahajournals.org/cgi/content/full/107/3/499. Accessed January 28, 2008.
Brooks NL, Moore KS, Clark RD, Perfetti MT, Trent CM, Combs TP. Do low levels of circulating adiponectin represent a biomarker or just another risk factor for the metabolic syndrome? Diabetes Obes Metab. 2007;9:246-258.
Beckley ET. New ADA initiative moves beyond `metabolic syndrome.' DOC News. 2006;3(7). Available at: http://docnews.diabetesjournals.org/cgi/content/full/3/7/1. Accessed January 31, 2008.
Virani SS, Nambi V. The role of lipoprotein-associated phospholipase A2 as a marker for atherosclerosis. Curr Atheroscler Rep. 2007;9:97-103.
Sjöström L, Narbro K, Sjöström CD, Karason K, Larsson B, Wedel H, et al; for the Swedish Obese Subjects Study. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med. 2007;357:741-752.
Adams TD, Gress RE, Smith SC, Halverson RC, Simper SC, Rosamond WD, et al. Long-term mortality after gastric bypass surgery. N Engl J Med. 2007;357:753-761.
The National Heart, Lung, and Blood Institute, and the North American Association for the Study of Obesity. The Practical Guide to the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. Bethesda, Md: National Institutes of Health; October 2000. NIH Publication Number 00-4084. Available at: http://209.85.173.104/search?q=cache:Dw1DtoWJIngJ:www.nhlbi.nih.gov/guidelines/obesity/prctgd_c.pdf+The+Practical+Guide+to+the+Identification,+Evaluation,+and+Treatment+of+Overweight+and+Obesity+in+Adults&hl=en&ct=clnk&cd=2&gl=us. Accessed January 28, 2008.
Buse JB, Ginsberg HN, Bakris GL, Clark NG, Costa F, Eckel R, et al; American Heart Association, American Diabetes Association. Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association. Diabetes Care. 2007;30:162-172. Available at: http://care.diabetesjournals.org/cgi/content/full/30/1/162. Accessed January 29, 2008.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-2497.
Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005;112:2735-2752. Available at: http://circ.ahajournals.org/cgi/content/full/112/17/2735 Accessed January 16, 2008.
Wadden TA, Berkowitz RI, Womble LG, Sarwer DB, Phelan S, Cato RK, et al. Randomized trial of lifestyle modification and pharmacotherapy for obesity. N Engl J Med. 2005;353:2111-2120. Available at: http://content.nejm.org/cgi/content/full/353/20/2111. Accessed January 29, 2008.
Li Z, Maglione M, Tu W, Arterburn D, Shugarman LR, Hilton L, et al. Meta-analysis: pharmacologic treatment of obesity. Ann Intern Med. 2005;142:532-546. Available at: http://www.annals.org/cgi/content/full/142/7/532. Accessed January 29, 2008.
Yanovski SZ, Yanovski JA. Obesity [review]. N Engl J Med. 2002;346:591-602.
James WP, Astrup A, Finer N, Hilsted J, Kopelman P, Rössner S, et al. Effect of sibutramine on weight maintenance after weight loss: a randomised trial. STORM Study Group. Sibutramine Trial of Obesity Reduction and Maintenance. Lancet. 2000;356:2119-2125.
James WP. The SCOUT study: risk-benefit profile of sibutramine in overweight high-risk cardiovascular patients. Eur Heart J. 2005;7(suppl L): L44-L48.
Torp-Pedersen C, Caterson I, Coutinho W, Finer N, Van Gaal L, Maggioni A, et al; on behalf of the SCOUT investigators. Cardiovascular responses to weight management and sibutramine in high-risk subjects: an analysis from the SCOUT trial. Eur Heart J. 2007;28:2915-2923. Available at: http://eurheartj.oxfordjournals.org/cgi/content/full/28/23/2915. Accessed January 29, 2008.
Torgerson JS, Hauptman J, Boldrin MN, Sjöström L. XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care. 2004;27:155-161. Available at: http://care.diabetesjournals.org/cgi/content/full/27/1/155. Accessed January 29, 2008.
Didangelos TP, Thanopoulou AK, Bousboulas SH, Sambanis CL, Athyros VG, Spanou EA,et al. The ORLIstat and CArdiovascular risk profile in patients with metabolic syndrome and type 2 DIAbetes (ORLICARDIA) study. Curr Med Res Opin. 2004;201 : 393-1401.
Pi-Sunyer FX, Aronne LJ, Heshmati HM, Rosenstock J; for the RIO-North America Study Group. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. JAMA. 2006;295:761-775.
Maggard MA, Shugarman LR, Suttorp M, Maglione M, Sugerman HJ, Livingston EH, et al. Meta-analysis: surgical treatment of obesity. Ann Intern Med. 2005;142:547-559. Available at: http://www.annals.org/cgi/content/full/142/7/547. Accessed January 29, 2008.
Buchwald H, Avidor Y, Braunwald E, Jensen MD, Pories W, Fahrbach K, et al. Bariatric surgery: a systematic review and meta-analysis. JAMA. 2004;292:1724-1737. Available at: http://jama.amaassn.org/cgi/content/full/292/14/1724. Accessed January 29, 2008.
Nguyen NT, Silver M, Robinson M, Needleman B, Hartley G, Cooney R, et al. Result of a national audit of bariatric surgery performed at academic centers: a 2004 University HealthSystem Consortium benchmarking project. Arch Surg. 2006;141:445-450. Available at: http://archsurg.amaassn.org/cgi/content/full/141/5/445. Accessed January 29, 2008.
Bardia A, Holtan SG, Slezak JM, Thompson WG. Diagnosis of obesity by primary care physicians and impact on obesity management. Mayo Clin Proc. 2007;82:927-932.
US Department of Health and Human Services. Reducing Tobacco Use: a Report of the Surgeon General. Atlanta, Ga: US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office of Smoking and Health; 2000. Available at: http://www.cdc.gov/tobacco/data_statistics/sgr/sgr_2000/sgr_tobacco_chap.htm. Accessed October 19, 2007.
Mercer SL, Green LW, Rosenthal AC, Husten CG, Khan LK, Dietz WH. Possible lessons from the tobacco experience for obesity control. Am J Clin Nutr. 2003;77(suppl):1073S-1082S. Available at: http://www.ajcn.org/cgi/content/full/77/4/1073S. Accessed January 29, 2008.
Figure 1.
Medical complications of obesity. (Sources: US Department of Health and Human Services. The Surgeon General's Call to Action to Prevent and Decrease Overweight and Obesity. Rockville, Md: US Department of Health and Human Services, Public Health Service, Office of the Surgeon General; 2001. Fontaine KR, Redden DT, Wang C, Westfall AO, Allison DB. Years of life lost due to obesity. JAMA. 2003;289:187-193. Malnick SDH, Knobler H. The medical complications of obesity. QJ Med.) 2006;99:565-579.
Figure 1.
Medical complications of obesity. (Sources: US Department of Health and Human Services. The Surgeon General's Call to Action to Prevent and Decrease Overweight and Obesity. Rockville, Md: US Department of Health and Human Services, Public Health Service, Office of the Surgeon General; 2001. Fontaine KR, Redden DT, Wang C, Westfall AO, Allison DB. Years of life lost due to obesity. JAMA. 2003;289:187-193. Malnick SDH, Knobler H. The medical complications of obesity. QJ Med.) 2006;99:565-579.
Figure 2.
Trends in prevalence of diabetes (includes gestational diabetes) in US adults. (Source: Centers for Disease Control and Prevention. Diabetes and Gestational Diabetes Trends Among Adults in the United States. Available at: www.cdc.gov/diabetes/statistics/maps. Accessed January 31, 2008.
Figure 2.
Trends in prevalence of diabetes (includes gestational diabetes) in US adults. (Source: Centers for Disease Control and Prevention. Diabetes and Gestational Diabetes Trends Among Adults in the United States. Available at: www.cdc.gov/diabetes/statistics/maps. Accessed January 31, 2008.
Figure 3.
Trends in prevalence of obesity in US adults. (Source: Centers for Disease Control and Prevention. US Obesity Trends 1985-2006. Available at: ww.cdc.gov/nccdphp/dnpa/obesity/trend/maps/. Accessed January 31, 2008.)
Figure 3.
Trends in prevalence of obesity in US adults. (Source: Centers for Disease Control and Prevention. US Obesity Trends 1985-2006. Available at: ww.cdc.gov/nccdphp/dnpa/obesity/trend/maps/. Accessed January 31, 2008.)
Figure 4.
Cardiometabolic actions of key adipokines produced by white adipose tissue. (Sources: Ahima RS. Adipose tissue as an endocrine organ. Obesity. 2006;14(suppl 5): 242S-249S. Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab. 2004;89:2548-2556. Ronti T, Lupattelli G, Mannarino E. The endocrine function of adipose tissue: an update. Clin Endocrinol. 2006;64:355-365. Hutley L, Prins JB. Fat as an endocrine organ: relationship to the metabolic syndrome. Am J Med Sci. 2005;330:280-289.)
Figure 4.
Cardiometabolic actions of key adipokines produced by white adipose tissue. (Sources: Ahima RS. Adipose tissue as an endocrine organ. Obesity. 2006;14(suppl 5): 242S-249S. Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab. 2004;89:2548-2556. Ronti T, Lupattelli G, Mannarino E. The endocrine function of adipose tissue: an update. Clin Endocrinol. 2006;64:355-365. Hutley L, Prins JB. Fat as an endocrine organ: relationship to the metabolic syndrome. Am J Med Sci. 2005;330:280-289.)
Figure 5.
Assessments that expert panel recommends be done after evaluating for obesity by measuring waist circumference.
Figure 5.
Assessments that expert panel recommends be done after evaluating for obesity by measuring waist circumference.
Figure 6.
Opportunities for future management of obesity suggested by the members of the expert panel participating in this roundtable discussion.
Figure 6.
Opportunities for future management of obesity suggested by the members of the expert panel participating in this roundtable discussion.