A. Health and Economic Costs
In 1973, and again in 1977, the John E. Fogarty International Center at the National Institutes of Health (NIH), as part of its preventive medicine series, sponsored two conferences that dealt with obesity as a public health problem; controversy was apparent regarding the cause-and-effect relationship between obesity and ill health [40, 41]. In 1985, an NIH Consensus Development Conference was held on the health implications of obesity. This conference provided important national recognition that obesity is a serious health condition that leads to increased morbidity and mortality. The Consensus Development Conference concluded that both prevention and treatment of obesity were medical priorities in the United States . In that conference, the terms ‘overweight’ and ‘obesity’ were defined as part of a continuum of increasing health risk.
In 1990, the Nation's health goals for the year 2000 were set forth with the release of Healthy People 2000 , in which a national goal to reduce the prevalence of overweight was articulated. In 1993, the Deputy Assistant Secretary for Health (J. Michael McGinnis) and the former Director of the Centers for Disease Control and Prevention (CDC) (William Foege) co-authored a journal article, “Actual Causes of Death in the U.S.” It concluded that a combination of dietary factors and sedentary activity patterns accounts for at least 300,000 deaths each year, and, obesity was a key contributor . In 1995, the Institute of Medicine issued a report that expressed concern about the growing prevalence of overweight and obesity in this country, and suggested ways to evaluate various weight loss and weight maintenance programs available to U.S. consumers .
1. Prevalence and Time Trends
Nationally representative U.S. health examination surveys, in which weight and height were measured in samples of the population, date back to 1960. Beginning with the Second National Health and Nutrition Examination Survey (NHANES II) (1976-1980), the definition of overweight that has been used to compare these epidemiologic surveys has been a statistical one that corresponded to the 85th percentile of body mass index (BMI) for men and women aged 20 through 29 years in NHANES II with no particular relation to a specific increase in disease risk . Adults in these surveys have been categorized as overweight with a BMI ≥ 27.8 kg/m2 for men and ≥ 27.3 kg/m2 for women . The rationale for using persons aged 20 to 29 years as the reference population is supported largely by the observation that the increases in body weight after age 29 that commonly occur with aging are attributable primarily to fat accumulation [46, 47]. However, the BMI levels used for the definition of overweight and obesity are somewhat arbitrary, since the relationship between body weight and disease risk is continuous with the exception of the extremely underweight: disease risk increases as weight increases.
Figure 1 depicts data from several NHANES surveys using the panel's definition of overweight as a BMI of 25 to 29.9 kg/m2 and of obesity as a BMI of ≥ 30 kg/m2. From 1960 to 1994, the prevalence of overweight increased slightly from 37.8 to 39.4 percent in men and from 23.6 to 24.7 percent in women (National Center for Health Statistics/CDC) . In men and women together, overweight increased from 30.5 to 32.0 percent . During the same time period, however, the prevalence of obesity increased from 10.4 to 19.9 percent in men and from 15.1 to 24.9 percent in women. In men and women together, obesity increased from 12.8 to 22.5 percent. Most of the increase occurred in the past decade. In addition to adults, obesity in U.S. children increased markedly as well  (see Appendix III) and, if unchecked, portends an even greater increase in adult obesity in the future.
Table II-1 shows the combined prevalence of overweight and obesity, defined as a BMI of ≥ 25.0 kg/m2, among persons aged 20 to 80 plus years, by age, race/ethnicity, and gender in the United States, 1960 to 1994 . The increase in overweight and obesity appears to have occurred among U.S. adults across all ages, genders, and racial/ethnic groups. The most recent NHANES III surveys, conducted from 1988-1994, reported that 59.4 percent of men and 50.7 percent of women in the United States are overweight or obese. The prevalence is much higher in non-Hispanic Black women (66.0 percent), in Mexican-American women (65.9 percent), and in Mexican-American men (63.9 percent).
Using the definition of obesity as a BMI of ≥ 30 kg/m2, Table II-2 shows that in the United States, 19.5 percent of men and 25.0 percent of women are obese . The prevalence of obesity is much higher in minority women, being 36.7 percent in non-Hispanic Black women and 33.3 percent in Mexican-American women.
2. Demographic Variations in Overweight and Obesity Prevalence
Although NHANES III data show that the prevalence of overweight and obesity is much higher in African-American and Mexican-American women than in white women or in men, these data provide ethnicity-specific estimates of overweight and obesity prevalence for only three racial-ethnic groups: non-Hispanic whites, non-Hispanic blacks, and Mexican-Americans. Examination survey data indicating a high overweight and obesity prevalence in other ethnic groups (e.g., for Puerto Ricans and Cuban-Americans) are available from the Hispanic HANES (HHANES) (1982-1984)  and for American Indians  and Pacific-Islander Americans , from smaller population-specific studies (see Appendix III). The prevalence of overweight and obesity is generally higher for men and women in racial-ethnic minority populations than in U.S. whites, with the exception of Asian-Americans, for whom overweight and obesity prevalence is lower than in the general population . In the 1982-1984 HHANES, the age-adjusted prevalence of a BMI of ≥ 27.3 in Puerto Rican women was 40 percent . The Strong Heart Study reported the average prevalence of overweight using BMI ≥ 27.8 or ≥ 27.3 for men and women, respectively, in three groups of American Indians studied during 1988-1989 as follows: in Arizona, 67 percent of the men and 80 percent of the women; in Oklahoma, 67 percent of the men and 71 percent of the women; and in South Dakota and North Dakota, 54 percent of the men and 66 percent of the women .
Women in the United States with low incomes or low education are more likely to be obese than those of higher socioeconomic status; the association of socioeconomic status with obesity is less consistent in men  (Appendix III). Obesity is less common after the age of 70 among both men and women, possibly due to a progressive decrease in BMI with increasing age past the fifth decade or to an excess in mortality associated with increasing BMI in the presence of increasing age .
3. Economic Costs of Overweight and Obesity
Alarm about the increasing prevalence of overweight and obesity in the United States in recent years [54, 55] centers on the link between obesity and increased health risks [42, 56], which translates into increased medical care and disability costs [46, 57]. The total cost attributable to obesity amounted to $99.2 billion in 1995. Approximately $51.6 billion of these dollars were direct medical costs associated with diseases attributable to obesity. The direct costs also associated with obesity represent 5.7 percent of the national health expenditure within the United States . The indirect costs attributable to obesity are $47.6 billion and are comparable to the economic costs of cigarette smoking [58, 59]. Indirect costs represent the value of lost output caused by morbidity and mortality, and may have a greater impact than direct costs at the personal and societal levels .
Although a comprehensive cost analysis of obesity is beyond the scope of this panel, a systematic review of the literature identified studies estimating the current economic burden of obesity in several Western countries [57, 60–63]. Published estimates of the economic costs of obesity such as those noted above use the prevalence-based approach, assuming that obesity is causally related to a range of chronic illnesses. Estimating the economic benefits of weight loss requires details of long-term weight maintenance and the time course of risk reduction following weight loss, and ultimately must also consider the costs of treatment to reduce weight.
B. Prevention of Overweight and Obesity
Prevention of overweight and obesity is as important as treatment. Prevention includes primary prevention of overweight or obesity itself, secondary prevention or avoidance of weight regain following weight loss, and prevention of further weight increases in obese individuals unable to lose weight [44 , 64].
National and international observational data suggest that environmental and behavioral factors are likely to be important in the tendency of individuals within and between populations to be obese during childhood or to gain weight progressively with age during adulthood . These factors are also influenced by the genetic makeup of individuals. There has been a paucity of intervention research to demonstrate how these factors can be manipulated to prevent obesity . In two community studies, namely the Minnesota Heart Health Program and the Stanford Five City Study, multifaceted weight loss and weight control programs within the community were not associated with prevention of weight gain in longitudinally followed cohorts . In another community study, the Pawtucket Heart Health Program, BMI levels did not change in the intervention cities while they increased in the comparison cities . One obesity prevention study of American Indian children who are at high risk of becoming obese is under way . Otherwise, the only long-term report suggesting an effective approach to obesity prevention is from follow-up of obese children in an experimental study in which they had been treated with or without a family-oriented treatment program. Long-term follow-up (10 years) of these children supported the importance of family involvement in reducing the progression of obesity . One population-based randomized controlled pilot study of obesity prevention suggests that programs for weight gain prevention are feasible and effective in adults . Another study in China has shown that the prevention of weight gain through diet, physical activity, and their combination can help prevent diabetes .
It has been suggested that primary prevention of obesity should include environmentally based strategies that address major societal contributors to over-consumption of calories and inadequate physical activity such as food marketing practices, transportation patterns, and lack of opportunities for physical activity during the workday [71, 72]. People at lower socioeconomic levels living in urban areas also lack access to physical activity sites. Such strategies will be essential for effective initial and long-term prevention of obesity for large numbers of individuals and for the community at large. Research is needed to clarify the role of societal policies, procedures, laws, and other factors that serve as disincentives to lifelong caloric balance. The importance of obesity prevention needs to be brought to the attention of health care payors and practitioners, employers, educators, and public officials as an important priority to be addressed in policies, programs, and direct services to individuals and families. The development and implementation of appropriate policies and programs will require outcomes research that identifies effective weight gain prevention approaches. These programs must be useful for multiple settings, including health care facilities, schools, worksites, community and religious institutions, and be applicable to a broad population. In the end, efforts should be made to make the general public more aware of the need to prevent overweight and obesity.
Efforts to understand the genetic, developmental, environmental, and behavioral underpinnings of obesity and to mount successful prevention strategies are particularly critical for populations in which overweight and obesity and related health problems such as diabetes are disproportionately prevalent; for example, women in lower socioeconomic groups and women and sometimes men in many racial/ethnic minority populations as described in Chapter 2.A.2 of this report. Public health approaches for preventing obesity, that is, approaches designed to reduce the difficulty for any given individual of adopting healthful eating and activity patterns, will particularly benefit the socially disadvantaged, who—compared to the more advantaged— may have less access to preventive health services and fewer feasible options for making changes in their daily routines and lifestyles [73–75].
Primary care practitioners are an important element in preventing and managing obesity in the United States. Prevention of overweight and obesity in primary care settings is compatible with efforts to prevent their health consequences, through control of dyslipidemia, high blood pressure, and type 2 diabetes. Thus, both the quality and quantity of life may be enhanced through preventive strategies. As detailed elsewhere in this report, high blood pressure, high blood cholesterol, and type 2 diabetes should be aggressively treated in overweight patients and may be treated prior to and in conjunction with weight loss.
C. Health Risks of Overweight and Obesity
Above a BMI of 20 kg/m2 , morbidity for a number of health conditions increases as BMI increases. Higher morbidity in association with overweight and obesity has been observed for hypertension [2–6, 76–80], type 2 diabetes [7, 8, 10, 81, 82, 84–89], coronary heart disease (CHD) [11, 42, 86, 88, 90], stroke [11–13], gallbladder disease [14, 15], osteoarthritis [16–18, 91–95], sleep apnea and respiratory problems [21, 96–98] and some types of cancer (endometrial, breast, prostate, and colon) [107–115]. Obesity is also associated with complications of pregnancy, menstrual irregularities, hirsutism, stress incontinence, and psychological disorders (depression) [112, 116–128].
The nature of obesity-related health risks is similar in all populations, although the specific level of risk associated with a given level of overweight or obesity may vary with race/ethnicity, and also with age, gender, and societal conditions. For example, the absolute risk of morbidity in chronic conditions such as CHD is highest in the aged population, while the relative risk of having CHD in obese versus nonobese individuals is highest in the middle adult years [129–131]. A high prevalence of diabetes mellitus in association with obesity is observed consistently across races/ethnicities, while the relative prevalence of hypertension and CHD in obese versus nonobese populations varies between groups.
The health risks of overweight and obesity are briefly described below:
Data from NHANES III show that the age-adjusted prevalence of high blood pressure increases progressively with higher levels of BMI in men and women (Figure 2) . High blood pressure is defined as mean systolic blood pressure ≥ 140 mm Hg, or mean diastolic blood pressure ≥ 90 mm Hg, or currently taking antihypertensive medication. The prevalence of high blood pressure in adults with BMI ≥ 30 is 38.4 percent for men and 32.2 percent for women, respectively, compared with 18.2 percent for men and 16.5 percent for women with BMI < 25, a relative risk of 2.1 and 1.9 for men and women, respectively. The direct and independent association between blood pressure and BMI or weight has been shown in numerous cross-sectional studies [3–5], including the large international study of salt (INTERSALT) carried out in more than 10,000 men and women . INTERSALT reported that a 10 kg (22 lb) higher body weight is associated with 3.0 mm Hg higher systolic and 2.3 mm Hg higher diastolic blood pressure . These differences in blood pressure translate into an estimated 12 percent increased risk for CHD and 24 percent increased risk for stroke . Positive associations have also been shown in prospective studies [76–80].
Obesity and hypertension are co-morbid risk factors for the development of cardiovascular disease. The pathophysiology underlying the development of hypertension associated with obesity includes sodium retention and associated increases in vascular resistance, blood volume, and cardiac output. These cardiovascular abnormalties associated with obesity are believed to be related to a combination of increased sodium retention, increased sympathetic nervous system activity, alterations of the renin-angiotensin system and insulin resistance. The precise mechanism whereby weight loss results in a decrease in blood pressure is unknown. However, it is known that weight loss is associated with a reduction in vascular resistance, total blood volume and cardiac output, an improvement in insulin resistance, a reduction in sympathetic nervous system activity, and suppression of the activity of the renin angiotensin aldosterone system [764–769].
1.b. Dyslipidemia, manifested by
High total cholesterol
The relationship of the age-adjusted prevalence of high total cholesterol, defined as ≥ 240 mg/dL (6.21 mmol/L), to BMI from NHANES III is shown in Figure 3 . At each BMI level, the prevalence of high blood cholesterol is greater in women than in men. In a smaller sample, higher body weight is associated with higher levels of total serum cholesterol in both men  and women  at levels of BMI > 25. Several large longitudinal studies also provide evidence that overweight, obesity and weight gain are associated with increased cholesterol levels [135–137]. In women, the incidence of hypercholesterolemia also increases with increasing BMI . In addition, the pattern of fat distribution appears to affect cholesterol levels independently of total weight. Total cholesterol levels are usually higher in persons with predominant abdominal obesity, defined as a waist-to-hip circumference ratio of ≥ 0.8 for women and ≥ 1.0 for men .
The strong association of triglyceride levels with BMI has been shown in both cross-sectional and longitudinal studies, for both sexes and all age groups [133, 134, 140, 141]. In three adult age groups, namely 20 to 44 years, 45 to 59 years, and 60 to 74 years, higher levels of BMI, ranging from 21 or less to more than 30, have been associated with increasing triglyceride levels; the difference in triglycerides ranged from 61 to 65 mg/dL (0.68 to 0.74 mmol/L) in women  and 62 to 118 mg/dL (0.70 to 1.33 mmol/L) in men .
Low high-density lipoprotein cholesterol
The age-adjusted prevalence of low high-density lipoprotein (HDL)-cholesterol in relation to BMI levels, based on NHANES III data, is shown in Figure 4 . HDL-cholesterol levels at all ages and weights are lower in men than in women. Although low HDL-cholesterol in this study was defined as < 35 mg/dL (0.91 mmol/L) in men and < 45 mg/dL (1.16 mmol/L) in women , the panel accepts the definition of low HDL-cholesterol as < 35 mg/dL for men and women used by the National Cholesterol Education Program's Second Report of the Expert Panel on the Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II Report) . Cross-sectional studies have reported that HDL-cholesterol levels are lower in men and women with higher BMI [143, 144]. Longitudinal studies have found that changes in BMI are associated with changes in HDL-cholesterol. A BMI change of 1 unit is associated with an HDL-cholesterol change of 1.1 mg/dL for young adult men and an HDL-cholesterol change of 0.69 mg/dL for young adult women .
Normal to elevated low-density lipoprotein cholesterol
The link between total serum cholesterol and CHD is largely due to low-density lipoprotein (LDL). A high-risk LDL-cholesterol is defined as a serum concentration of ≥ 160 mg/dL. This lipoprotein is the predominant atherogenic lipoprotein and is therefore the primary target of cholesterol-lowering therapy. Cross-sectional data suggest that LDL-cholesterol levels are higher by 10 to 20 mg/dL in relation to a 10 unit difference in BMI, from levels of 20 to 30 kg/m2 [133, 134]. According to extensive epidemiological data, a 10 mg/dL rise in LDL-cholesterol corresponds to approximately a 10 percent increase in CHD risk over a period of 5 to 10 years .
Small, dense low-density lipoprotein particles
Few large-scale epidemiological data are available on small, dense LDL particles [147–149]. Clinical studies have shown that small, dense LDL particles are particularly atherogenic and tend to be present in greater proportion in hypertriglyceridemic patients with insulin resistance syndrome associated with abdominal obesity [148–152].
1.c. Diabetes Mellitus
The increased risk of diabetes as weight increases has been shown by prospective studies in Norway , the United States , Sweden , and Israel . More recently, the Nurses' Health Study, using data based on self-reported weights, found that the risk of developing type 2 diabetes increases as BMI increases from a BMI as low as 22 . Since women in particular tend to under- report weight, the actual BMI values associated with these risks are likely to be higher than the Nurses' Health Study data would suggest. An association between type 2 diabetes and increasing relative weight is also observed in populations at high risk for obesity and diabetes, such as in American Indians [153, 154]. In recent studies, the development of type 2 diabetes has been found to be associated with weight gain after age 18 in both men  and women . The relative risk of diabetes increases by approximately 25 percent for each additional unit of BMI over 22 kg/m2 . In addition, in a prospective study representative of the U.S. population, it was recently estimated that 27 percent of new cases of diabetes was attributable to weight gain in adulthood of 5 kg (11 lb) or more . Both cross-sectional [85–87] and longitudinal studies [82, 88, 89] show that abdominal obesity is a major risk factor for type 2 diabetes [82, 87].
1.d. Coronary Heart Disease
Observational studies have shown that overweight, obesity, and excess abdominal fat are directly related to cardiovascular risk factors, including high levels of total cholesterol, LDL-cholesterol, triglycerides, blood pressure, fibrinogen and insulin , and low levels of HDL-cholesterol . Plasminogen activator inhibitor-1 causing impaired fibrinolytic activity is elevated in persons with abdominal obesity . Over- weight, obesity, and abdominal fat are also associated with increased morbidity and mortality from CHD [11, 42, 155–161].
Recent studies have shown that the risks of nonfatal myocardial infarction and CHD death increase with increasing levels of BMI. Risks are lowest in men and women with BMIs of 22 or less and increase with even modest elevations of BMI. In the Nurses' Health Study, which controlled for age, smoking, parental history of CHD, menopausal status, and hormone use, relative risks for CHD were twice as high at BMIs of 25 to 28.9, and more than three times as high at BMIs of 29 or greater, compared with BMIs of less than 21 . Weight gains of 5 to 8 kg (11 to 17.6 lb) increased CHD risk (nonfatal myocardial infarction and CHD death) by 25 percent, and weight gains of 20 kg (44 lb) or more increased risk more than 2.5 times in comparison with women whose weight was stable within a range of 5 kg (11 lb) . In British men, CHD incidence increased at BMIs above 22 and an increase of 1 BMI unit was associated with a 10 percent increase in the rate of coronary events . Similar relationships between increasing BMI and CHD risk have been shown in Finnish, Swedish, Japanese, and U.S. populations [90, 163, 164].
A relationship between obesity and CHD has not always been found. Two reasons may account for this: the first is an inappropriate controlling for cholesterol, blood pressure, diabetes, and other risk factors in statistical analysis; and the second is that there was not an adequate control for the confounding effect of cigarette smoking on weight . People who smoke often have a lower body weight but more CHD.
1.e. Congestive Heart Failure
Overweight and obesity have been identified as important and independent risk factors for congestive heart failure (CHF) in a number of studies, including the Framingham Heart Study [11, 165–169]. CHF is a frequent complication of severe obesity and a major cause of death; duration of the obesity is a strong predictor of CHF . Since hypertension and type 2 diabetes are positively associated with increasing weight, the coexistence of these conditions facilitates the development of CHF . Data from the Bogalusa Heart Study demonstrate that excess weight may lead to acquisition of left ventricular mass beyond that expected from normal growth . Obesity can result in alterations in cardiac structure and function even in the absence of systemic hypertension or underlying heart disease. Ventricular dilatation and eccentric hypertrophy may result from elevated total blood volume and high cardiac output. Diastolic dysfunction from eccentric hypertrophy and systolic dysfunction from excessive wall stress result in so-called “obesity cardiomyopathy” [172, 173]. The sleep/apnea obesity hyperventilation syndrome occurs in 5 percent of severely obese individuals, and is potentially life-threatening. Extreme hypoxemia induced by obstructive sleep apnea syndrome may result in heart failure in the absence of cardiac dysfunction .
The relationship of cerebrovascular disease to obesity and overweight has not been as well studied as the relationship to CHD. A report from the Framingham Heart Study suggested that overweight might contribute to the risk of stroke, independent of the known association of hypertension and diabetes with stroke . More recently published reports [12, 13] are based on larger samples and delineate the importance of stroke subtypes in assessing these relationships. They also attempt to capture all stroke events, whether fatal or nonfatal. These studies suggest distinct risk factors for ischemic stroke as compared to hemorrhagic stroke, and found overweight to be associated with the former, but not the latter. This may explain why studies that use only fatal stroke outcomes (and thus overrepresent hemorrhagic strokes) show only weak relationships between overweight and stroke. These recent prospective studies demonstrate that the risk of stroke shows a graded increase as BMI rises. For example, ischemic stroke risk is 75 percent higher in women with BMI > 27, and 137 percent higher in women with a BMI > 32, compared with women having a BMI < 21 .
The risk of gallstones increases with adult weight. Risk of either gallstones or cholecystectomy is as high as 20 per 1,000 women per year when BMI is above 40, compared with 3 per 1,000 among women with BMI < 24 . According to NHANES III data, the prevalence of gallstone disease among women increased from 9.4 percent in the first quartile of BMI to 25.5 percent in the fourth quartile of BMI. Among men, the prevalence of gallstone disease increased from 4.6 percent in the first quartile of BMI to 10.8 percent in the fourth quartile of BMI .
Individuals who are overweight or obese increase their risk for the development of osteoarthritis [16–18, 91, 92]. The association between increased weight and the risk for development of knee osteoarthritis is stronger in women than in men . In a study of twin middle-aged women, it was estimated that for every kilogram increase of weight, the risk of developing osteoarthritis increases by 9 to 13 percent. The twins with knee osteoarthritis were generally 3 to 5 kg (6.6 to 11 lb) heavier than the co-twin with no disease . An increase in weight is significantly associated with increased pain in weight-bearing joints . There is no evidence that the development of osteoarthritis leads to the subsequent onset of obesity . A decrease in BMI of 2 units or more during a 10-year period decreased the odds for developing knee osteoarthritis by more than 50 percent; weight gain was associated with a slight increase in risk .
A randomized controlled trial of 6 months' duration examined the effect of weight loss on clinical improvement in patients with osteoarthritis . Patients taking phentermine had an average weight loss of 12.6 percent after 6 months while the control group had an average weight loss of 9.2 percent. There was improvement in pain-free range of motion and a decrease in analgesic use in association with weight loss; patients with knee disease showed a stronger association than those with hip disease. Similarly, improvement of joint pain was observed in individuals who had undergone gastric stapling, resulting in an average weight loss of 45 kg (99 lb) [94, 95].
1.i. Sleep Apnea
Obesity, particularly upper body obesity, is a risk factor for sleep apnea and has been shown to be related to its severity [19, 20]. The major pathophysiologic consequences of severe sleep apnea include arterial hypoxemia, recurrent arousals from sleep, increased sympathetic tone, pulmonary and systemic hypertension, and cardiac arrhythmias . Most people with sleep apnea have a BMI > 30 [96, 97]. Large neck girth in both men and women who snore is highly predictive of sleep apnea. In general, men whose neck circumference is 17 inches or greater and women whose neck circumference is 16 inches or greater are at higher risk for sleep apnea . Additional information on sleep apnea is included as Appendix IV.
Many studies have found a positive relation between obesity and colon cancer in men but a weaker association in women [8, 22–24, 99–106]. More recent data from the Nurses' Health Study suggest that the relationship between obesity and colon cancer in women may be similar to that seen in men. Twice as many women with a BMI of > 29 kg/m2 had distal colon cancer as women with a BMI < 21 kg/m2 . In men, the relationship between obesity and total colon cancer was weaker than that for distal colon cancer.
Other data from the Nurses' Health Study show a substantially stronger relationship between waist-to-hip ratio and the prevalence of colon polyps on sigmoidoscopy, than with BMI alone . Even among leaner women, a high waist-to-hip ratio is also associated with significantly increased risk of colon polyps .
Epidemiologic studies consistently show that obesity is directly related to mortality from breast cancer, predominantly in postmenopausal women , but inversely related to the incidence of premenopausal breast cancer [109–112]. Ten or more years after menopause, the premenopausal “benefit” of obesity has dissipated . Among postmenopausal women, peripheral fat is the primary source of estrogens, the major modifiable risk factor for postmenopausal breast cancer. This crossover in the relationship of obesity with breast cancer, pre- and postmenopausally, complicates prevention messages for this common female cancer. Recent data from the Nurses' Health Study, however, show that adult weight gain is positively related to risk of postmenopausal breast cancer. This relation is seen most clearly among women who do not use postmenopausal hormones. A gain of more than 20 lb from age 18 to midlife doubles a woman's risk of breast cancer. Even modest weight gains are positively related to risk of postmenopausal cancer .
Obesity increases the risk of endometrial cancer. The risk is three times higher among obese women (BMI ≥ 30 kg/m2) compared to normal-weight women . However, the absolute risk of this condition is low when compared to breast cancer, heart disease, and diabetes. Adult weight gain is also related to increased risk .
Obesity is related to the risk of gallbladder cancer, particularly among women . Using a weight index of 100 as the average weight with a corresponding mortality ratio of 1.0 for the cohort, mortality ratios were 1.16 at a weight index of 120 to 129, 1.22 at 130 to 139, and 1.53 at ≥140.
1.k. Obesity and Women's Reproductive Health
Menstrual Function and Fertility
Obesity in premenopausal women is associated with menstrual irregularity and amenorrhea [112, 116]. As part of the Nurses' Health Study, a case control study suggested that the greater the BMI at age 18 years, even at levels lower than those considered obese, the greater the risk of subsequent ovulatory infertility . The most prominent condition associated with abdominal obesity is polycystic ovarian syndrome , a combination of infertility, menstrual disturbances, hirsutism, abdominal hyperandrogenism, and anovulation. This syndrome is strongly associated with hyperinsulinemia and insulin resistance .
Pregnancy can result in excessive weight gain and retention. The 1988 National Maternal and Infant Survey observed that 41.6 percent of women reported retaining ≥ 9 lb of their gained weight during pregnancy, with 33.8 percent reporting ≥14 lb of retained weight gain . The retained weight gain associated with pregnancy was corroborated by the study of Coronary Artery Risk Development in Young Adults (CARDIA). As a result of their first pregnancy, both black and white young women had a sustained weight gain of 2 to 3 kg (4.4 to 6.6 lb) of body weight . Another study on a national cohort of women followed for 10 years reported that weight gain associated with childbearing ranged from 1.7 kg (3.7 lb) for those having one live birth during the study to 2.2 kg (4.9 lb) for those having three . In addition, higher prepregnancy weights have been shown to increase the risk of late fetal deaths .
Obesity during pregnancy is associated with increased morbidity for both the mother and the child. A tenfold increase in the prevalence of hypertension and a 10 percent incidence of gestational diabetes have been reported in obese pregnant women . Obesity also is associated with difficulties in managing labor and delivery, leading to a higher rate of induction and primary Caesarean section. Risks associated with anesthesia are higher in obese women, as there is greater tendency toward hypoxemia and greater technical difficulty in administering local or general anesthesia . Finally, obesity during pregnancy is associated with an increased risk of congenital malformations, particularly of neural tube defects .
A certain amount of weight gain during pregnancy is desirable. The fetus itself, expanded blood volume, uterine enlargement, breast tissue growth, and other products of conception generate an estimated 13 to 17 lb of extra weight. Weight gain beyond this, however, is predominantly maternal adipose tissue. It is this fat tissue that, in large measure, accounts for the postpartum retention of weight gained during pregnancy. In turn, this retention reflects a postpartum energy balance that does not lead to catabolism of the gained adipose tissue. In part, this may reflect reduced energy expenditure through decreased physical activity, even while caring for young children, but it may also reflect retention of the pattern of increased caloric intake acquired during pregnancy .
One difficulty in developing recommendations of optimal weight gain during pregnancy relates to the health of the infants. A balance must be achieved between high-birth-weight infants who may pose problems during delivery and who may face a higher rate of Caesarean sections and low-birth-weight infants who face a higher infant mortality rate . However, data from the Pregnancy Nutrition Surveillance System from the CDC showed that very overweight women would benefit from a reduced weight gain during pregnancy to help reduce the risk for high-birth-weight infants .
The 1990 Institute of Medicine report made recommendations concerning maternal weight gain . It recommended that each woman have her BMI measured and recorded at the time of entry into prenatal care. For women with a BMI of less than 20, the target weight gain should be 0.5 kg (1.1 lb) of weight gain per week during the second and third trimester. For a woman whose BMI is greater than 26, the weight gain target is 0.3 kg (0.7 lb) per week during the last two trimesters.
Women who are overweight or obese at the onset of pregnancy are advised to gain less total weight during the pregnancy (see box above) .
1.l. Psychosocial Aspects of Overweight and Obesity
A number of reviews have been published on the psychosocial aspects of obesity [124–128, 183]. The specific topics that will be reviewed here include social stigmatization, psychopathology, binge eating, and body image perceptions.
In American and other Westernized societies there are powerful messages that people, especially women, should be thin, and that to be fat is a sign of poor self-control [125, 126, 128, 184, 185]. Negative attitudes about the obese have been reported in children and adults [186–191], in health care professionals [192–194], and in the overweight themselves [195, 196].
People's negative attitudes toward the obese often translate into discrimination in employment opportunities [197–199], college acceptance , less financial aid from their parents in paying for college [195, 201], job earnings , rental availabilities , and opportunities for marriage .
Much of the research on the social stigma of obesity has suffered from methodological limitations. For example, a number of the early studies relied on line drawings rather than more lifelike representations of obese people and on checklists that forced one to make YES or NO choices. More importantly, there has been a lack of research that has looked at the impact of obesity in the context of other variables, such as physical attractiveness, the situational context, and the degree of obesity [184, 185]. In addition, social stigma toward the obese has primarily been assessed among white individuals. There is some evidence that members of other racial and ethnic groups are less harsh in their evaluation of obese persons. One study assessed 213 Puerto Rican immigrants to the United States, and found a wide range of acceptable weights among them . Crandall found that Mexican students were significantly less concerned about their own weight and were more accepting of other obese people than were U.S. students . In addition, the degree of acceptance of obesity among people of lower education and income has not been well studied. Thus, these data are very incomplete with respect to racial and ethnic groups other than whites.
Psychopathology and Obesity
Research relating obesity to psychological disorders and emotional distress is based on community studies and clinical studies of patients seeking treatment. In general, community-based studies in the United States have not found significant differences in psychological status between the obese and nonobese [126, 183, 207, 208]. However, several recent European studies in general populations do suggest a relationship between obesity and emotional problems [209–211]. Thus, it may be premature to state that there is no association between obesity and psychopathology or emotional distress in the general population. More focused, hypothesis-driven, and long-term studies are needed [127, 212].
Overweight people seeking weight loss treatment may, in clinic settings, show emotional disturbances [213–215]. In a review of dieting and depression, there was a high incidence of emotional illness symptoms in outpatients treated for obesity . However, several factors influenced these emotional responses, including childhood onset versus adult onset of obesity (those with childhood onset obesity appear more vulnerable). Another study that compared different eating disorder groups found that obese patients seeking treatment showed considerable psychopathology, most prominently mild to severe depression . Sixty-two percent of the obese group seeking treatment showed clinically significant elevations on the depression subscale of the Minnesota Multiphasic Personality Inventory, and 37 percent of this same group showed a score of 20 or higher (indicating clinical depression) on the Beck Depression Inventory. Focusing on depression was considered an important component of the weight loss program. Another study compared obese people who had not sought treatment to an obese group that had sought treatment in a professional, hospital-based program, and to normal weight controls . Again, obese individuals seeking treatment reported more psychopathology and binge eating compared to the other groups. Both obese groups reported more symptoms of distress than did normal weight controls. The authors suggest that the obese population is not a homogenous group, and thus, may not respond in the same way to standardized treatment programs. In particular, obese individuals seeking treatment in clinic settings are more likely than obese individuals not seeking treatment and normal controls to report more psychopathology and binge eating.
Binge Eating Disorder
Binge eating disorder (BED) is characterized by eating larger amounts of food than most people would eat in a discrete time period (e.g., 2 hours) with a sense of lack of control during these episodes . It is estimated to occur in 20 to 50 percent of individuals who seek specialized obesity treatment [216–218]. In community-based samples, the prevalence is estimated to be approximately 2 percent . Comparisons have been made between BED and bulimia nervosa (BN), an eating disorder characterized by recurrent and persistent binge eating, accompanied by the regular use of behaviors such as vomiting, fasting, or using laxatives. Studies comparing normal weight individuals who have BN with obese BED individuals have found that obese binge eaters are less likely to demonstrate dietary restraint and show few if any adverse reactions to moderate or severe dieting. Most obese binge eaters do not engage in inappropriate compensatory behaviors such as purging . Compared with BN, the demographic distribution of BED is broader with respect to age, gender, and race [218, 219, 221–225] while data suggest that BED is as common in African-American women as in white women . The difference between BED and BN is dramatic regarding gender. Very few men have BN , whereas the distribution is close to equal in BED [225, 228, 229].
Compared to obese nonbingers, obese individuals with BED tend to be heavier , report greater psychological distress, and are more likely to have experienced a psychiatric illness (especially affective disorders) [225, 231–236]. They also report an earlier onset of obesity and a greater percentage of their lifetime on a diet [237, 238]. Some studies have shown histories of greater weight fluctuation or weight cycling in obese binge eaters compared with nonbingers [219, 237, 238], but others have not . These individuals are also more likely than nonbinging obese people to drop out of behavioral weight loss programs , and to regain weight more quickly [220, 233, 240].
Critics of behavioral treatment of obesity have argued that caloric restriction may cause or contribute to the episodes of binge eating and BN . Three studies have tested this hypothesis [218, 242, 243]. Neither moderate nor severe caloric restriction exacerbated binge eating. All three studies showed that weight control treatment featuring caloric restriction significantly reduced the frequency of binge eating in these patients.
Body image is defined as the perception of one's own body size and appearance and the emotional response to this perception [183, 244]. Inaccurate perception of body size or proportion and negative emotional reactions to size perceptions contribute to poor body image. Obese individuals, especially women, tend to overestimate their body size [245–249].
People at greater risk for a poor body image are binge eaters, women, those who were obese during adolescence or with early onset of obesity, and those with emotional disturbances [127, 235, 244, 250–253]. It is no surprise, then, that in some groups of obese persons, these individuals are more dissatisfied and preoccupied with their physical appearance, and avoid more social situations due to their appearance [254, 255]. Body image dissatisfaction and the desire to improve physical appearance often drives individuals to seek weight loss. However, obese persons seeking weight reduction must come to terms with real limits in their biological and behavioral capacities to lose weight. Otherwise, weight loss attempts may only intensify the sense of failure and struggle that is already present among many obese individuals. For this reason, psychosocial interventions which incorporate strategies to improve body image may be helpful for those who want to lose weight and are very concerned about their physical appearance. A review of body image interventions in obese persons can be found in Rosen (1996) .
Body image perceptions of individuals in various ethnic and racial groups may be different, on average, from those of the mainstream culture. There may be a similar range of attitudes but on a different scale; for example, it may take a much greater degree of overweight to elicit negative reactions . Differences in body image and weight-related concerns between black and white girls and women have been observed . In general, black girls and women report: less social pressure to be slim [258–260], fewer incidences of weight-related discrimination , less weight and body dissatisfaction, and greater acceptance of overweight than their white counterparts [259, 262–266]. College-age black women report less concern and fear about fatness, less drive to be thin, and less concern about dieting than do college-age white women . In addition, black women may ascribe some positive qualities to being large, such as having stamina, strength, and solidity, and are less likely to link body size to health than white women. Black elementary school and high school girls were more likely to be trying to gain weight [268, 269] and less likely to be trying to lose weight as compared to white girls . Because of the above, it is possible that weight control initiatives may elicit different reactions from black and white women. Less is known about the relationship between obesity and body image disturbance in other racial and ethnic groups .
2. Overweight/Obesity and Morbidity in Minority Populations
The data on overweight and obesity in minority populations include men and women across a wide age range and geographic area. Relevant studies increasingly consist of well-designed, population-based surveys and longitudinal studies. These studies have standardized, objective measurements of overweight and obesity and risk factors or disease outcomes. There is now a wealth of evidence to demonstrate that overweight and obesity incidence (both generalized and abdominal) predisposes to chronic diseases in racial/ethnic minority populations as it does in whites, though the absolute risk may differ [51–52, 271–284]. Indications for treatment of overweight and obesity in minority populations are, therefore, the same as those for non-Hispanic whites. Apparent differences in the strength of association between obesity and disease in various populations are not necessarily relevant to individuals in clinical settings, and obesity should be treated in any situation in which excess weight is associated with an observable or probable risk of morbidity. In addition, from a public health perspective, the need for obesity prevention and treatment is particularly pressing in racial/ethnic minority populations because of the high proportion of overweight and obese persons in many such populations.
3. Obesity and Mortality
As stated in the introduction to the guidelines, in the majority of epidemiologic studies, mortality begins to increase with BMIs above 25 kg/m2 [28–32]. The increase in mortality generally tends to be modest until a BMI of 30 kg/m2 is reached [28, 29, 31, 32]. For persons with a BMI of 30 kg/m2 or above, mortality rates from all causes, and especially from cardiovascular disease, are generally increased by 50 to 100 percent above that of persons with BMIs in the range of 20 to 25 kg/m2 [28, 31, 32]. Three aspects of the association between obesity and mortality remain unresolved:
3.a. Association of Body Mass Index With Mortality
Many of the observational epidemiologic studies of BMI and mortality have reported a ‘U-’ or ‘J-shaped’ relationship between BMI and mortality . Mortality rates are elevated in persons with low BMI (usually below 20) as well as in persons with high BMI [28, 31, 32]. In some studies, adjustment for factors that potentially confound the relationship between BMI and mortality, such as smoking status and pre-existing illness, tends to reduce the upturn in mortality rate at low BMI , but in a meta-analysis the higher mortality at low BMIs was not eliminated after adjustment for confounding factors . It is unclear whether the elevated mortality observed at low BMI is due to an artifact of incomplete control for confounding factors , inadequate body fat and/or inadequate body protein stores that result from unintentional weight loss , or individual genetic factors. Currently, there is no evidence that intentional weight gain in persons with low BMIs will lead to a reduction in mortality.
3.b. Association of Body Mass Index With Mortality in Older Adults
Many of the observational epidemiologic studies suggest that the relationship between BMI and mortality weakens with increasing age, especially among persons aged 75 and above [287–290]. Several factors have been proposed to explain this observation. Older adults are more likely than younger adults to have diseases that both increase mortality and cause weight loss leading to lower body weight [291–293]. In addition, as people age, they tend to have larger waist circumferences that increase their risk of mortality even at lower BMIs . Also, weight in middle age is positively related to risk of mortality in old age . The impact of smoking on body weight and mortality is likely to be much stronger in older adults because of the cumulative health effects of smoking .
BMI, which is an indirect estimate of adiposity, may underestimate adiposity in older adults whose BMI is similar to younger adults . It is also possible that persons most sensitive to the adverse health effects of obesity are more likely to have died before reaching older ages, resulting in older cohorts that are more “resistant” to the health effects of obesity. Recently, a 20-year prospective study of a nationally representative sample of U.S. adults aged 55 to 74 years suggested that lowest mortality occurs in the BMI range of 25 to 30 [297 298]. After adjusting for smoking status and pre-existing illness, lowest mortality occurred at a BMI of 24.5 in white men, 26.5 in white women, 27.0 in black men, and 29.8 in black women (see commentary on older adults on pages 90–91).
3.c. Association of Body Mass Index With Mortality in Ethnic Minorities
The levels of BMI associated with increased mortality are based on epidemiological studies of primarily white populations. The interest in confirming the association between BMI and mortality in other racial/ethnic groups stems partly from observations that lower-than-average total mortality has been observed among some populations with a high BMI level , and partly from observations that within certain populations there appears to be no effect of obesity at all or at the BMI levels that are associated with higher mortality in whites.
Three small cohort studies of narrowly defined populations of African-Americans failed to show the expected association of BMI and mortality based on data from white populations [300–303]. Although the shape of the association of BMI and mortality in two large, representative U.S. data sets (the National Health and Nutrition Examination Follow-up Study and the National Health Interview Survey) is similar for black and white males and females , the BMI-related increase in risk begins at a 1 to 3 kg/m2 higher BMI level for blacks than for whites. For example, in the National Health and Nutrition Examination Follow-up Survey, the estimated BMI associated with minimum mortality was 27.1 for black men and 26.8 for black women, compared with 24.8 and 24.3, respectively, for white men and women. On the basis of these data, the use of the cutpoint of BMI ≥ 30 kg/m2 for defining obesity is clearly applicable to African-Americans as well as to whites.
Other Ethnic Minority Populations
Limited data relating obesity to mortality in American Indians were identified, but no data were found relating obesity to mortality in Hispanic-Americans, Asian-Americans, or Pacific Islanders . The lowest mortality rate among Pima men is observed at a BMI range of 35 to 40 kg/m2 for men, and no relationship between BMI and mortality is observed among Pima women [306, 307]. Based on mortality data alone, it would be hard to justify using the same standard for defining obesity in populations, such as American Indians, among whom the mean BMI is much higher than in the general U.S. population. However, diabetes-related morbidity among obese American Indians is extremely high , and the overall age-specific mortality among American Indians is generally higher than in the U.S. general population [306, 307]. Thus, obesity in American Indians is associated with a compromised overall survival of the population.
Although the data on mortality are still fragmentary for many minority populations, there are no studies that would support the exclusion of any racial/ethnic group from the current definitions of obesity. Secular trends in many populations in the United States and throughout the world have demonstrated that longstanding overweight and obesity eventually leads to the emergence of chronic diseases. Therefore, prevalent overweight and obesity cannot be ignored even where the associated health problems have not reached the level that would be expected on the basis of data for white populations.
D. Weight Loss and Mortality
A number of studies of “generic weight loss” (cause of weight loss unknown), “weight cycling” (cycles of weight loss followed by weight regain), and mortality have been published [308–311]. In most [308, 309, 311], but not all , of these studies, generic weight loss and weight cycling are associated with increases in mortality. None of these studies, however, differentiated between intentional and unintentional weight loss . With the exception of the studies below, very little is currently known about factors related to intentional and unintentional weight loss in the general population or about the relationship between weight loss intention and mortality .
Two studies of factors related to weight loss intention have been carried out in the general population: French and colleagues assessed correlates of intentional and unintentional weight loss of > 20 lb in the Iowa Women's Health Study, a cohort study of approximately 29,000 women with a mean age of about 65 years; [313–315] and Meltzer and Everhart analyzed data on 1-year self-reported weight change from approximately 9,000 participants in the nationally representative U.S. National Health Interview Survey, aged 45 years and above . The results of these two studies suggest the following:
- In cross-sectional studies of weight loss recall, heavier persons are more likely to report intentional weight loss than unintentional weight loss, while the reverse is true for leaner persons;
- Intentional and unintentional weight losses occur with similar frequency in the U.S. population and contribute similarly to long-term weight fluctuation;
- The frequency of intentional weight loss is lower at older ages, while the frequency of unintentional weight loss is higher at older ages; and
- Unintentional weight loss occurs more often in persons who report that their health status is poor, who use medications for chronic health conditions, and who smoke .
To date, only three studies have examined the relationship between intentional weight loss and mortality. Singh and colleagues  published results from a 1-year randomized controlled trial of a “cardioprotective diet” in East Indian patients hospitalized with recent myocardial infarction (mean age 50 years, mean BMI about 24 kg/m2 ). Although this study was not designed to specifically test the efficacy of intentional weight loss on lower mortality, the authors found that those who lost at least 0.5 kg (1.1 lb) had a 50 percent lower incidence of cardiac events and a 54 percent lower risk of overall mortality compared with counterparts who lost < 0.5 kg (1.1 lb) .
Williamson and colleagues  published a 12-year prospective observational study of weight loss and mortality that directly assessed weight loss intention. They analyzed data from 43,457 overweight (BMI > 27), never-smoking, white women ages 40 to 64 years. Mortality ratios were compared for women who intentionally lost weight with those for women who had no change in weight. In women with obesity-related comorbidities, intentional weight loss of any amount was associated with a statistically significant 20 percent reduction in all-cause mortality, primarily due to a significant 40 to 50 percent reduction in mortality from obesity-related cancers; diabetes-related mortality was also significantly reduced by 30 to 40 percent in those who intentionally lost weight. In women with no comorbidities, intentional weight loss was generally unrelated to mortality; however, after subdividing intentional weight loss by time interval, it was found that a loss of at least 20 lb that occurred within the previous year was associated with small to modest increases in mortality. The authors concluded that the association between intentional weight loss and longevity in middle-age overweight women depends on health status. In addition, preliminary evidence suggests that intentional weight loss in middle-age overweight men may be associated with a similar reduction of diabetes-related mortality as was observed in the overweight women .
The ongoing Swedish Obesity Study is a controlled trial of surgically induced weight loss and subsequent morbidity and mortality over a 10-year follow-up period (1,006 participants aged 37 to 57 years; initial BMI of 34 in men and 38 in women [320, 321]). Although the study is not randomized (participants self-select for surgery), the controls (who receive a behavioral weight loss program) are computer-matched to surgical participants on a large number of potential confounders including weight . In a preliminary abstract , the study reported the 2-year incidence rates shown in Table II-3.
These results for disease and risk factor incidences suggest that 10-year mortality will ultimately be lower in the surgical intervention group. Definitive mortality results have not been reported to date.
The environment is a major determinant of overweight and obesity. Environmental influences on overweight and obesity are primarily related to food intake and physical activity behaviors . In countries like the United States, there is an overall abundance of palatable, calorie-dense food. In addition, aggressive and sophisticated food marketing in the mass media, supermarkets, and restaurants, and the large portions of food served outside the home, promote high calorie consumption. Many of our sociocultural traditions promote overeating and the preferential consumption of high calorie foods. For many people, even when caloric intake is not above the recommended level, the number of calories expended in physical activity is insufficient to offset consumption. Mechanization limits the necessity of physical activity required to function in society. Many people are entrenched in sedentary daily routines consisting of sitting at work, sitting in traffic, and sitting in front of a television or a computer monitor for most of their waking hours.
In this obesity-promoting environment, individual attitudes and behaviors are critical in weight management. Many individuals may need extended treatment in clinical or community settings to enable them to cope with the complexities of long-term weight management, especially if there is a history of unsuccessful attempts at self-treatment . When the typical daily routine is so strongly biased towards promoting and perpetuating overweight and obesity, very high levels of knowledge, motivation, personal behavioral management skill, and lifestyle flexibility are required for an overweight or obesity-prone individual to avoid becoming overweight, or progressing to moderate or severe obesity.
Although there are undoubtedly some inter- and intrapopulation variations in the genetic predisposition to become overweight or obese, several lines of evidence suggest that genetic factors alone cannot explain the demographic and ethnic variations in overweight and obesity prevalence. For example, there is a difference in obesity prevalence among low- and high-income white women in industrialized societies [323, 324]. Other studies of populations, including migration studies, have shown an increase in average body weight in those who move from a traditional to a Westernized environment [325–328]. Culturally determined attitudes about food, physical activity, and factors that vary with income, education, and occupation may increase the level of difficulty in weight management. Body image concerns and other motivations for avoiding obesity or controlling weight within given limits also vary with ethnic background, age, socioeconomic status, and gender. Thus, the competence of practitioners in working with diverse sociocultural perspectives can be a critical factor in the success of obesity treatment . For a discussion of cultural issues in obesity treatment and related references, see Appendix III.
F. Genetic Influence in the Development of Overweight and Obesity
Obesity is a complex multifactorial chronic disease developing from interactive influences of numerous factors—social, behavioral, physiological, metabolic, cellular, and molecular. Genetic influences are difficult to elucidate and identification of the genes is not easily achieved in familial or pedigree studies. Furthermore, whatever the influence the genotype has on the etiology of obesity, it is generally attenuated or exacerbated by nongenetic factors.
A large number of twin, adoption, and family studies have explored the level of heritability of obesity; that is, the fraction of the population variation in a trait (e.g., BMI) that can be explained by genetic transmission. Recent studies of individuals with a wide range of BMIs, together with information obtained on their parents, siblings, and spouses, suggest that about 25 to 40 percent of the individual differences in body mass or body fat may depend on genetic factors [329–331]. However, studies with identical twins reared apart suggest that the genetic contribution to BMI may be higher, i.e., about 70 percent . There are several other studies of monozygotic twins reared apart that yielded remarkably consistent results . Some of the reasons behind the different results obtained from twin versus family studies have been reported [334–336]. The relative risk of obesity for first-degree relatives of overweight, moderately obese, or severely obese persons in comparison to the population prevalence of the condition reaches about 2 for overweight, 3 to 4 for moderate obesity, and 5 and more for more severe obesity [337, 338].
Support for a role of specific genes in human obesity or body fat content has been obtained from studies of Mendelian disorders with obesity as one of the clinical features, single-gene rodent models, quantitative trait loci from crossbreeding experiments, association studies, and linkage studies. From the research currently available, several genes seem to have the capacity to cause obesity or to increase the likelihood of becoming obese . The rodent obesity gene for leptin, a natural appetite-suppressant hormone, has been cloned  as has been its receptor . In addition, other single gene mutants have been cloned [341, 342]. However, their relationship to human disease has not been established, except for one study describing two subjects with a leptin mutation . This suggests that for most cases of human obesity, susceptibility genotypes may result from variations of several genes.
Severely or morbidly obese persons are, on the average, about 10 to 12 BMI units heavier than their parents and siblings. Several studies have reported that a single major gene for high body mass was transmitted from the parents to their children. The trend implies that a major recessive gene, accounting for about 20 to 25 percent of the variance, is influenced by age and has a frequency of about 0.2 to 0.3 . However, no gene(s) has (have) yet been identified. Evidence from several studies has shown that some persons are more susceptible to either weight gain or weight loss than others [344, 345]. It is important for the practitioner to recognize that the phenomenon of weight gain cannot always be attributed to lack of adherence to prescribed treatment regimens.
National Heart, Lung, and Blood Institute, Bethesda (MD)
NHLBI Obesity Education Initiative Expert Panel on the Identification, Evaluation, and Treatment of Obesity in Adults (US). Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults: The Evidence Report. Bethesda (MD): National Heart, Lung, and Blood Institute; 1998 Sep. Chapter 2, Overweight and Obesity: Background.