≥88 cm (≥35 inches) in womenElevated blood triglycerides (TG)≥150 mg/dL (1.7 mmol/L) or on drug treatment for elevated triglycerides^‡Low blood HDL-C<40 mg/dL (1.03 mmol/L) in men or < 50 mg/dL (1.3 mmol/L) in women or on drug treatment for reduced HDL-C^‡Elevated blood pressure≥130 mmHg systolic blood pressure or ≥85 mmHg diastolic blood pressure or on antihypertensive drug treatment in a patient with a history of hypertensionElevated fasting glucose≥100 mg/dL or on drug treatment for elevated glucose

*To measure waist circumference, place a measuring tape in a horizontal plane around the abdomen level with the top of the iliac crest. Ensure that the tape is snug but does not compress the skin and is parallel to the floor. Measurement is made at the end of a normal expiration.

†Some US adults of non-Asian origin (e.g., White, Black, Hispanic) with marginally increased waist circumference (i.e., 94–101 cm [37–39 inches] in men; 80–87 cm [31–34 inches] in women) may have a strong genetic contribution to insulin resistance and should benefit from changes in lifestyle habits, similar to men with categorical increases in waist circumference. A lower waist circumference cut-off (≥90 cm [35 inches] in men; ≥80 cm [31 inches] in women) appears to be appropriate for Asian Americans.

‡Fibrates and nicotinic acid are the most commonly used drugs for elevated TG and reduced HDL-C. Patients taking one of these drugs are presumed to have high TG and low HDL.

It has been established that, independent of the degree of obesity, fat distribution, especially abdominal obesity, is an important determinant of disease risk, particularly type 2 diabetes, dyslipidemia, and hypertension (83). Results of available studies suggest it is the intra-abdominal, or visceral, fat that is crucial in this regard (84), but other fat depots have also been shown to be associated positively or negatively (protective) with metabolic syndrome; these relationships are modulated by the degree of overall obesity (85).

Several molecules originating in adipose tissue are thought to play a role in the relationship between abdominal obesity and the clustered metabolic syndrome components: these are non-esterified free fatty acids (NEFA) and cytokines, such as tumor necrosis factor α, and resistin, adiponectin, leptin, and PAI-1. However, the exact mechanisms underlying the associations are not understood (76). Insulin resistance and hyperinsulinemia are thought to be at the heart of the metabolic syndrome manifestations (76), as they are tightly associated with glucose intolerance, hyperlipidemia, and adipose tissue abnormalities, such as low adiponectin levels, high leptin levels and abnormal cytokine levels.

The two particular abnormalities of circulating lipids associated with visceral obesity are elevated triglycerides and reduced high-density lipoprotein cholesterol (HDL-C) levels. Elevated triglyceride levels are due to both increased production by the liver from high NEFA and hyperinsulinemia, and decreased clearance of triglycerides at the periphery due to decreased activity of lipoprotein lipase (86). Since HDL-C levels are low in obese persons, while low-density lipoprotein cholesterol (LDL-C) levels are usually only mildly elevated or within the normal range, the ratio of LDL-C to HDL-C is always elevated. This combination raises the risk of CVD.

Management of the metabolic syndrome has been outlined in several recent statements (74). Weight loss of 5–7% of body weight will improve most manifestations of the metabolic syndrome. Therefore, the first line of therapy for the metabolic syndrome consists of lifestyle changes for the treatment of abdominal obesity (hypocaloric non-atherogenic diet, exercise, and behavior modification) (74).

Cardiovascular Disease

Coronary heart disease (CHD) is usually described epidemiologically as cardiovascular disease (CVD). Outcomes of CVD are angina pectoris, nonfatal myocardial infarction, and sudden death. These outcomes occur more frequently in obese persons (83). There has been much controversy as to how important obesity is in increasing CVD morbidity and mortality. It is well known, as mentioned above, that obesity enhances the risk of hypertension, dyslipidemia, and diabetes, all of which are strong, independent risk factors for CVD (87). However, it is still controversial whether, when these factors are controlled in statistical, multivariate analyses, obesity itself remains an independent risk factor for CVD and for CVD morbidity and mortality. In studies carried out for longer than 15 years, obesity was consistently a risk factor for CVD morbidity and mortality in men (in addition to physical inactivity, smoking, etc.) (88–90) and in women (78, 90, 91). These associations were most likely modulated by the presence of CVD risk factors such as abnormal glucose tolerance, hypertension, and dyslipidemia, which could have been undiagnosed (92). Recent analyses that controlled for conditions that are made worse by obesity continued to yield positive, negative, and U-shaped relationships between obesity as assessed by the body mass index (BMI) and CVD mortality (93–98). Some epidemiologists proposed that it is a mistake, when assessing obesity risk, to control for such conditions; thus the issue is not settled (54). The associations of CVD risk factors with obesity, and especially with central obesity, were found to be independent of cardiovascular fitness (99, 100). In fact, abdominal obesity and upper body fat distribution are not only predictors of CVD risk factors independent of overall obesity but are also better determinants of CVD outcomes in longitudinal studies than overall obesity (101, 102). Similarly, not BMI but other measures of fatness, such as leptin levels, which have been causally related to CVD, might be better predictors of CVD mortality (103) reflecting the underlying pathophysiological mechanism.

Cardiac and vascular conditions other than CVD also associated with obesity are stroke and congestive heart failure (104–107). An increased risk of stroke is directly linked to the increased prevalence of hypertension in obese persons. In the Framingham Study, for instance, there was a steep rise in stroke with increasing weight. For example, in men under the age of 50 years, a rise in weight from <110 kg to >130 kg increased the risk of stroke from 22/1,000 to 49/1,000 (104). In addition, obesity, especially abdominal obesity, was a risk factor for congestive heart failure independent of the presence of coronary disease, hypertension, or left ventricular hypertrophy (104, 105).

Cancer

It is now established that obesity is a risk factor for several cancers (see Table 12-2). Data from a large prospective analysis sponsored by the American Cancer Society showed that in men 14% of cancer deaths (from a list of certain cancer types) and 20% of similar cancer deaths in women are attributable to overweight and obesity (108). Obesity was found to be associated with increased risk of death from cancer of the stomach and prostate in men, of the uterus, cervix, and ovary in women, and of the breast in postmenopausal women. Obesity also increased risk of death from cancers of the esophagus, gallbladder, and kidney, independently of smoking. The associations of colon and pancreatic cancer with overweight/obesity were stronger in men than in women. In men with a BMI > 30, the risk of colorectal cancer was up to 80% higher than in normal-weight men (BMI 18.5–24.9).

Table 12-2 Obesity-related Cancers

Adapted from ref. 113.

Relative risks associated with overweight and obesity in the United States (US) and the European Union (EU).

*Relative risk estimates are summarized from the literature cited in the main text from (113). BMI, body mass index in kg/m²; ND, not determined. Medscape®. www.medscape.com>

Nat. Rev. Cancer ^© 2004 Nature Publishing Group.

The links found in epidemiological studies are supported by data from animal models, which show that obesity enhances tumor development (109) and calorie restriction inhibits tumor growth (110). A recent analysis of modifiable behavioral and environmental risk factors for 12 types of cancers in seven World Bank regions for 2001 found that smoking, alcohol use, and low fruit and vegetable intake were the leading factors associated with cancer deaths worldwide and in low- and middle-income countries, while smoking, alcohol use, and overweight/obesity were the most important factors associated with cancer deaths in high-income countries (111). In this study, corpus uteri cancer, colorectal cancer after age 30, breast cancer in women after age 45, gallbladder cancer, and kidney cancer were those whose rates were raised with increased BMI. In addition, physical inactivity was associated with breast cancer, colorectal cancer, and prostate cancer.

The mechanisms underlying the association between overweight/obesity and cancer are not completely understood, but several hypotheses have been proposed and tested. First, associations of low fruit and vegetable intake and physical inactivity with cancer may underlie the association of cancer deaths with overweight/obesity in some studies, although independent associations were also found. The association between diets high in saturated fat and cancer risks has been less consistent. The most recent mechanisms proposed are related to the increased concentrations of endogenous hormones, such as insulin and insulin-like growth factor 1 (IGF-1), the higher bioavailability of steroid sex hormones, an abnormal adipokine pattern, and chronic inflammation and oxidative stress, which are all observed with overweight/obesity (112, 113).

It has been hypothesized that insulin resistance (characterized by hyperinsulinemia) and hyperglycemia may play a role in tumor growth by providing a conducive environment for the growth of cancer cells (114, 115). Moreover, studies evaluating type 2 diabetes and insulin resistance in relation to development of cancer have found deleterious associations (115–117). We evaluated the longitudinal associations of obesity, hyperglycemia, and measures of insulin resistance in relation to overall cancer mortality using data from the National Health and Nutrition Examination Survey III (NHANES III) (1988–94) (115). For every 50 mg/dL increase in plasma glucose there was a 22% increase risk of overall cancer mortality. Insulin resistance was associated with a 41% increased risk of cancer mortality (115). Thus, obesity, chronic hyperglycemia, and insulin resistance, in addition to a state of low-grade inflammation, are considered the interrelated factors underlying the now well-recognized connection between type 2 diabetes and cancer (117).

It is thought that insulin resistance and hyperinsulinemia may contribute through an IGF-1-like effect (118). Increased IGF-1 has been implicated in tumor growth; in animal studies, its restoration ablates the anti-tumor effect of calorie restriction (110). However, we have recently shown that total IGF-1 levels are inversely associated with the number of metabolic syndrome abnormalities in NHANES III (118). The role of IGF-1 in cancer and cancer mortality might be related to hyperinsulinemia (117). Both insulin and IGF-1 regulate cellular growth and differentiation via the PI3-kinase/Akt pathway, which is also a carcinogenesis-related pathway (119). Moreover, increased insulin levels decrease the liver synthesis of binding proteins for insulin-like growth factor, leading to an increase in the bioavailability of IGF-1 (120).

Certain cytokines and low-grade inflammation may also contribute to the association between obesity, type 2 diabetes, and cancer (117). Elevated leptin levels in obesity and insulin-resistant states have been hypothesized to contribute, but cancer incidence is also increased in the insulin-resistant fatless mouse, where leptin levels are not elevated (112). One adipokine that might be responsible is adiponectin. Adiponectin is low in obesity and is completely absent in the fatless mouse; recently, low levels of adiponectin have been linked to increased breast cancer risk (121). Animal studies show that adiponectin inhibits tumor growth (112), probably through its anti-diabetic and anti-inflammatory properties. Low adiponectin could be the link between obesity and inflammation, oxidative stress and cancer.

Inflammation and oxidative stress resulting in oxidative DNA damage could also result from high intake of highly processed CHO and fats (112), which, together with low adiponectin levels, are common in obesity. Chronic inflammation is associated with increased cancer risk (122) and has now been shown to exist in obesity due to an increased number of macrophages in the adipose tissue of obese individuals (123).

Other implicated hormones in the link between obesity and cancer are the estrogen hormones; higher, unopposed levels in postmenopausal, obese women are implicated in the higher incidence of cancer of the uterus and breast (113, 124, 125). Higher estrogen levels in obese individuals are the result of estrogen production by excessive adipose tissue using sex-hormone precursors that are soluble in fat, are deposited in fat, and are converted there to active estrogen.

The metabolic changes that increase cancer risk in obesity also precede the development of full-blown type 2 diabetes. Lifestyle choices that decrease the risk of cancer also promote control of type 2 diabetes. For cancer prevention, maintaining a healthy weight with BMI < 25 throughout adulthood, 30–60 minutes/day of moderate physical activity or 30 minutes of vigorous physical activity, moderate alcohol use combined with a mostly plant-based diet and avoiding energy-dense foods, sugary drinks, and red or processed meat, are currently recommended (117). Additionally, the World Cancer Research Fund recommends eating whole grains and/or legumes with each meal and limiting “fast foods” (126).

In summary, there is increasing epidemiological evidence linking overweight and obesity with an increased risk of death from cancer. The proposed mechanisms and the available evidence suggest that calorie restriction and weight loss in the obese might have a favorable effect on cancer prevention in humans (127, 128) (see Table 12-3).

Table 12-3 American Cancer Society Guidelines on Nutrition and Physical Activity for Cancer Prevention*

Adapted from ref. 128.

Conclusion

The medical complications of obesity are considerable. It must be realized that diabetes mellitus, hypertension, dyslipidemia, cardiovascular disease, and stroke are, after cancer, HIV/AIDS, and violence, the leading causes of morbidity and mortality in the developed world. If cancer is added to the list, obesity is an even larger contributor to the burden of disease affecting industrialized countries. Whether the effect on these diseases is direct and independent, or indirect through enhancing other risk factors, is essentially irrelevant from a public health perspective. If obesity could be prevented, a very significant and positive reduction in chronic disease and mortality would occur.