strongly with insulin resistance. Excess upper body fat can accumulate either intraperitoneally (visceral fat) or subcutaneously. Many investigators claim that excess visceral fat is more strongly associated with insulin resistance than any other adipose tissue compartment4, 15–21; other workers find that excess subcutaneous abdominal (or truncal) fat also carries a significant association with insulin resistance. 22–27 Regardless of the relative contributions of visceral fat and abdominal subcutaneous fat to insulin resistance, a pattern of abdominal (or upper-body) obesity correlates more strongly with insulin resistance and the metabolic syndrome than does lower-body obesity. 28 An interesting feature of upper-body obesity is an unusually high release of nonesterified fatty acids from adipose tissue12, 14, 28; this contributes to accumulation of lipid in sites other than adipose tissue. Ectopic lipid accumulation in muscle and liver seemingly predisposes to insulin resistance29 and dyslipidemia. 30 According to many experts, the increasing burden of obesity in the United States is the driving force behind the rising prevalence of the metabolic syndrome. 1–4, 31, 32 This view needs to be harmonized with the insulin resistance hypothesis. Abnormalities in adipose tissue metabolism may be the crux of the issue. Adipose tissue in obese people is insulin resistant, which raises nonesterified fatty acid levels, worsening insulin resistance in muscle29, 33 and altering hepatic metabolism31; in addition, the adipose tissue of obesity exhibits abnormalities in the production of several adipokines that may separately affect insulin resistance and/or modify risk for ASCVD. 34 These include increased production of inflammatory cytokines, 35, 36 plasminogen activator inhibitor-1, 37 and other bioactive products38–40; at the same time the potentially protective adipokine, adiponectin, is reduced. 41, 42 All of these changes have been implicated as causes of the metabolic risk factors. Indeed, as mentioned before, some individuals exhibit the metabolic syndrome with only a moderate degree of total body obesity. 43, 44 Notable are many South Asians who appear to be inherently insulin resistant, 45 a condition that is exacerbated by mild abdominal obesity. 14 Moreover, the population of the United States varies considerably in degree of insulin resistance46; those having more inherent insulin resistance can develop the metabolic syndrome with only moderate excess in abdominal fat, 43, 44 but even people with little or no inherent insulin resistance can develop the metabolic syndrome if they accumulate marked abdominal obesity. 3, 8 These findings support the idea that body fat distribution, particularly excess abdominal fat, plays an important role in the etiology of the syndrome. Recently, this syndrome has been noted to be associated with a state of chronic, low-grade inflammation. 47, 48 Some researchers speculate that inflammation of this type underlies or exacerbates the syndrome. For example, inflammatory cytokines reportedly induce insulin resistance in both adipose tissue and muscle. 48–51 In the presence of obesity, adipose tissue indeed produces cytokines in excess, whereas output of adiponectin is diminished; these responses appear to heighten the connection between obesity and inflammation. 35 Interestingly, insulin-resistant people manifest evidence of low-grade inflammation even without an increase of total body fat. 52

Finally, considerable individual and ethnic variation exists in the clinical pattern of metabolic risk factors in obese/insulin-resistant subjects. 53, 54 It is likely that the expression of each metabolic risk factor falls partially under its own …