See related article, pages 624–634 The epidemic of obesity has become among the most serious health problems worldwide because the weight gain carries a high risk of developing life-threatening diseases such as type 2 diabetes, hypertension, coronary artery disease, and heart failure. Recent work has highlighted the key role of adipokines in the adverse clinical consequences of excessive fat mass. The increase in circulating levels of leptin and other adipocyte-derived factors, resulting from the expansion of adipose tissue, has been shown to promote insulin resistance, inflammation, hypertension, and endothelial dysfunction.1,2 Unlike many other adipokines whose circulating levels increase in obesity, the circulating levels of adiponectin decrease in obese subjects, particularly among patients with excess visceral adiposity (Figure).1 Clinical studies suggest that the attendant hypoadiponectinemia that occurs in obesity correlates with the development of hyperglycemia and type 2 diabetes, hypertension, coronary artery disease, sympathetic nerve activation, and impaired vasoreactivity.1,3 Consistent with this, adiponectin null mice have impaired glucose homeostasis and severe insulin resistance.3 Adiponectin has beneficial effects on biological processes that are relevant to the pathogenesis of diabetes and cardiovascular diseases including an improvement in insulin sensitivity (Figure).3,4 In endothelial cells, adiponectin stimulates the activity of endothelial nitric oxide synthase and increases production of NO.5 Moreover, administration of adiponectin decreases arterial pressure and renal sympathetic nerve outflow in rats.6 Together, these findings implicate dysregulated production of adiponectin in obesity as a potential mediator of the metabolic and cardiovascular abnormalities associated with this condition. Therefore, understanding the mechanisms that regulate the expression and production of adiponectin is critical. Figure. Paradigm for expression and the beneficial actions of adiponectin. Adiponectin in the lean state is associated with an increase in insulin sensitivity, an increase in NO resulting in improved endothelial function, and a …