Genetics, obesity, and the metabolic syndrome: The Professor Donald S. Fredrickson Memorial Lecture

The metabolic syndrome consists of a clustering of metabolic risk factors in one individual. These risk factors consist of atherogenic dyslipidemia (high triglycerides, high apolipoprotein B [apo B], small LDL particles, and low HDL), elevated blood pressure, insulin resistance±elevated plasma glucose, a prothrombotic state, and a proinflammatory state. Although the metabolic syndrome is increasingly common around the world and represents an important cause of cardiovascular disease (CVD), its pathogenesis is not well understood. The two major underlying causes appear to be obesity or other disorders of adipose tissue and insulin resistance. There is little doubt that genetic susceptibility plays an important role in the development of the metabolic syndrome. This paper addresses the question of the interaction between obesity and genetic susceptibility in the etiology of the metabolic syndrome. Genetic susceptibility appears to exist at three levels: within adipose tissue itself, in insulin signaling pathways, and in regulation of individual risk factors. A major research challenge for the future is to unravel the complex genetic architecture that gives rise to the metabolic syndrome once a person becomes obese.