Clustering of metabolic abnormalities in obese individuals: the role of genetic factors

The objective of this paper is to review the current evidence in support of genetic factors underlying the clustering of components of the metabolic syndrome in obese individuals. It has become clear that individual features of the metabolic syndrome are partially determined by familial factors some of which are unique to a given component and others that are shared among several features. A few candidate genes, encoding proteins of glucose, insulin and lipid metabolism, lipolytic cascade, fatty acid intestinal absorption, glucocorticoid metabolism, haemostasis and blood pressure, have been associated with a clustering of metabolic abnormalities, although the functional significance of these associations remains to be established. Furthermore, genetic polymorphisms, such as those detected at several lipoprotein metabolism loci, can modulate the relationships between different components of the metabolic syndrome. An overfeeding study conducted on identical twins has demonstrated that genetic factors play an important role in the responsiveness to changing energy balance conditions. Leptin receptor, β2 adrenergic receptor and glucocorticoid receptor gene polymorphisms have been associated with an augmented clustering of metabolic abnormalities in response to overfeeding. Gene-gene interaction effects between markers of the α2A, β2 and β3 adrenergic receptor genes on components of the metabolic syndrome have been described. Genetic factors also seem to modify the responsiveness of metabolic syndrome features to endurance training. A growing understanding of the genetic architecture of the metabolic syndrome may help in the prevention of this condition. The reduction of excess body fat, the most common clinical feature among the cluster of metabolic abnormalities, should be the focus of the prevention and treatment of the metabolic syndrome.