Obesity and its potential mechanistic basis.

Obesity plays a central role in the development of the thrifty phenotype. The metabolic disturbances of the cardiovascular metabolic syndrome, frequently ascribed to the thrifty phenotype, are rare in the absence of obesity and their expression is generally proportional to the size of the excess fat mass. Thus obesity interacts with early-life programming in the establishment of disease. Surprisingly, the evidence that fetal or infant diet leads to programming of obesity itself is rather weak, though this may be explained by the fact that life-style influences obscure the linkage between metabolic predisposition and maturity-onset obesity. This paper summarises the possible metabolic basis of obesity with special reference to those processes for which there are plausible mechanisms by which long-term programming may operate. It is concluded that the newly-emerging molecular discoveries in body weight regulatory systems point to the need for detailed studies of gene-environment interactions and life-course influences before we will fully understand the aetiology of complex phenotypes such as the metabolic syndrome.