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index (BMI, kg/m2) studies have been conducted in twins8, adoptees9, and family members10. The most convincing evidence that obesity is largely a genetic disease comes from studies of monozygotic twins reared apart. These studies are based on the assumption that when genetically identical individuals are separated at a young age and assigned randomly to different families, their shared environment is no larger than in the general population. Under these conditions the degree of correlation of the BMI between individuals represents an estimate of the heritability of obesity (heritability being defined as the proportion of between person phenotypic variance that is attributable to between person genotypic variance). Studies in populations of twins from Europe11, Asia12 and the US12-13 indicate that as much as 60-70% of the intraindividual variability in BMI is determined by a common genetic background. In Pima Indians, a population with one of the highest reported prevalence rates of obesity, family studies confirmed this estimate10. Therefore, our studies concerning the mechanisms of weight gain in humans have been based on 2 main assumptions: a) the variability in BMI among individuals from the same population who have uniform access to food and similar requirements for physical activity is largely determined by genes (Figure 1); b) because obesity is the result of a chronic energy imbalance between energy intake and expenditure, it is likely that genes control both aspects of the energy balance equation, i.e., energy intake and energy expenditure (Figure 2). Introduction