Inactivity and nutritional aberrations result in an expanding population of individuals with compromised metabolic function including obesity and insulin resistance. From this pool of individuals an increasing percentage develops overt diabetes leading to vast personal and social burden. Natural interventions are beneficial and exercise accompanied by weight loss can reverse insulin resistance, at least partially. Metabolic stress history has significant impact on the long-term organization of metabolic adaptive responses, especially during early stages of life (intrauterine and early postnatal). Individual variability of genetic background and metabolic-stress history coincides with the need for diverse interventions, in order to optimize metabolic control. Linking distinct markers of metabolic aberrations with genetic and metabolic stress history components will provide tools for individualized approaches for treating patients, which will facilitate our efforts to “normalize” a maladaptive metabolic profile in the context of a sedentary/hypercaloric life style. The general aim of the proposed study is to define the experimental tools that will shape a model animal system for the study of the metabolic impact of interventions that may be used therapeutically in states of compromised metabolism. The specific aims include (a) the identification of serum and tissue markers that specifically characterize the metabolic derangements associated with distinct mouse models of in utero metabolic risk and (b) the examination of the effects of nutritional, medicinal, hormonal and physical activity interventions on these markers and their association with changes in insulin resistance and metabolic balance. Establishing an experimental model that will facilitate the assessment of the metabolic effects of medicinal and, primarily, life-style measures, such as exercise and nutritional/caloric modifications, will help the study of debilitating states such as diabetes and cachexia.