Chronic physical inactivity, sedentary behavior, and low aerobic fitness are linked to the development of chronic disease conditions including obesity, insulin resistance, fatty liver disease, type 2 diabetes, and cardiovascular disease. In contrast, daily physical activity and maintenance of aerobic fitness throughout the lifespan are associated with protection against chronic disease(s). The mechanism(s) underlying the development of these diseases and the role that activity and fitness status play in altering susceptibility remain largely unknown and are the focus of our research. We utilize integrative (multi-tissue and whole body), translational (cells, rodents, humans) approaches to perform studies in these areas with a focus on clinical or human relevance.