ABSTRACT
It is well established that obesity and insulin resistance are associated with an increased risk for developing type 2 diabetes in addition to developing other cardiometabolic risk factors1-4. Fortunately, over the recent past, there has been a rapid and substantive increase in our understanding of the underlying physiologic systems and molecular pathways modulating these conditions. Specifically, key regulators of energy balance and insulin signaling have been elucidated that have aided greatly our understanding of the link between obesity and insulin resistance. As such, the concept of obesity may be simple to grasp in that it develops over time when we take in more calories than we burn, but insight into the mechanisms behind this observation has revealed systems that are complex and highly integrated5. Specifically, the epidemic of obesity that is occurring globally indicates the inability of homeostatic mechanisms to offset a sedentary lifestyle and increased caloric intake6,7. Furthermore, it is understood that there is a dynamic interplay between the adipose tissue and other key tissues in the body, such as liver, muscle and regulatory centers of the brain. Altered regulation of this integrated and coordinated system inevitably leads to accumulation of body fat, insulin resistance and type 2 diabetes (Figure 4.1). While it is understood that lifestyle intervention is the cornerstone of therapy for obesity, it is also apparent that effective pharmacotherapy, designed to reduce the cardiometabolic risk profile, is urgently needed. In order to develop effective strategies that may modulate molecular mechanisms contributing to obesity and insulin resistance, there must be sound scientific evidence in support of and agreement on the
pathogenic mechanisms. This chapter will therefore focus on the physiologic systems and pathways proposed to regulate whole-body energy metabolism and that contribute to or modulate pathways relevant to the development of obesity and/or insulin resistance.
