The prevalence of obesity and diabetes is rising to epidemic proportions worldwide. Insulin resistance is central to the pathogenesis of type 2 diabetes. The role of insulin sensitive tissues and organs, such as adipose, liver, muscle and hypothalamus, in regulating insulin sensitivity has been extensively studied. However, the existence and nature of inter-tissue communication in the regulation of insulin action is unresolved. A major factor in the development of insulin resistance is obesity, especially abdominal obesity. Chronically positive energy balance leads to a process gradually progressing to insulin resistance in obese states. Increased adipocyte size is positively correlated with the frequency of adipocyte death in obesity. The death of the hypertrophic adipocytes facilitates the infiltration of macrophages, which further perpetuates adipose inflammation and insulin resistance, characterized by low liposynthetic capacity and high lipolytic capacity, causing increased release of free fatty acids (FFA). The inflamed adipose tissue releases FFA, inflammatory cytokines, and hormones that act as circulatory factors to regulate insulin sensitivity in distant organs. In addition, perivascular adipose tissue participates in regulating insulin sensitivity, vascular inflammation and function in an endocrine/paracrine manner through adipose-derived relaxing and contracting factors, cytokines and infiltration of inflammatory cells. Thus, adipose tissue releases cytokines, hormones and lipids that signal distant organs to regulate systemic metabolic homeostasis, as well as signal local blood vessels to modulate vascular inflammation and function. These findings may lead to uncovering new therapeutic targets to fight obesity and type 2 diabetes by restructuring the adipokine profile and lipid metabolism.