Taken together, these studies indicate that stress messenger FGF21 and adipose FGFR1-KLB team up to respond to stress caused by a wide range of metabolic abnormalities and pathogenesis. The stress-responsive communication mediated by extra-adipose FGF21 and adipocyte FGFR1-KLB occurs predominantly between adipose tissue and at least two tissues whose roles in metabolism are quite different, but when stressed have major consequences on the organism: (1) liver whose role is to maintain lipid, carbohydrate, and organism metabolic homeostasis through synthesis, degradation, and temporary storage; and (2) muscle which is a major fuel consumer predominantly powered by the oxidation of fats and carbohydrates (Figure 1). Although so far liver and muscle have received the most attention as two major organs that send out FGF21 as a stress signal, other organs may utilize the same mechanism to call on adipocytes in major fat depots (WAT and BAT) or in the microenvironment of diverse tissues. Within the microenvironment of tissues that contains ectopic or interspersed adipose tissue or adipocytes, such as the breast, bone marrow, and the perirenal and epicardial regions, FGF21 may serve
