PROJECT SUMMARY Obesity and its associated type II diabetes have reached worldwide epidemic. Exercise training is a robust means to increase energy expenditure and downregulate chronic inflammation, and serves as an excellent primary intervention to combat obesity and associated metabolic disorders. Exercise mediates an increase in the circulating levels of certain hormones released from muscle that mediate certain exercise-induced adaptations of the body. Irisin is the first polypeptide molecule identified from the exercised muscle: irisin stimulates several adaptations, including the “beiging” of white adipose tissue, bone remodeling, and improvement of cognition and motor function in Alzheimer’s and Parkinson’s diseases. In collaboration with the Diane Mathis lab, we identified a specific immune pathway—the IL33-ST2 pathway— that is regulated by irisin to modulate adipose inflammation, in inguinal fat tissue (iWAT) and also in visceral fat tissue (eWAT). The molecular basis of irisin actions has been elaborated in my recent published work: (1) irisin collaborates with Hsp90α, another extracellular proteinthat activates integrin structure to allow high-affinity binding; (2) Hsp90α itself is induced with exercise in mice; (3) irisin binds to a face that is distinct from the docking sites of the classical integrin ligands, implying that this surface can be targeted by agonists without interfering with canonical integrin functions. My current research plan is devised to (i) test our molecular mechanistic model in the context of adipose-immune cross talk (Aim 1); (ii) further dissect the downstream immune response pathways that respond to irisin action (Aim 2), (iii) understand how the irisin-mediated immune pathway regulates different thermogenic programs (Aim 2), and (iv) identify other “irisin-style” hormone molecules that serve a protective role in metabolic diseases such as diabetes (Aim 3), a discovery-based study planned to pave the road to my first R01. Collec