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. Collectively, this work will contribute to fundamental knowledge of integrin biology as well as to the development of therapeutics for treating metabolic disorders and beyond. Integrins are a large receptor family that is well known for mediating cell adhesion. Irisin is the first known hormone ligand that uses integrin as its receptor in a noncanonical manner, to convey pleiotropic effects - such as induction of IL33 expression in adipose stromal cells - that cannot be triggered by canonical integrin ligands. Uncovering the cellular signaling pathways that are specifically activated by irisin will greatly expand our knowledge of integrin cellular function, and the kinases and other key players in these novel pathways will serve as new targets for tissue-level immune regulation and drug development. This proposal will allow me to undertake mechanistic studies at different levels, and from different angles. Armed with my previous training in biochemistry and molecular metabolism and supported by two strong mentors in the immunometabolism field and six contributors that have all necessary expertise required to complete my proposed experiments, I envision no insurmountable obstacles in fulfilling the proposed projects and in transitioning to independence.

PROJECT NARRATIVE Exercise benefits the body in multiple ways - and irisin, one of the exercise-induced hormones from muscle, recapitulates several aspects of these benefits, including the induction of heat generation from white fat tissue, strengthening bones, and improving brain functions such as memory and brain-directed movements. In obese and diabetic mice, irisin restores the metabolic functions of fat tissue, and reduces inflammation of fat tissue through upregulation of a cytokine IL33. The proposed project is focused on understanding the molecular interplay between irisin and IL33 in fat tissue and how their interaction affects different pathways in the fat cells responsible for heat generation.