The mechanistic study on irisin-mediated immune response and its role in adipose tissue dynamics

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.

Grant Number: 5K01DK141969-02
NIH Institute/Center: NIH
Principal Investigator: Mu A