Role of Biomechanical Interfaces Created by Focal Adhesion Kinase in Catecholamine Signaling

Pioneering work by our MPI team established biomechanical signals as a critical driver of brown adipose tissue (BAT) function. We demonstrated a new signaling cascade in interscapular BAT that integrates ß-adrenergic signaling, PKA activation, Ca2+ release via L-type calcium channels, and myosin light chain kinase 1 (MLCK1) activation. MLCK1 in turn stimulates force generation by myosin 7 (Myh7, a.k.a. cardiac/skeletal myosin heavy chain beta) and translocation of YAP and TAZ to the nucleus, leading to greater UCP1 expression and enhanced thermogenesis. Besides classical BAT, inducible beige adipocytes (BeAT) can also contribute to non-shivering thermogenesis by forming UCP1-positive cells within white adipose tissue (WAT) depots and are thought to be major drivers of non-shivering thermogenesis in adult humans. While BA are also activated by ß-adrenergic signals, we found that BeAT do not express Myh7, raising the question of whether BeAT thermogenesis is driven by contractile signals or some distinct mechanism. Here, we postulate that biointerfacial and biomechanical forces regulate b-adrenergic receptor (b-AR) signaling in BeAT to link catecholamine signaling to BeAT differentiation and induction of thermogenesis via Myh9-driven tension. Further, we propose that extracellular matrix (ECM) modulates ß-AR signaling by integrating, at the level of FAK, myosin-based intracellular tension signals with biomechanical extracellular matrix clues and outside-in integrin signaling resulting in spatio-temporal control of BeAT induction.