MOLECULAR CONTROL OF REGULATED EXOCYTOSIS IN ADIPOCYTES

Abstract

Akt2 activation is essential for governing insulin actions to promote GLUT4 translocation from intracellular storage compartment to the cell surface. Using mass-spec approach, we identified Tropomodulin 3 (Tmod3), a ubiquitously expressed actin-capping protein, as an Akt2-interacting partner in differentiated 3T3-L1 adipocytes. We demonstrate that Tmod3 is an Akt2 substrate, phosphorylated at Ser71 in response to insulin signaling, and required for insulin-stimulated glucose transport and GLUT4 translocation. Tmod3 phosphorylation modulates insulin-induced actin remodeling, an indispensable step preceding GLUT4 fusion into the PM, but not the trafficking of GSVs to the periphery. Insulin signaling modulates the spatial and temporal dynamics of Tmod3 and Tm5NM1, its cognate Tropomyosin partner, to PIP3-rich membrane and such interaction is important to glucose transport. Together, these data establish that cortical actin can be intrinsically controlled by insulin signaling to facilitate GLUT4 insertion and suggest that defects in membrane cytoskeletal-based mechanism could contribute to GLUT4 dysregulation in insulin-resistance.