The Involvement of the Small GTPase Rac1 in Insulin Signaling That Regulates Plasma Membrane Translocation of the...

A fraction of the insulin-stimulated uptake of long-chain fatty acids (FAs) is mediated by the FA translocase cluster of differentiation 36 (CD36) in white adipocytes. Intracellular vesicle-localized CD36 is redistributed to the plasma membrane following insulin stimulation, enhancing the uptake of long-chain FAs across the plasma membrane. We previously developed an epitope-tagged CD36 reporter, which enabled the visualization and quantification of the plasma membrane translocation of CD36. Herein, we demonstrate that the insulin-stimulated CD36 translocation is regulated by the phosphoinositide 3-kinase (PI3K)/Akt2/Rac1/RalA axis in adipocytes of subcutaneous white adipose tissue (WAT) in living mice. The uptake of long-chain FAs by insulin was completely abrogated in white adipocytes isolated from adipocyte-specific rac1-knockout (adipo-rac1-KO) mice. Correspondingly, the translocation of CD36 to the plasma membrane by insulin was also totally inhibited in Rac1-deficient white adipocytes. PI3K and Akt2 acted upstream of Rac1, and the guanin nucleotide exchange factor FLJ00068 served as a regulator for Rac1. Furthermore, the involvement of another small GTPase RalA was suggested by inhibitory effects of a dominant-negative mutant. Taken together, these results support the notion that insulin regulates the plasma membrane translocation of CD36 by mechanisms similar to those for the translocation of the glucose transporter GLUT4 in white adipocytes.