P21-activated kinase 2 (PAK2) regulates glucose uptake and insulin sensitivity in neuronal cells

• Insulin stimulation decreases activity of PAK2 in N2A cells.
• Downregulation of PAK2 improves neuronal GLUT4 translocation and glucose uptake.
• PAK2 negatively regulates neuronal insulin sensitivity.
• PI3K-Akt are insulin-dependent regulators of PAK2 activity in neuronal cells.
• Rac1 and PP2A are insulin-independent regulators of PAK2 activity in neuronal cells.

P21-activated kinases (PAKs) are recently reported as important players of insulin signaling and glucose homeostasis in tissues like muscle, pancreas and liver. However, their role in neuronal insulin signaling is still unknown. Present study reports the involvement of PAK2 in neuronal insulin signaling, glucose uptake and insulin resistance. Irrespective of insulin sensitivity, insulin stimulation decreased PAK2 activity. PAK2 downregulation displayed marked enhancement of GLUT4 translocation with increase in glucose uptake whereas PAK2 over-expression showed its reduction. Treatment with Akti-1/2 and wortmannin suggested that Akt and PI3K are mediators of insulin effect on PAK2 and glucose uptake. Rac1 inhibition demonstrated decreased PAK2 activity while inhibition of PP2A resulted in increased PAK2 activity, with corresponding changes in glucose uptake. Taken together, present study demonstrates an inhibitory role of insulin signaling (via PI3K-Akt) and PP2A on PAK2 activity and establishes PAK2 as a Rac1-dependent negative regulator of neuronal glucose uptake and insulin sensitivity.