PAK4 phosphorylates and inhibits AMPKα to control glucose uptake

Dandan Wu, Hwang Chan Yu, Hye-Na Cha, Soyoung Park, Yoonji Lee, Sun-Jung Yoon, So-Young Park (), Byung-Hyun Park () and Eun Ju Bae ()
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Dandan Wu: Jeonbuk National University
Hwang Chan Yu: Korea Advanced Institute of Science and Technology
Hye-Na Cha: Yeungnam University
Soyoung Park: Yeungnam University
Yoonji Lee: Chung-Ang University
Sun-Jung Yoon: Jeonbuk National University Hospital
So-Young Park: Yeungnam University
Byung-Hyun Park: Korea Advanced Institute of Science and Technology
Eun Ju Bae: Jeonbuk National University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Our recent studies have identified p21-activated kinase 4 (PAK4) as a key regulator of lipid catabolism in the liver and adipose tissue, but its role in glucose homeostasis in skeletal muscle remains to be explored. In this study, we find that PAK4 levels are highly upregulated in the skeletal muscles of diabetic humans and mice. Skeletal muscle-specific Pak4 ablation or administering the PAK4 inhibitor in diet-induced obese mice retains insulin sensitivity, accompanied by AMPK activation and GLUT4 upregulation. We demonstrate that PAK4 promotes insulin resistance by phosphorylating AMPKα2 at Ser491, thereby inhibiting AMPK activity. We additionally show that skeletal muscle-specific expression of a phospho-mimetic mutant AMPKα2S491D impairs glucose tolerance, while the phospho-inactive mutant AMPKα2S491A improves it. In summary, our findings suggest that targeting skeletal muscle PAK4 may offer a therapeutic avenue for type 2 diabetes.

Date: 2024
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DOI: 10.1038/s41467-024-51240-w

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