• [Nature Communications] PAK4 phosphorylates and inhibits AMPKα to control glucose uptake
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  • 2024-11-15 17:13:34|
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[Title]
PAK4 phosphorylates and inhibits AMPKα to control glucose uptake

[Author]
Dandan Wu1, Hwang Chan Yu2, Hye-Na Cha3, Soyoung Park3, Yoonji Lee 4, Sun-Jung Yoon5, So-YoungPark 3 , Byung-Hyun Park 2* & Eun JuBae 1*

1 School of Pharmacy and Institute of New Drug Development, Jeonbuk National University, Jeonju 54896, Republic of Korea.
2 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejon 34141, Republic of Korea.
3 Department of Physiology, College of Medicine, YeungnamUniversity,Daegu 42415, Republic of Korea.
4 College of Pharmacy, Chung-Ang University, Seoul06974, Republic of Korea.
5 Department of Orthopedic Surgery, Jeonbuk National University Hospital, Jeonju 54907, Republic of Korea.
* Correspondence

[Journal] 

Nature Communications volume 15, Article number: 6858 (2024) 

[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.

 
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