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PAK4 phosphorylates and inhibits AMPKα to control glucose uptake

Author

Listed:
  • 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)

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.

Suggested Citation

  • Dandan Wu & Hwang Chan Yu & Hye-Na Cha & Soyoung Park & Yoonji Lee & Sun-Jung Yoon & So-Young Park & Byung-Hyun Park & Eun Ju Bae, 2024. "PAK4 phosphorylates and inhibits AMPKα to control glucose uptake," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51240-w
    DOI: 10.1038/s41467-024-51240-w
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    References listed on IDEAS

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    1. Lei Ying & Luyao Wang & Kaiwen Guo & Yushu Hou & Na Li & Shuyi Wang & Xingfeng Liu & Qijin Zhao & Jie Zhou & Longwei Zhao & Jianlou Niu & Chuchu Chen & Lintao Song & Shaocong Hou & Lijuan Kong & Xiaok, 2021. "Paracrine FGFs target skeletal muscle to exert potent anti-hyperglycemic effects," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    2. Min Yan Shi & Hwang Chan Yu & Chang Yeob Han & In Hyuk Bang & Ho Sung Park & Kyu Yun Jang & Sangkyu Lee & Jeong Bum Son & Nam Doo Kim & Byung-Hyun Park & Eun Ju Bae, 2023. "p21-activated kinase 4 suppresses fatty acid β-oxidation and ketogenesis by phosphorylating NCoR1," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    3. Yohendran Baskaran & Khay C. Ang & Praju V. Anekal & Wee L. Chan & Jonathan M. Grimes & Ed Manser & Robert C. Robinson, 2015. "An in cellulo-derived structure of PAK4 in complex with its inhibitor Inka1," Nature Communications, Nature, vol. 6(1), pages 1-11, December.
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