Related Experiment Video

Updated: Jun 17, 2025

Measurement of Insulin- and Contraction-Stimulated Glucose Uptake in Isolated and Incubated Mature Skeletal Muscle from Mice
08:01

Measurement of Insulin- and Contraction-Stimulated Glucose Uptake in Isolated and Incubated Mature Skeletal Muscle from Mice

Published on: May 16, 2021

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PAK4 phosphorylates and inhibits AMPKα to control glucose uptake

Dandan Wu1, Hwang Chan Yu2, Hye-Na Cha3

  • 1School of Pharmacy and Institute of New Drug Development, Jeonbuk National University, Jeonju, 54896, Republic of Korea.

Nature Communications
|August 10, 2024
PubMed

Insights

p21-activated kinase 4 (PAK4) is upregulated in diabetic skeletal muscle. Targeting PAK4 improves insulin sensitivity and glucose tolerance, suggesting it as a therapeutic target for type 2 diabetes.

Area of Science:

  • Biochemistry
  • Metabolism
  • Endocrinology

Background:

  • p21-activated kinase 4 (PAK4) regulates lipid metabolism.
  • The role of PAK4 in skeletal muscle glucose homeostasis is unknown.
  • PAK4 is upregulated in diabetic skeletal muscle.

Purpose of the Study:

  • To investigate the role of PAK4 in skeletal muscle glucose homeostasis.
  • To determine if PAK4 inhibition can improve insulin sensitivity in diet-induced obesity.

Main Methods:

  • Skeletal muscle-specific Pak4 ablation in mice.
  • Administration of a PAK4 inhibitor in diet-induced obese mice.
  • Analysis of insulin sensitivity, AMPK activation, and GLUT4 expression.
  • Investigation of AMPKα2 phosphorylation at Ser491 using phospho-mimetic and phospho-inactive mutants.

Main Results:

  • PAK4 levels are elevated in skeletal muscle of diabetic humans and mice.
  • Pak4 ablation or inhibition in mice improves insulin sensitivity and upregulates GLUT4.
  • PAK4 phosphorylates AMPKα2 at Ser491, inhibiting its activity.
  • Expression of AMPKα2S491D impairs glucose tolerance, while AMPKα2S491A improves it.

Conclusions:

  • PAK4 promotes insulin resistance in skeletal muscle by inhibiting AMPK activity.
  • Targeting skeletal muscle PAK4 is a potential therapeutic strategy for type 2 diabetes.

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