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PAK4 phosphorylates and inhibits AMPKα to control glucose uptake
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Journal Article
PAK4 phosphorylates and inhibits AMPKα to control glucose uptake
2024
Overview
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 AMPKα2
S491D
impairs glucose tolerance, while the phospho-inactive mutant AMPKα2
S491A
improves it. In summary, our findings suggest that targeting skeletal muscle PAK4 may offer a therapeutic avenue for type 2 diabetes.
While AMPKα is known for its role in regulating GLUT4 trafficking and subsequent glucose uptake into cells, its upstream regulators are not well understood. The authors provide evidence that PAK4 acts as an inhibitory kinase for AMPKα, thus impairing glucose uptake in skeletal muscle.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 14/19
/ 42/109
/ 42/89
/ 45/70
/ 64/110
/ 64/60
/ Ablation
/ AMP-Activated Protein Kinases - metabolism
/ Animals
/ Diabetes mellitus (non-insulin dependent)
/ Diabetes Mellitus, Type 2 - metabolism
/ Glucose
/ Glucose Transporter Type 4 - genetics
/ Glucose Transporter Type 4 - metabolism
/ Humanities and Social Sciences
/ Humans
/ Insulin
/ Kinases
/ Lipids
/ Male
/ Mice
/ Muscle, Skeletal - metabolism
/ Muscles
/ Mutants
/ p21-Activated Kinases - genetics
/ p21-Activated Kinases - metabolism
/ Science
