Blocking AMPK β1 myristoylation enhances AMPK activity and protects mice from high-fat diet-induced obesity and hepatic steatosis
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AMP-activated protein kinase (AMPK) is a master regulator of cellular energy homeostasis and a therapeutic target for metabolic diseases. Co/post-translational N-myristoylation of glycine-2 (Gly2) of the AMPK β subunit has been suggested to regulate the distribution of the kinase between the cytosol and membranes through a “myristoyl switch” mechanism. However, the relevance of AMPK myristoylation for metabolic signaling in cells and in vivo is unclear. Here, we generated knockin mice with a Gly2-to-alanine point mutation of AMPKβ1 (β1-G2A). We demonstrate that non-myristoylated AMPKβ1 has reduced stability but is associated with increased kinase activity and phosphorylation of the Thr172 activation site in the AMPK α subunit. Using proximity ligation assays, we show that loss of β1 myristoylation impedes colocalization of the phosphatase PPM1A/B with AMPK in cells. Mice carrying the β1-G2A mutation have improved metabolic health with reduced adiposity, hepatic lipid accumulation, and insulin resistance under conditions of high-fat diet-induced obesity.
Original language | English |
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Article number | 111862 |
Journal | Cell Reports |
Volume | 41 |
Issue number | 12 |
Number of pages | 26 |
ISSN | 2211-1247 |
DOIs | |
Publication status | Published - 2022 |
Bibliographical note
Publisher Copyright:
© 2022 The Author(s)
- adiposity, AMPK, CP: Metabolism, myristoylation, phosphatase, signal transduction, steatosis
Research areas
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