Blocking AMPK β1 myristoylation enhances AMPK activity and protects mice from high-fat diet-induced obesity and hepatic steatosis Journal Articles uri icon

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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.


  • Neopane, Katyayanee
  • Kozlov, Natalie
  • Negoita, Florentina
  • Murray-Segal, Lisa
  • Brink, Robert
  • Hoque, Ashfaqul
  • Ovens, Ashley J
  • Tjin, Gavin
  • McAloon, Luke M
  • Yu, Dingyi
  • Ling, Naomi XY
  • Sanders, Matthew J
  • Oakhill, Jonathan S
  • Scott, John W
  • Steinberg, Gregory
  • Loh, Kim
  • Kemp, Bruce E
  • Sakamoto, Kei
  • Galic, Sandra

publication date

  • December 2022