Blocking AMPK?1 myristoylation enhances AMPK activity and protects mice from high-fat diet-induced obesity and hepatic steatosis

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 0 subunit has been suggested to regulate the distribution of the kinase between the cytosol and membranes through a myristoyl switchmechanism. 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 AMPK01 (01-G2A). We demonstrate that non-myristoylated AMPK01 has reduced stability but is associated with increased kinase activity and phosphorylation of the Thr172 activation site in the AMPK a subunit. Using proximity ligation assays, we show that loss of 01 myristoylation impedes colocalization of the phosphatase PPM1A/B with AMPK in cells. Mice carrying the 01-G2A mutation have improved metabolic health with reduced adiposity, hepatic lipid accumulation, and insulin resistance under conditions of high-fat diet-induced obesity.

Automated summary

This study demonstrates the relevance of AMPK myristoylation for cellular metabolic signaling. Non-myristoylated AMPK shows increased kinase activity and has an improved metabolic health under conditions of high-fat diet-induced obesity.