Ampk activation by glycogen expenditure primes the exit of naïve pluripotency

Embryonic and epiblast stem cells in pre-and post-implantation embryos are characterized by their naïve and primed states, respectively, which represent distinct phases of pluripotency. Thus, the cellular transition from naïve to primed pluripotency recapitulates a drastic metabolic and cellular remodeling after implantation to adapt to changes in extracellular conditions. Here, we found that inhibition of Ampk occurred during naïve transition with two conventional inhibitors (2i) of the Mek1 and Gsk3 pathways. The accumulation of glycogen due to the inhibition of Gsk3 was responsible for Ampk inhibition, which accounted for high de novo fatty acid synthesis in naïve embryonic stem cells (ESCs). The knockout of glycogen synthase 1 (Gys1) in naïve ESCs (GKO), resulting in a drastic glycogen loss, led to a robust Ampk activation and lowered the level of fatty acids. GKO lost the cellular characteristics of naïve ESCs and rapidly transitioned to a primed state. The characteristics of GKO were restored by the simultaneous knockout of Ampk. These findings suggest that glycogen in naïve ESCs within the blastocyst may act as a signaling molecule for the timely activation of Ampk, thus ultimately contributing to the transition to the epiblast stage.