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<p>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, 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 occurs during naïve transition with two conventional inhibitors of the MEK1 and GSK3β pathways. The accumulation of glycogen due to iGSK3β is responsible for AMPK inhibition, which accounts for high de novo fatty acid synthesis in naïve (ESCs). The knockout of glycogen synthase 1 in naïve ESCs; GKO, resulting in a drastic glycogen loss, leads to a robust AMPK activation and lowers the level of fatty acids. GKO loses cellular characteristics of naïve ESCs and rapidly transitioned to a primed state. The characteristics of GKO are restored by the simultaneous AMPK KO. These findings suggest that high glycogen in epiblast within pre-implantation blastocyst may act as a signaling molecule for timely activation of AMPK, thus ultimately contributing to transition to post-implantation stage epiblast.</p>

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AMPK activation by glycogen expenditure primes the exit of naïve pluripotency

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月17日

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  • Seong-Min Kim,
  • Eun-Ji Kwon,
  • Ji-Young Oh,
  • Han Sun Kim,
  • Sunghyouk Park,
  • Goo Jang,
  • Jeong Tae Do,
  • Keun-Tae Kim,
  • Hyuk-Jin Cha

摘要

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, 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 occurs during naïve transition with two conventional inhibitors of the MEK1 and GSK3β pathways. The accumulation of glycogen due to iGSK3β is responsible for AMPK inhibition, which accounts for high de novo fatty acid synthesis in naïve (ESCs). The knockout of glycogen synthase 1 in naïve ESCs; GKO, resulting in a drastic glycogen loss, leads to a robust AMPK activation and lowers the level of fatty acids. GKO loses cellular characteristics of naïve ESCs and rapidly transitioned to a primed state. The characteristics of GKO are restored by the simultaneous AMPK KO. These findings suggest that high glycogen in epiblast within pre-implantation blastocyst may act as a signaling molecule for timely activation of AMPK, thus ultimately contributing to transition to post-implantation stage epiblast.