AMP Kinase as a Metabolic Pathway that Guides Differentiation and Maturation from Epithelial Stem Cells Mahliyah Adkins-Threats1, Zhi-Feng Miao2, and Jason C. Mills1 1 Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA email@example.com, firstname.lastname@example.org 2 Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, First Hospital of China Medical University, Shenyang, Liaoning, China email@example.com Traditionally, governance of stem cell differentiation and cell fate decisions is attributed to transcription factors and the growth factors regulating them. However, a century ago it was thought differentiation was largely based on metabolic switches. The gastric corpus is regenerated via a pool of constitutive stem cells ideal for studying epithelial cell differentiation and lineage allocation dynamics. Here we demonstrate that the intracellular energy sensor AMPK acts as a metabolic switch that encourages gastric adult stem cells and progenitor cells to become acid-secreting parietal cells and promotes parietal cell maturation in differentiated cells. At homeostasis and after gastric injury, parietal cell-specific deletion of AMPK and its target PGC1α increased progenitor proliferation and decreased parietal cell census and maturation. Conversely, when AMPK was pharmacologically activated with Metformin, progenitor proliferation decreased while parietal regeneration increased. We also identify KLF4, a transcription factor that dictates fate choice in stem cells, as a progenitor-cell-specific target of AMPK that is upregulated by metformin. We conclude that AMPK acts in stem cells through KLF4 to prevent self-renewal, and promote parietal cell fate; it also acts in committed parietal cells through PCG1α to promote parietal cell maturation. These results provide insight into mechanisms that govern gastric stem cell fate decisions. Moreover, they establish the importance of cell metabolism in guiding epithelial cell fate.