A Metformin-Responsive Metabolic Pathway Controls Distinct Steps in Gastric Progenitor Fate Decisions and Maturation

Cellular metabolism plays important functions in dictating stem cell behaviors, although its role in stomach epithelial homeostasis has not been evaluated in depth. Here, we show that the energy sensor AMP kinase (AMPK) governs gastric epithelial progenitor differentiation. Administering the AMPK activator metformin decreases epithelial progenitor proliferation and increases acid-secreting parietal cells (PCs) in mice and organoids. AMPK activation targets Krppel-like factor 4 (KLF4), known to govern progenitor proliferation and PC fate choice, and PGC1 alpha, which we show controls PC maturation after their specification. PC-specific deletion of AMPK alpha or PGC1 alpha causes defective PC maturation, which could not be rescued by metformin. However, metformin treatment still increases KLF4 levels and suppresses progenitor proliferation. Thus, AMPK activates KLF4 in progenitors to reduce self-renewal and promote PC fate, whereas AMPK-PGC1 alpha activation within the PC lineage promotes maturation, providing a potential suggestion for why metformin increases acid secretion and reduces gastric cancer risk in humans.