Hepatocyte Piezo1 regulates glycogen metabolism via the FGF21-STAT3 pathway

The metabolism of glycogen in the liver plays a crucial role in regulating blood glucose levels. Previous studies have underscored the critical involvement of Piezo1 in glucose metabolism. However, the role of Piezo1 in hepatic glycogen metabolism remain unexplored. We induced liver-specific deletion of Piezo1 in Piezo1^fl/fl mice using Cre adenovirus via tail vein injection. Compared to Piezo1^fl/fl treated with GFP adenovirus, those treated with AAV-Cre exhibited impaired glucose tolerance, elevated GYS2 and PYGL levels, and decreased FGF21 levels, implicating inhibition of the STAT3 signaling pathway. Furthermore, mice with hepatocyte-specific Piezo1 deletion (Alb-Piezo1^-/-) on a high-fat diet experienced exacerbated blood glucose levels, decreased hepatic FGF21 production, and enhanced PYGL expression and activity. These effects were alleviated by PF-05231023, an FGF21 analog. Additionally, intraperitoneal injection of Yoda1, a Piezo1 agonist, raised FGF21 levels, activating the STAT3 pathway and suppressing PYGL activity, thereby improving glucose tolerance. In vitro studies showed that knockdown of Piezo1 or Stat3 increased PYGL expression. Conversely, activation of Piezo1 led to decreased PYGL expression. Our study reveals a previously unexplored regulatory mechanism of glycogen metabolism by Piezo1 in liver cells, offering new insights into diabetes treatment.