Hepatic p38α regulates gluconeogenesis by suppressing AMPK

Area of Science:

• Metabolic regulation
• Molecular signaling pathways
• Liver physiology

Background:

• The role of p38 in gluconeogenesis is proposed but lacks genetic evidence and mechanistic understanding.
• Hepatic p38α's precise function in glucose production during fasting remains unclear.

Purpose of the Study:

• To investigate the role of hepatic p38α in gluconeogenesis using a genetic loss-of-function approach.
• To elucidate the underlying molecular mechanisms connecting p38α to glucose metabolism.

Main Methods:

• Utilized mice with liver-specific p38α deletion to assess fasting glucose and gluconeogenesis.
• Employed pyruvate tolerance tests and G6Pase promoter activity imaging.
• Confirmed findings in vitro and in vivo using adenoviral constructs for p38α and AMPKα, and assessed upstream kinase involvement.

Main Results:

• Loss of hepatic p38α reduced fasting glucose and impaired gluconeogenesis.
• Hepatic p38α deficiency increased AMPKα phosphorylation, suggesting a negative regulatory role.
• Treatment with activated p38α ameliorated hyperglycemia in diabetic mice, indicating therapeutic potential.

Conclusions:

• Hepatic p38α acts as a negative regulator of AMP-activated protein kinase (AMPK) signaling in gluconeogenesis.
• Dysregulation of the p38α-AMPK network contributes to excessive glucose production in diabetes.
• Hepatic p38α emerges as a potential therapeutic target for managing hyperglycemia.