PP2A inhibition results in hepatic insulin resistance despite Akt2 activation

Area of Science:

• Metabolic regulation
• Hepatology
• Molecular endocrinology

Background:

• Insulin normally suppresses liver glucose production (gluconeogenesis) via the Akt pathway, inactivating Forkhead Box O1 (FoxO1).
• Hyperactive Protein Phosphatase 2A (PP2A) and impaired Akt signaling are linked to insulin resistance.

Purpose of the Study:

• To investigate if inhibiting PP2A could improve insulin signaling and reduce hepatic glucose production.
• To explore the role of PP2A in insulin resistance and glucose metabolism.

Main Methods:

• In vitro and in vivo experiments using PP2A inhibitors in hepatocytes and animal models.
• Assessed Akt phosphorylation, FoxO1 inactivation, gluconeogenesis, and glycogen metabolism markers (glycogen synthase and phosphorylase activity).

Main Results:

• PP2A inhibition increased hepatic Akt phosphorylation and FoxO1 inactivation, suppressing gluconeogenesis in hepatocytes.
• Paradoxically, PP2A inhibition worsened insulin resistance in vivo.
• This exacerbation was due to PP2A inhibition causing inactivation of glycogen synthase and activation of phosphorylase, impairing glycogen storage.

Conclusions:

• PP2A plays a critical role in regulating hepatic glycogen metabolism through glycogen synthase and phosphorylase.
• While PP2A inhibition initially appears beneficial for insulin signaling, it disrupts glycogen storage, contributing to insulin resistance.
• Targeting PP2A requires careful consideration of its impact on glycogen metabolism for effective management of glucose regulation.