HIF2α Is an Essential Molecular Brake for Postprandial Hepatic Glucagon Response Independent of Insulin Signaling.

ABSTRACT: Glucagon drives hepatic gluconeogenesis and maintains blood glucose levels during fasting. The mechanism that attenuates glucagon action following refeeding is not understood. The present study demonstrates an increase in perivenous liver hypoxia immediately after feeding, which stabilizes hypoxia-inducible factor 2α (HIF2α) in liver. The transient postprandial increase in hepatic HIF2α attenuates glucagon signaling. Hepatocyte-specific disruption of HIF2α increases postprandial blood glucose and potentiates the glucagon response. Independent of insulin/AKT signaling, activation of hepatic HIF2α resulted in lower blood glucose, improved glucose tolerance, and decreased gluconeogenesis due to blunted hepatic glucagon action. Mechanistically, HIF2α abrogated glucagon-PKA signaling by activat

SUBMITTER: Ramakrishnan SK 

PROVIDER: S-EPMC4785079 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature