HIF2? 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 2? (HIF2?) in liver. The transient postprandial increase in hepatic HIF2? attenuates glucagon signaling. Hepatocyte-specific disruption of HIF2? increases postprandial blood glucose and potentiates the glucagon response. Independent of insulin/AKT signaling, activation of hepatic HIF2? resulted in lower blood glucose, improved glucose tolerance, and decreased gluconeogenesis due to blunted hepatic glucagon action. Mechanistically, HIF2? abrogated glucagon-PKA signaling by activating cAMP-phosphodiesterases in a MEK/ERK-dependent manner. Repression of glucagon signaling by HIF2? ameliorated hyperglycemia in streptozotocin-induced diabetes and acute insulin-resistant animal models. This study reveals that HIF2? is essential for the acute postprandial regulation of hepatic glucagon signaling and suggests HIF2? as a potential therapeutic target in the treatment of diabetes.

SUBMITTER: Ramakrishnan SK 

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

REPOSITORIES: biostudies-literature