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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 activating cAMP-phosphodiesterases in a MEK/ERK-dependent manner. Repression of glucagon signaling by HIF2α ameliorated hyperglycemia in streptozotocin-induced diabetes and acute insulin-resistant animal models. This study reveals that HIF2α is essential for the acute postprandial regulation of hepatic glucagon signaling and suggests HIF2α as a potential therapeutic target in the treatment of diabetes.

journal_name

Cell Metab

journal_title

Cell metabolism

authors

Ramakrishnan SK,Zhang H,Takahashi S,Centofanti B,Periyasamy S,Weisz K,Chen Z,Uhler MD,Rui L,Gonzalez FJ,Shah YM

doi

10.1016/j.cmet.2016.01.004

subject

Has Abstract

pub_date

2016-03-08 00:00:00

pages

505-16

issue

3

eissn

1550-4131

issn

1932-7420

pii

S1550-4131(16)00038-3

journal_volume

23

pub_type

杂志文章

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