| First Author | Ramakrishnan SK | Year | 2016 |
| Journal | Cell Metab | Volume | 23 |
| Issue | 3 | Pages | 505-16 |
| PubMed ID | 26853750 | Mgi Jnum | J:233030 |
| Mgi Id | MGI:5780628 | Doi | 10.1016/j.cmet.2016.01.004 |
| Citation | Ramakrishnan SK, et al. (2016) HIF2alpha Is an Essential Molecular Brake for Postprandial Hepatic Glucagon Response Independent of Insulin Signaling. Cell Metab 23(3):505-16 |
| abstractText | 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 2alpha (HIF2alpha) in liver. The transient postprandial increase in hepatic HIF2alpha attenuates glucagon signaling. Hepatocyte-specific disruption of HIF2alpha increases postprandial blood glucose and potentiates the glucagon response. Independent of insulin/AKT signaling, activation of hepatic HIF2alpha resulted in lower blood glucose, improved glucose tolerance, and decreased gluconeogenesis due to blunted hepatic glucagon action. Mechanistically, HIF2alpha abrogated glucagon-PKA signaling by activating cAMP-phosphodiesterases in a MEK/ERK-dependent manner. Repression of glucagon signaling by HIF2alpha ameliorated hyperglycemia in streptozotocin-induced diabetes and acute insulin-resistant animal models. This study reveals that HIF2alpha is essential for the acute postprandial regulation of hepatic glucagon signaling and suggests HIF2alpha as a potential therapeutic target in the treatment of diabetes. |
