Calcium signaling through CaMKII regulates hepatic glucose production in fasting and obesity.

Abstract

Hepatic glucose production (HGP) is crucial for glucose homeostasis, but the underlying mechanisms have not been fully elucidated. Here, we show that a calcium-sensing enzyme, CaMKII, is activated in a calcium- and IP3R-dependent manner by cAMP and glucagon in primary hepatocytes and by glucagon and fasting in vivo. Genetic deficiency or inhibition of CaMKII blocks nuclear translocation of FoxO1 by affecting its phosphorylation, impairs fasting- and glucagon/cAMP-induced glycogenolysis and gluconeogenesis, and lowers blood glucose levels, while constitutively active CaMKII has the opposite effects. Importantly, the suppressive effect of CaMKII deficiency on glucose metabolism is abrogated by transduction with constitutively nuclear FoxO1, indicating that the effect of CaMKII deficiency requires nuclear exclusion of FoxO1. This same pathway is also involved in excessive HGP in the setting of obesity. These results reveal a calcium-mediated signaling pathway involved in FoxO1 nuclear localization and hepatic glucose homeostasis.

• Authors: Lale Ozcan, Catherine C L Wong, Gang Li, Tao Xu, Utpal Pajvani, Sung Kyu Robin Park, Anetta Wronska, Bi-Xing Chen, Andrew R Marks, Akiyoshi Fukamizu, Johannes Backs, Harold A Singer, John R Yates 3rd, Domenico Accili, Ira Tabas
• Journal: Cell metabolism (Cell Metab) Vol. 15 Issue 5 Pg. 739-51 (May 02 2012) ISSN: 1932-7420 [Electronic] United States
• PMID: 22503562 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Blood Glucose
• Forkhead Box Protein O1
• Forkhead Transcription Factors
• Foxo1 protein, mouse
• Inositol 1,4,5-Trisphosphate Receptors
• Glucagon
• Cyclic AMP
• Proto-Oncogene Proteins c-akt
• Calcium-Calmodulin-Dependent Protein Kinase Type 2
• p38 Mitogen-Activated Protein Kinases
• Glucose
• Calcium

Topics

• Animals
• Blood Glucose (metabolism)
• Calcium (metabolism)
• Calcium Signaling (physiology)
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (metabolism)
• Cell Nucleus (metabolism)
• Cyclic AMP (metabolism)
• Fasting (metabolism)
• Forkhead Box Protein O1
• Forkhead Transcription Factors (metabolism)
• Glucagon (metabolism)
• Gluconeogenesis
• Glucose (metabolism)
• Glycogenolysis
• Hepatocytes (metabolism)
• Homeostasis
• Inositol 1,4,5-Trisphosphate Receptors (metabolism)
• Liver (metabolism)
• Mice
• Mice, Inbred C57BL
• Obesity (metabolism)
• Phosphorylation
• Protein Transport
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction
• p38 Mitogen-Activated Protein Kinases (metabolism)