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

Cell Metab. 2012 May 2;15(5):739-51. doi: 10.1016/j.cmet.2012.03.002. Epub 2012 Apr 12.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • 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