title: 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.affiliation: Department of Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: Lale
authors.initials: L
authors.lastname: Ozcan
authors.forename: Catherine C L
authors.initials: CC
authors.lastname: Wong
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.forename: Tao
authors.initials: T
authors.lastname: Xu
authors.forename: Utpal
authors.initials: U
authors.lastname: Pajvani
authors.forename: Sung Kyu Robin
authors.initials: SK
authors.lastname: Park
authors.forename: Anetta
authors.initials: A
authors.lastname: Wronska
authors.forename: Bi-Xing
authors.initials: BX
authors.lastname: Chen
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Marks
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Fukamizu
authors.forename: Johannes
authors.initials: J
authors.lastname: Backs
authors.forename: Harold A
authors.initials: HA
authors.lastname: Singer
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.forename: Domenico
authors.initials: D
authors.lastname: Accili
authors.forename: Ira
authors.initials: I
authors.lastname: Tabas
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D005215:Fasting / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005934:Glucagon / Q000378:metabolism; D005943:Gluconeogenesis; D005947:Glucose / Q000378:metabolism*; D050261:Glycogenolysis; D022781:Hepatocytes / Q000378:metabolism; D006706:Homeostasis; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000378:metabolism*; D010766:Phosphorylation; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D053496:Inositol 1,4,5-Trisphosphate Receptors; D005934:Glucagon; D000242:Cyclic AMP; D051057:Proto-Oncogene Proteins c-akt; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D048051:p38 Mitogen-Activated Protein Kinases; D005947:Glucose; D002118:Calcium