@article{b687ebf2948548babb66c928223b33c1,
title = "Activation of calcium/calmodulin-dependent protein kinase II in obesity mediates suppression of hepatic insulin signaling",
abstract = "A hallmark of obesity is selective suppression of hepatic insulin signaling ({"}insulin resistance{"}), but critical gaps remain in our understanding of the molecular mechanisms. We now report a major role for hepatic CaMKII, a calcium-responsive kinase that is activated in obesity. Genetic targeting of hepatic CaMKII, its downstream mediator p38, or the p38 substrate and stabilizer MK2 enhances insulin-induced p-Akt in palmitate-treated hepatocytes and obese mouse liver, leading to metabolic improvement. The mechanism of improvement begins with induction of ATF6 and the ATF6 target p58IPK, a chaperone that suppresses the PERK - p-eIF2α - ATF4 branch of the UPR. The result is a decrease in the ATF4 target TRB3, an inhibitor of insulin-induced p-Akt, leading to enhanced activation of Akt and its downstream metabolic mediators. These findings increase our understanding of the molecular mechanisms linking obesity to selective insulin resistance and suggest new therapeutic targets for type 2 diabetes and metabolic syndrome.",
author = "Lale Ozcan and {Cristina De Souza}, Jane and Harari, {Alp Avi} and Johannes Backs and Olson, {Eric N.} and Ira Tabas",
note = "Funding Information: We thank Dr. Harold A. Singer (Albany Medical College) for adeno-LacZ, T287D-CaMKII, and K43A-CaMKII; Dr. Marc Montminy (Salk Institute for Biological Studies) for adeno-TRB3 and adeno-TRB3 RNAi; Randal J. Kaufman (Sanford-Burnham Medical Research Institute) for adeno-ATF4; and Dr. Domenico Accili (Columbia University) for adeno-FoxO1-ADA. This work was supported by an American Heart Association Scientist Development Grant (11SDG5300022) and a NYONRC Pilot and Feasibility Grant (DK26687) to L.O.; by FAPESP/BEPE 2012/21290-4 to J.C.S.; by the DZHK (German Centre for Cardiovascular Research), BMBF (German Ministry of Education and Research), DFG (Deutsche Forschungsgemeinschaft; BA 2258/2-1), and the European Commission (FP7-Health-2010; MEDIA-261409) to J.B.; and by NIH grants HL087123 and HL075662 to I.T. Authors L.O. and I.T. are in the group of cofounders of Tabomedex Biosciences LLC, which is developing inhibitors of the pathway described in this report for treatment of type 2 diabetes. ",
year = "2013",
month = dec,
day = "3",
doi = "10.1016/j.cmet.2013.10.011",
language = "English (US)",
volume = "18",
pages = "803--815",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "6",
}