Activation of calcium/calmodulin-dependent protein kinase II in obesity mediates suppression of hepatic insulin signaling

Lale Ozcan, Jane Cristina De Souza, Alp Avi Harari, Johannes Backs, Eric N. Olson, Ira Tabas

Research output: Contribution to journalArticle

61 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)803-815
Number of pages13
JournalCell Metabolism
Volume18
Issue number6
DOIs
StatePublished - Dec 3 2013

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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