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 p58(IPK), 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.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Calcium-Calmodulin-Dependent Protein Kinase Type 2 / antagonists & inhibitors
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Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
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Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
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Cells, Cultured
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Endoplasmic Reticulum Stress / drug effects
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Hepatocytes / cytology
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Hepatocytes / drug effects
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Hepatocytes / metabolism*
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Humans
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Insulin / metabolism*
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Insulin / pharmacology
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Obese
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Mice, Transgenic
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Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 14 / genetics
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Mitogen-Activated Protein Kinase 14 / metabolism
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Obesity / metabolism*
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Obesity / pathology
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Palmitates / pharmacology
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Phosphorylation / drug effects
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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Signal Transduction*
Substances
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Insulin
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Intracellular Signaling Peptides and Proteins
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Palmitates
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MAP-kinase-activated kinase 2
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Camk2g protein, mouse
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Mitogen-Activated Protein Kinase 14