| Full text | |
| Author(s): |
Ozcan, Lale
[1]
;
de Souza, Jane Cristina
[1]
;
Harari, Alp Avi
[1]
;
Backs, Johannes
[2, 3]
;
Olson, Eric N.
[4]
;
Tabas, Ira
[1, 5, 6]
Total Authors: 6
|
| Affiliation: | [1] Columbia Univ, Dept Med, New York, NY 10032 - USA
[2] Heidelberg Univ, Dept Cardiol, Lab Cardiac Epigenet, D-69120 Heidelberg - Germany
[3] DZHK German Ctr Cardiovasc Res, D-69120 Heidelberg - Germany
[4] Univ Texas SW Med Ctr Dallas, Dept Mol Biol, Dallas, TX 75390 - USA
[5] Columbia Univ, Dept Physiol & Cellular Biophys, New York, NY 10032 - USA
[6] Columbia Univ, Dept Pathol & Cell Biol, New York, NY 10032 - USA
Total Affiliations: 6
|
| Document type: | Journal article |
| Source: | Cell Metabolism; v. 18, n. 6, p. 803-815, DEC 3 2013. |
| Web of Science Citations: | 52 |
| 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-eIF2 alpha-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. (AU) | |
| FAPESP's process: | 12/21290-4 - Cholesterol metabolism and insulin secretion in islets from hypercholesterolemic mice: possible participate of endoplasmic reticulum stress |
| Grantee: | Jane Cristina de Souza Sporkens |
| Support Opportunities: | Scholarships abroad - Research Internship - Post-doctor |