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Cell Metab. 2012 Sep 5;16(3):311-21. doi: 10.1016/j.cmet.2012.08.004.

Maintenance of metabolic homeostasis by Sestrin2 and Sestrin3.

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1
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California, San Diego, San Diego, CA 92093, USA. leeju@umich.edu

Abstract

Chronic activation of mammalian target of rapamycin complex 1 (mTORC1) and p70 S6 kinase (S6K) in response to hypernutrition contributes to obesity-associated metabolic pathologies, including hepatosteatosis and insulin resistance. Sestrins are stress-inducible proteins that activate AMP-activated protein kinase (AMPK) and suppress mTORC1-S6K activity, but their role in mammalian physiology and metabolism has not been investigated. We show that Sestrin2--encoded by the Sesn2 locus, whose expression is induced upon hypernutrition--maintains metabolic homeostasis in liver of obese mice. Sesn2 ablation exacerbates obesity-induced mTORC1-S6K activation, glucose intolerance, insulin resistance, and hepatosteatosis, all of which are reversed by AMPK activation. Furthermore, concomitant ablation of Sesn2 and Sesn3 provokes hepatic mTORC1-S6K activation and insulin resistance even in the absence of nutritional overload and obesity. These results demonstrate an important homeostatic function for the stress-inducible Sestrin protein family in the control of mammalian lipid and glucose metabolism.

PMID:
22958918
PMCID:
PMC3687365
DOI:
10.1016/j.cmet.2012.08.004
[Indexed for MEDLINE]
Free PMC Article

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