Cell metabolism, 2012-09, Vol.16 (3), p.311-321
2012
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- Autor(en) / Beteiligte
- Titel
- Maintenance of Metabolic Homeostasis by Sestrin2 and Sestrin3
- Ist Teil von
- Cell metabolism, 2012-09, Vol.16 (3), p.311-321
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2012
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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. [Display omitted] ► Stress-inducible Sestrins have an important homeostatic function ► Sestrin2 prevents obesity-induced insulin resistance and diabetic progression ► Sestrin2/3-DKO mice exhibit spontaneous mTORC1 activation and insulin resistance ► Sestrin2 potentiates AKT activation through the AMPK-mTORC1 axis
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1550-4131eISSN: 1932-7420DOI: 10.1016/j.cmet.2012.08.004Titel-ID: cdi_proquest_miscellaneous_1039039066
- Format
- –
- Schlagworte
- Adipose Tissue - metabolism, AMP-Activated Protein Kinases - metabolism, Animals, Energy Metabolism - physiology, Fatty Liver - etiology, Fatty Liver - metabolism, Heat-Shock Proteins - metabolism, Homeostasis - physiology, Insulin Resistance - genetics, Liver - metabolism, Liver - physiology, Mechanistic Target of Rapamycin Complex 1, Mice, Mice, Knockout, Mice, Obese, Multiprotein Complexes, Nuclear Proteins, Obesity - complications, Obesity - metabolism, Proteins - genetics, Proteins - metabolism, Ribosomal Protein S6 Kinases, 70-kDa - metabolism, TOR Serine-Threonine Kinases