Lee, J.H., Budanov, A.V., Talukdar, S., Park, E.J., Park, H.L., Park, H.W., Bandyopadhyay, G., Li, N., Aghajan, M., Jang, I., Wolfe, A.M., Perkins, G.A., Ellisman, M.H., Bier, E., Scadeng, M., Foretz, M., Viollet, B., Olefsky, J., Karin, M. (2012). Maintenance of metabolic homeostasis by Sestrin2 and Sestrin3.  Cell Metab. 16(3): 311--321.

FBrf0244812

Research paper

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.

PMC3687365 (PMC) (EuropePMC)