Maintenance of metabolic homeostasis by Sestrin2 and Sestrin3

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Adipose Tissue / 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*
  • Peroxidases
  • Proteins / genetics
  • Proteins / metabolism*
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • TOR Serine-Threonine Kinases

Substances

  • Heat-Shock Proteins
  • Multiprotein Complexes
  • Nuclear Proteins
  • Proteins
  • SESN3 protein, mouse
  • Peroxidases
  • sestrin 2 protein, mouse
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Ribosomal Protein S6 Kinases, 70-kDa
  • AMP-Activated Protein Kinases