Maintenance of metabolic homeostasis by Sestrin2 and Sestrin3
Open accessAbstract
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.
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Transgenic mice deficient in Sens2 and Sens3 genes have demonstrated the important role of these proteins in the suppression of age and obesity-associated mitochondrial disorders.
“transgenic mice deficient in Sens2 and Sens3 genes have demonstrated the important role of these proteins in the suppression of age and obesity-associated mitochondrial disorders (Bae et al., 2013; Lee et al., 2012).”
From Mitochondrial Activity and Dynamics Changes Regarding Metabolism in Ageing and Obesity (2017) · cites this paper as Lee et al., 2012
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References 45 · Cited by 295
Research works printed but not linked: 1
- Haslam DW James WP Obesity Lancet 2005 366 1197 1209 16198769
- Authors
- 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.
- Affiliations
- University of Michigan (US)
- Virginia Commonwealth University (US)
- University of California San Diego (US)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Lee, Jun Hee
- Karin, Michael
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2012-09
- Volume
- 16
- Issue
- 3
- Pages
- 311-321
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC3687365
- OpenAlex
- W2012015257
- Cited by
- 295
- References
- 45
- Citations by year
- 2026: 14 · 2025: 20 · 2024: 14 · 2023: 23 · 2022: 22 · 2021: 32 · 2020: 42 · 2019: 22 · 2018: 18 · 2017: 15 · 2016: 23 · 2015: 20 · 2014: 20 · 2013: 9
- FWCI
- 6.30
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Arrow@dit (Dublin Institute of Technology) (submittedVersion, cc-by-nc-sa)
- Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion)
- Funders
- American Diabetes Association
- Ellison Medical Foundation (AG‐NS‐0932‐12)
- American Liver Foundation
- American Association for the Study of Liver Diseases
- National Institutes of Health (AG013283, ES010337, AG-024824, RR004050, DK034933, CA46592, CA118165, ES006376)
- University of California, San Diego
- Natural Sciences and Engineering Research Council of Canada
- National Institute on Aging (P30AG013283, P30AG024824)
- National Cancer Institute (P30-CA 46592, P30-CA-23100, CA155120, R01CA118165, R01CA155120, CA118165, P30CA023100, P30CA046592)
- National Institute of General Medical Sciences (R01GM067247)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK034933, DK082080, R37DK033651, R01DK033651, K99DK082080, P30DK063491)
- National Institute of Environmental Health Sciences (P42ES010337, ES-006376, R01ES006376)
- National Center for Research Resources (P41RR004050)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- Sestrin2, SESN3, mTORC1, p70 S6 kinase, AMPK, overnutrition, obesity, insulin resistance, impaired glucose tolerance, hepatic steatosis, hepatic lipid metabolism, glucose metabolism, metabolic homeostasis, stress proteins
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Sestrins, Adipose Tissue, Animals, Energy Metabolism, Fatty Liver, Heat-Shock Proteins, Homeostasis, Insulin Resistance, Liver, Mice, Obese, Nuclear Proteins, Obesity, Peroxidases, Proteins, Mice, Knockout, Ribosomal Protein S6 Kinases, 70-kDa, Multiprotein Complexes, Mice, AMP-Activated Protein Kinases, TOR Serine-Threonine Kinases
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