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PMID:22958918

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Citation

Lee, JH, Budanov, AV, Talukdar, S, Park, EJ, Park, HL, Park, HW, Bandyopadhyay, G, Li, N, Aghajan, M, Jang, I, Wolfe, AM, Perkins, GA, Ellisman, MH, Bier, E, Scadeng, M, Foretz, M, Viollet, B, Olefsky, J and Karin, M (2012) Maintenance of metabolic homeostasis by sestrin2 and sestrin3. Cell Metab. 16:311-21

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.

Links

PubMed Online version:10.1016/j.cmet.2012.08.004

Keywords


Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:LEP

acts_upstream_of_or_within

GO:0006635: fatty acid beta-oxidation

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:2651874

P

Seeded From UniProt

complete

MOUSE:LEP

acts_upstream_of_or_within

GO:0042593: glucose homeostasis

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:2651874

P

Seeded From UniProt

complete

MOUSE:SESN1

acts_upstream_of_or_within

GO:0051896: regulation of protein kinase B signaling

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SESN3

acts_upstream_of_or_within

GO:0032868: response to insulin

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:2651874

P

Seeded From UniProt

complete

MOUSE:SESN3

acts_upstream_of_or_within

GO:0051896: regulation of protein kinase B signaling

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SESN3

acts_upstream_of_or_within

GO:0042593: glucose homeostasis

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:2651874

P

Seeded From UniProt

complete

MOUSE:SESN2

acts_upstream_of_or_within

GO:0032868: response to insulin

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:104663
MGI:MGI:1922997

P

Seeded From UniProt

complete

MOUSE:SESN2

acts_upstream_of_or_within

GO:0042593: glucose homeostasis

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:104663

P

Seeded From UniProt

complete

MOUSE:SESN2

GO:0010255 : glucose mediated signaling pathway

ECO:0000314:

P

Figure 1A and 1B show that a deficiency in SESN2 had a great effect on the activation and production of Glucose.

complete
CACAO 5082

MOUSE:SESN2

GO:0000723: telomere maintenance

ECO:0000021:

UniProtKB:Q9Y478


P

From the graphical abstract one can see that SESN2 would be used as an activating and maintainer of AMPK. This is also seen in figure one where the concentration of SESN2 effects the activation of AMPK

complete
CACAO 5083

MOUSE:SESN2

acts_upstream_of_or_within

GO:0006111: regulation of gluconeogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3587950

P

Seeded From UniProt

complete

MOUSE:SESN2

acts_upstream_of_or_within

GO:0009749: response to glucose

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:104663
MGI:MGI:1922997

P

Seeded From UniProt

complete

MOUSE:SESN2

acts_upstream_of_or_within

GO:0009749: response to glucose

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3587950

P

Seeded From UniProt

complete

MOUSE:SESN2

acts_upstream_of_or_within

GO:0007005: mitochondrion organization

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3587950

P

Seeded From UniProt

complete

MOUSE:SESN2

acts_upstream_of_or_within

GO:0006635: fatty acid beta-oxidation

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:104663

P

Seeded From UniProt

complete

MOUSE:SESN2

acts_upstream_of_or_within

GO:0001932: regulation of protein phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3587950

P

Seeded From UniProt

complete

MOUSE:SESN2

acts_upstream_of_or_within

GO:0032042: mitochondrial DNA metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3587950

P

Seeded From UniProt

complete

MOUSE:SESN2

acts_upstream_of_or_within

GO:0032868: response to insulin

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3587950

P

Seeded From UniProt

complete

MOUSE:SESN2

acts_upstream_of_or_within

GO:0043491: protein kinase B signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3587950

P

Seeded From UniProt

complete

MOUSE:SESN2

acts_upstream_of_or_within

GO:0046323: glucose import

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3587950

P

Seeded From UniProt

complete

MOUSE:SESN2

acts_upstream_of_or_within

GO:0070328: triglyceride homeostasis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3587950

P

Seeded From UniProt

complete

MOUSE:SESN2

acts_upstream_of_or_within

GO:1904504: positive regulation of lipophagy

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3587950

P

Seeded From UniProt

complete

MOUSE:SESN2

acts_upstream_of_or_within

GO:2000479: regulation of cAMP-dependent protein kinase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3587950

P

Seeded From UniProt

complete


See also

References

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