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Chronic inhibition of the mTORC1/S6K1 pathway increases insulin-induced PI3K activity but inhibits Akt2 and glucose transport stimulation in 3T3-L1 adipocytes.
Mol Endocrinol. 2010 Apr; 24(4):766-78.ME

Abstract

The mammalian target of rapamycin complex 1 (mTORC)1 pathway has emerged as a critical signaling component in the modulation of insulin's metabolic action. This effect is triggered by a nutrient- and insulin-mediated negative feedback loop in which mTOR and S6 kinase (S6K)1 phosphorylate insulin receptor substrate (IRS)-1 on serine residues, which blunts phosphatidylinositol 3-kinase (PI3K) activation. Acute inhibition of mTORC1/S6K1 by rapamycin increases insulin signaling and glucose uptake in myocytes and adipocytes, but whether these effects can be maintained under chronic inhibition of mTORC1 or S6K1 remains unclear. Here, we analyzed the effect of chronic rapamycin inhibition or small interfering RNA-based down-regulation of specific elements of the mTORC1/S6K1 pathway on insulin signaling and glucose transport in adipocytes. Both chronic inhibition of mTORC1 by rapamycin or knockdown of either mTOR, raptor, or S6K1 reduced inhibitory serine phosphorylation of IRS-1, while increasing its insulin-stimulated tyrosine phosphorylation and associated PI3K activity. However, knockdown of either mTOR or raptor selectively blunted IRS-1 phosphorylation on Ser636/639, whereas only S6K1 knockdown was found to reduce phosphorylation of IRS-1 on Ser1101. Unexpectedly, insulin-induced activation of Akt2 and glucose transporter 4 expression were reduced after chronic disruption of the mTORC1/S6K1 pathway, impairing insulin-mediated glucose uptake despite increased PI3K activation. In conclusion, these data indicate that both mTORC1 and S6K1 are key elements of the negative feedback loop but inhibit insulin-induced PI3K activity through phosphorylation of specific serine residues in IRS-1. However, this study also shows that chronic inhibition of the mTORC1/S6K1 pathway uncouples IRS-1/PI3K signaling from insulin-induced glucose transport due to impaired activation of Akt2 and blunted glucose transporter 4 expression.

Authors+Show Affiliations

Department of Medicine, Faculty of Medicine, Laval University Hospital Research Center, Québec, Canada.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20203102

Citation

Veilleux, Alain, et al. "Chronic Inhibition of the mTORC1/S6K1 Pathway Increases Insulin-induced PI3K Activity but Inhibits Akt2 and Glucose Transport Stimulation in 3T3-L1 Adipocytes." Molecular Endocrinology (Baltimore, Md.), vol. 24, no. 4, 2010, pp. 766-78.
Veilleux A, Houde VP, Bellmann K, et al. Chronic inhibition of the mTORC1/S6K1 pathway increases insulin-induced PI3K activity but inhibits Akt2 and glucose transport stimulation in 3T3-L1 adipocytes. Mol Endocrinol. 2010;24(4):766-78.
Veilleux, A., Houde, V. P., Bellmann, K., & Marette, A. (2010). Chronic inhibition of the mTORC1/S6K1 pathway increases insulin-induced PI3K activity but inhibits Akt2 and glucose transport stimulation in 3T3-L1 adipocytes. Molecular Endocrinology (Baltimore, Md.), 24(4), 766-78. https://doi.org/10.1210/me.2009-0328
Veilleux A, et al. Chronic Inhibition of the mTORC1/S6K1 Pathway Increases Insulin-induced PI3K Activity but Inhibits Akt2 and Glucose Transport Stimulation in 3T3-L1 Adipocytes. Mol Endocrinol. 2010;24(4):766-78. PubMed PMID: 20203102.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Chronic inhibition of the mTORC1/S6K1 pathway increases insulin-induced PI3K activity but inhibits Akt2 and glucose transport stimulation in 3T3-L1 adipocytes. AU - Veilleux,Alain, AU - Houde,Vanessa P, AU - Bellmann,Kerstin, AU - Marette,André, Y1 - 2010/03/04/ PY - 2010/3/6/entrez PY - 2010/3/6/pubmed PY - 2010/7/14/medline SP - 766 EP - 78 JF - Molecular endocrinology (Baltimore, Md.) JO - Mol. Endocrinol. VL - 24 IS - 4 N2 - The mammalian target of rapamycin complex 1 (mTORC)1 pathway has emerged as a critical signaling component in the modulation of insulin's metabolic action. This effect is triggered by a nutrient- and insulin-mediated negative feedback loop in which mTOR and S6 kinase (S6K)1 phosphorylate insulin receptor substrate (IRS)-1 on serine residues, which blunts phosphatidylinositol 3-kinase (PI3K) activation. Acute inhibition of mTORC1/S6K1 by rapamycin increases insulin signaling and glucose uptake in myocytes and adipocytes, but whether these effects can be maintained under chronic inhibition of mTORC1 or S6K1 remains unclear. Here, we analyzed the effect of chronic rapamycin inhibition or small interfering RNA-based down-regulation of specific elements of the mTORC1/S6K1 pathway on insulin signaling and glucose transport in adipocytes. Both chronic inhibition of mTORC1 by rapamycin or knockdown of either mTOR, raptor, or S6K1 reduced inhibitory serine phosphorylation of IRS-1, while increasing its insulin-stimulated tyrosine phosphorylation and associated PI3K activity. However, knockdown of either mTOR or raptor selectively blunted IRS-1 phosphorylation on Ser636/639, whereas only S6K1 knockdown was found to reduce phosphorylation of IRS-1 on Ser1101. Unexpectedly, insulin-induced activation of Akt2 and glucose transporter 4 expression were reduced after chronic disruption of the mTORC1/S6K1 pathway, impairing insulin-mediated glucose uptake despite increased PI3K activation. In conclusion, these data indicate that both mTORC1 and S6K1 are key elements of the negative feedback loop but inhibit insulin-induced PI3K activity through phosphorylation of specific serine residues in IRS-1. However, this study also shows that chronic inhibition of the mTORC1/S6K1 pathway uncouples IRS-1/PI3K signaling from insulin-induced glucose transport due to impaired activation of Akt2 and blunted glucose transporter 4 expression. SN - 1944-9917 UR - https://www.unboundmedicine.com/medline/citation/20203102/Chronic_inhibition_of_the_mTORC1/S6K1_pathway_increases_insulin_induced_PI3K_activity_but_inhibits_Akt2_and_glucose_transport_stimulation_in_3T3_L1_adipocytes_ L2 - https://academic.oup.com/mend/article-lookup/doi/10.1210/me.2009-0328 DB - PRIME DP - Unbound Medicine ER -