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Inhibition of insulin signaling and adipogenesis by rapamycin: effect on phosphorylation of p70 S6 kinase vs eIF4E-BP1.
Int J Obes Relat Metab Disord. 2004 Feb; 28(2):191-8.IJ

Abstract

OBJECTIVE

Insulin-responsive adipogenic signaling molecules include insulin receptor substrates (IRS)-1 and -2, phosphoinositide 3-kinase (PI3K), and protein kinase B (PKB; also known as Akt). Mammalian target of rapamycin (mTOR) is a PKB substrate, and regulates p70 S6 kinase (p70 S6K). Since p70 S6K is an insulin-responsive kinase downstream of PI3K and PKB, its potential role in adipogenic insulin signaling was investigated.

DESIGN

We measured the effect of rapamycin, a specific inhibitor of mTOR, on insulin-induced 3T3-L1 adipogenesis and on insulin-stimulated p70 S6K activation.

RESULTS

Rapamycin partially reduced differentiation, measured by Oil Red O staining, triacylglycerol accumulation (by up to 46%), and peroxisome proliferator-activated receptor gamma protein expression (by 50%). In contrast, rapamycin completely inhibited insulin-stimulated p70 S6K activation, assessed by phosphorylation of p70 S6K and its substrate, S6. Expression of a constitutively activated form of p70 S6K did not promote 3T3-L1 adipogenesis. The considerable residual differentiation in the presence of rapamycin, despite the complete blockade of p70 S6K activation, prompted us to measure the phosphorylation of another rapamycin-sensitive protein, eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1). Insulin-stimulated 4E-BP1 phosphorylation in 3T3-L1 preadipocytes was only partially affected by rapamycin, consistent with the differentiation data. Phosphorylation of eIF4E itself, an expected consequence of 4E-BP1 phosphorylation, was also only partially inhibited.

CONCLUSION

Our data suggest that adipogenic mTOR signaling occurs via the 4E-BP1/eIF4E pathway, rather than through p70 S6K.

Authors+Show Affiliations

Department of Medicine and Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa Health Research Institute, Ottawa, Canada K1Y 4E9.No affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

14970836

Citation

El-Chaâr, D, et al. "Inhibition of Insulin Signaling and Adipogenesis By Rapamycin: Effect On Phosphorylation of P70 S6 Kinase Vs EIF4E-BP1." International Journal of Obesity and Related Metabolic Disorders : Journal of the International Association for the Study of Obesity, vol. 28, no. 2, 2004, pp. 191-8.
El-Chaâr D, Gagnon A, Sorisky A. Inhibition of insulin signaling and adipogenesis by rapamycin: effect on phosphorylation of p70 S6 kinase vs eIF4E-BP1. Int J Obes Relat Metab Disord. 2004;28(2):191-8.
El-Chaâr, D., Gagnon, A., & Sorisky, A. (2004). Inhibition of insulin signaling and adipogenesis by rapamycin: effect on phosphorylation of p70 S6 kinase vs eIF4E-BP1. International Journal of Obesity and Related Metabolic Disorders : Journal of the International Association for the Study of Obesity, 28(2), 191-8.
El-Chaâr D, Gagnon A, Sorisky A. Inhibition of Insulin Signaling and Adipogenesis By Rapamycin: Effect On Phosphorylation of P70 S6 Kinase Vs EIF4E-BP1. Int J Obes Relat Metab Disord. 2004;28(2):191-8. PubMed PMID: 14970836.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of insulin signaling and adipogenesis by rapamycin: effect on phosphorylation of p70 S6 kinase vs eIF4E-BP1. AU - El-Chaâr,D, AU - Gagnon,A, AU - Sorisky,A, PY - 2004/2/19/pubmed PY - 2004/4/13/medline PY - 2004/2/19/entrez SP - 191 EP - 8 JF - International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity JO - Int. J. Obes. Relat. Metab. Disord. VL - 28 IS - 2 N2 - OBJECTIVE: Insulin-responsive adipogenic signaling molecules include insulin receptor substrates (IRS)-1 and -2, phosphoinositide 3-kinase (PI3K), and protein kinase B (PKB; also known as Akt). Mammalian target of rapamycin (mTOR) is a PKB substrate, and regulates p70 S6 kinase (p70 S6K). Since p70 S6K is an insulin-responsive kinase downstream of PI3K and PKB, its potential role in adipogenic insulin signaling was investigated. DESIGN: We measured the effect of rapamycin, a specific inhibitor of mTOR, on insulin-induced 3T3-L1 adipogenesis and on insulin-stimulated p70 S6K activation. RESULTS: Rapamycin partially reduced differentiation, measured by Oil Red O staining, triacylglycerol accumulation (by up to 46%), and peroxisome proliferator-activated receptor gamma protein expression (by 50%). In contrast, rapamycin completely inhibited insulin-stimulated p70 S6K activation, assessed by phosphorylation of p70 S6K and its substrate, S6. Expression of a constitutively activated form of p70 S6K did not promote 3T3-L1 adipogenesis. The considerable residual differentiation in the presence of rapamycin, despite the complete blockade of p70 S6K activation, prompted us to measure the phosphorylation of another rapamycin-sensitive protein, eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1). Insulin-stimulated 4E-BP1 phosphorylation in 3T3-L1 preadipocytes was only partially affected by rapamycin, consistent with the differentiation data. Phosphorylation of eIF4E itself, an expected consequence of 4E-BP1 phosphorylation, was also only partially inhibited. CONCLUSION: Our data suggest that adipogenic mTOR signaling occurs via the 4E-BP1/eIF4E pathway, rather than through p70 S6K. UR - https://www.unboundmedicine.com/medline/citation/14970836/Inhibition_of_insulin_signaling_and_adipogenesis_by_rapamycin:_effect_on_phosphorylation_of_p70_S6_kinase_vs_eIF4E_BP1_ L2 - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=linkout&SEARCH=14970836.ui DB - PRIME DP - Unbound Medicine ER -