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Endocrinology Vol. 142, No. 1 205-212
Copyright © 2001 by The Endocrine Society

ARTICLES

Phosphatidylinositol-3,4,5-Trisphosphate Is Required for Insulin-Like Growth Factor 1-Mediated Survival of 3T3-L1 Preadipocytes1

AnneMarie Gagnon2, Patti Dods, Nicolas Roustan-Delatour, Ching-Shih Chen and Alexander Sorisky

The Departments of Medicine and Biochemistry, Microbiology & Immunology (A.G., P.D., N.R.-D., A.S.), Loeb Health Research Institute, Ottawa Hospital, University of Ottawa, Ottawa, Canada; and the Division of Medicinal Chemistry and Pharmaceutics (C.-S.C.), College of Pharmacy, University of Kentucky, Lexington, Kentucky

Address all correspondence and requests for reprints to: Dr. Alexander Sorisky, Loeb Health Research Institute at the Ottawa Hospital, 725 Parkdale Avenue, Ottawa, Ontario, Canada, K1Y 4E9. E-mail: asorisky{at}Lri.ca

Adipocyte number, a determinant of adipose tissue mass, reflects the balance between the rates of proliferation/differentiation vs. apoptosis of preadipocytes. The percentage of 3T3-L1 preadipocytes undergoing cell death following serum deprivation was reduced by 10 nM insulin-like growth factor (IGF)-1 (from 50.0 ± 0.7% for control starved cells to 27.5 ± 3.1%). TUNEL staining confirmed the apoptotic nature of the cell death. The protective effect of IGF-1 was blocked by phosphoinositide 3-kinase (PI3K) inhibitors, wortmannin, and LY294002, but was unaffected by rapamycin, PD98059, or SB203580, which inhibit mammalian target of rapamycin (mTOR), ERK kinase (MEK1), and p38 MAPK respectively. Exogenous PI(3,4,5)P3 (10 µM), the principal product of IGF-1-stimulated PI3K in 3T3-L1 preadipocytes, had a modest survival effect on its own, reducing cell death from 47.9 ± 3.4% to 35.6 ± 3.5%. When added to the combination of IGF-1 and LY294002, PI(3,4,5)P3 reversed most of the inhibitory effect of LY294002 on IGF-1-dependent cell survival, protein kinase B/Akt phosphorylation, and caspase-3 activity. Taken together, these results implicate PI(3,4,5)P3 as a necessary signal for the anti-apoptotic action of IGF-1 on 3T3-L1 preadipocytes.




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