Activation of protein kinase B and induction of adipogenesis by insulin in 3T3-L1 preadipocytes - Contribution of phosphoinositide-3,4,5-trisphosphate versus phosphoinositide-3,4-bisphosphate

被引:58
作者
Gagnon, A
Chen, CS
Sorisky, A
机构
[1] Univ Ottawa, Ottawa Hosp, Dept Med, Loeb Res Inst, Ottawa, ON, Canada
[2] Univ Ottawa, Ottawa Hosp, Dept Biochem, Loeb Res Inst, Ottawa, ON, Canada
[3] Univ Kentucky, Coll Pharm, Div Med Chem & Pharmaceut, Lexington, KY 40536 USA
关键词
D O I
10.2337/diabetes.48.4.691
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Ectopic expression of activated protein kinase B (PKB) induces the differentiation of confluent 3T3-L1 preadipocytes into adipocytes. PKB is regulated by the lipid products of phosphoinositide 3-kinase (PI 3-kinase), phosphatidylinositol-3,4-bisphosphate [PI(3,4)P2], and phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3]. However, the relative contribution of each 3-phosphorylated phosphoinositide species in activating PKB remains unclear. Treatment of intact 3T3-L1 preadipocytes with synthetic 3-phosphorylated phosphoinositides revealed that only PI(3,4)P2 stimulated PKB activity. PKB was also activated by insulin, in a dose- and time-dependent manner. This activation was associated with an isolated rise in PI(3,4,5)P3, without any detectable change in PI(3,4)P2, demonstrating that this lipid was sufficient to activate PKB. Wortmannin and LY294002, inhibitors of PI 3-kinase, reduced insulin-dependent activation of PKB, whereas rapamycin, an inhibitor of p70 S6 kinase, had no effect. Platelet-derived growth factor (PDGF), which is not adipogenic, stimulated the production of both 3-phosphorylated phosphoinositide species, and this was associated with a greater activation of PKB than that observed with insulin. A low dose of PDGF (1 ng/ml), which increased the production of only PI(3,4,5)P3 and mirrored the insulin effect, was unable to induce adipocyte differentiation. In summary, insulin and PDGF differ with respect to the accumulation of 3-phosphorylated phosphoinositides and to PKB activation in 3T3-L1 preadipocytes, but these responses do not themselves explain why insulin, but not PDGF, is adipogenic.
引用
收藏
页码:691 / 698
页数:8
相关论文
共 40 条
[1]   TARGETED INACTIVATION OF THE INSULIN-RECEPTOR GENE IN MOUSE 3T3-L1 FIBROBLASTS VIA HOMOLOGOUS RECOMBINATION [J].
ACCILI, D ;
TAYLOR, SI .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1991, 88 (11) :4708-4712
[2]   Biphasic activation of PKBα/Akt in platelets -: Evidence for stimulation both by phosphatidylinositol 3,4-bisphosphate, produced via a novel pathway, and by phosphatidylinositol 3,4,5-trisphosphate [J].
Banfic, H ;
Downes, CP ;
Rittenhouse, SE .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (19) :11630-11637
[3]   A signaling pathway to translational control [J].
Brown, EJ ;
Schreiber, SL .
CELL, 1996, 86 (04) :517-520
[4]   PROTEIN-KINASE-B (C-AKT) IN PHOSPHATIDYLINOSITOL-3-OH INASE SIGNAL-TRANSDUCTION [J].
BURGERING, BMT ;
COFFER, PJ .
NATURE, 1995, 376 (6541) :599-602
[5]   CSF-1 receptor insulin receptor chimera permits CSF-1-dependent differentiation of 3T3-L1 preadipocytes [J].
Chaika, OV ;
Chaika, N ;
Volle, DJ ;
Wilden, PA ;
Pirrucello, SJ ;
Lewis, RE .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (18) :11968-11974
[6]   PHOSPHATIDYLINOSITOL 3-KINASE ACTIVATION IS REQUIRED FOR INSULIN STIMULATION OF PP70 S6 KINASE, DNA-SYNTHESIS, AND GLUCOSE-TRANSPORTER TRANSLOCATION [J].
CHEATHAM, B ;
VLAHOS, CJ ;
CHEATHAM, L ;
WANG, L ;
BLENIS, J ;
KAHN, CR .
MOLECULAR AND CELLULAR BIOLOGY, 1994, 14 (07) :4902-4911
[7]   ADIPSIN/ACYLATION STIMULATING PROTEIN SYSTEM IN HUMAN ADIPOCYTES - REGULATION OF TRIACYLGLYCEROL SYNTHESIS [J].
CIANFLONE, K ;
RONCARI, DAK ;
MASLOWSKA, M ;
BALDO, A ;
FORDEN, J ;
SNIDERMAN, AD .
BIOCHEMISTRY, 1994, 33 (32) :9489-9495
[8]   INHIBITION OF GLYCOGEN-SYNTHASE KINASE-3 BY INSULIN-MEDIATED BY PROTEIN-KINASE-B [J].
CROSS, DAE ;
ALESSI, DR ;
COHEN, P ;
ANDJELKOVICH, M ;
HEMMINGS, BA .
NATURE, 1995, 378 (6559) :785-789
[9]  
DERMAN MP, 1997, J BIOL CHEM, V272, P6455
[10]  
DOWNWARD J, 1998, NATUERE, V279, P673