Inhibition of adipose differentiation by phosphatidylinositol 3-kinase inhibitors.
Phosphatidylinositol (PI) 3-kinase plays an important role in various cellular signaling mechanisms in several cell systems. The role of PI 3-kinase in adipose differentiation was investigated. For this purpose, we examined the effect of specific inhibitors of PI 3-kinase on the differentiation of two adipogenic cell lines, 1246 and 3T3-L1. The results show that two structurally different inhibitors of PI 3-kinase, i.e., LY294002 and wortmannin, blocked adipose differentiation in a time and dose-dependent fashion. The results from time- course studies indicated that PI 3-kinase activity is most important in the early phase (day 4 to day 6) of the differentiation program. The effect of PI 3-kinase inhibitor on the expression of the peroxisome proliferator-activated receptor (PPAR) gamma, a master regulator in adipogenesis induced during the differentiation process, was also examined. LY294002 significantly inhibited the induction of PPARgamma mRNA expression. During the initiation phase of adipogenesis (day 4 to day 6), the expression of PPARgamma was induced and LY294002 blocked the increase of expression of PPARgamma mRNA. The inhibition of expression of PPARgamma may provide a molecular mechanism for the action of PI 3-kinase inhibitors on adipose differentiation.
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Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, USA.
Serrero
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D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D000818:Animals; D015152:Blotting, Northern; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002867:Chromones / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D051379:Mice; D009025:Morpholines / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one