IKKbeta and the anti-adipogenic effect of platelet-derived growth factor in human abdominal subcutaneous preadipocytes.
To clarify how anti-adipogenic factors act on preadipocytes to inhibit their differentiation, we compared preadipocyte signaling responses generated by platelet-derived growth factor (PDGF; anti-adipogenic) versus insulin (pro-adipogenic). PDGF, but not insulin, stimulated the phosphorylation of inhibitor of kappaB kinase beta (IKKbeta) in a time-dependent manner. This PDGF-dependent phosphorylation event was inhibited by 60% (P<0.05) when the cells were pretreated with wortmannin, indicating a requirement for the phosphatidylinositol (PI) 3-kinase/AKT pathway. IKKbeta phosphorylation by PDGF was neither accompanied by IkappaBalpha degradation nor NF-kappaB activation. PDGF inhibited human adipocyte differentiation, assessed by triacylglycerol accumulation (75% reduction; P<0.01) and by fatty acid synthase protein expression (60% reduction; P<0.05); these responses were no longer apparent in the presence of sc-514, a selective inhibitor of IKKbeta. Our data describe a novel PDGF response in human preadipocytes that involves the pro-inflammatory kinase IKKbeta and demonstrate that it is required for the inhibition of adipogenesis.
Gagnon
AnneMarie
A
Chronic Disease Program, Ottawa Health Research Institute, Ottawa, Ontario, Canada.
Landry
Anne
A
Sorisky
Alexander
A
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000502:physiology; D050156:Adipogenesis / Q000187:drug effects*; D000328:Adult; D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism / Q000502:physiology*; D007328:Insulin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D050507:Subcutaneous Fat, Abdominal / Q000166:cytology / Q000187:drug effects*
D019440:Anti-Obesity Agents; D007328:Insulin; D010982:Platelet-Derived Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D051550:I-kappa B Kinase