Investigating the role of class-IA PI 3-kinase isoforms in adipocyte differentiation

PI 3-kinases, in particular class-IA, are key signalling molecules controlling many cellular processes including growth, proliferation, migration and differentiation. In this study, we have used a collection of isoform selective PI 3-kinase inhibitors to determine whether attenuation of signalling through class-IA PI 3-kinase isoforms will impact adipocyte differentiation. First, we analysed the expression profiles and found that fibroblastic pre-adipocytes express detectable levels of p110alpha and p110delta and that after differentiation, p110delta levels fall while p110alpha levels rise, together with C/EBPalpha and PPARgamma. When using specific inhibitors during the differentiation process, we observed that neither p110beta nor p110delta inhibition, had any significant effect. In contrast PIK-75, a selective p110alpha inhibitor completely abolished adipocyte differentiation as assessed by morphology, transcript and protein levels of adipocyte markers. These results indicate that long term treatment with p110alpha inhibitors could potentially have a severe impact on fat cell numbers in vivo.