PHOSPHATIDYLINOSITOL 3-KINASE IS A REQUIREMENT FOR INSULIN-LIKE-GROWTH-FACTOR I-INDUCED DIFFERENTIATION, BUT NOT FOR MITOGENESIS, IN FETAL BROWN ADIPOCYTES

In the present study we have examined the role of phosphatidylinositol 3-kinase (PI 3-kinase) in the insulin-like growth factor I (IGF-I)-si gnaling pathways involved in differentiation and in mitogenesis in fet al rat brown adipocytes. Activation of Pi 3-kinase in response to IGF- I was markedly inhibited by two PI 3-kinase inhibitors (wortmannin and LY294002) in a dose-dependent manner. IGF-I-stimulated glucose uptake was also inhibited by both compounds. The expression of adipogenic-re lated genes such as fatty acid synthase, malic enzyme, glycerol 3-phos phate dehydrogenase, and acetylcoenzyme A carboxylase induced by IGF-I was totally prevented in the presence of IGF-I and any of those inhib itors, resulting in a marked decrease of the cytoplasmic lipid content . Moreover, the expression of the thermogenic marker uncoupling protei n induced by IGF-I was also down-regulated in the presence of wortmann in/LY294002. IGF-I-induced adipogenic- and thermogenic-related gene ex pression was only partly inhibited by the p70(S6k) inhibitor rapamycin . In addition, pretreatment of brown adipocytes with either wortmannin or LY294002, but not with rapamycin, blocked protein kinase C zeta ac tivation by IGF-I. In contrast, IGF-I-induced fetal brown adipocyte pr oliferation was PI 3-kinase-independent. Our results show for the firs t time an essential requirement of PI 3-kinase in the IGF-I-signaling pathways leading to fetal brown adipocyte differentiation, but not lea ding to mitogenesis. In addition, protein kinase C zeta seems to be a signaling molecule also involved in the IGF-I differentiation pathways downstream from PI 3-kinase.