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Departamento de Bioquimica y Biologia Molecular II Instituto de Bioquimica Facultad de Farmacia Universidad Complutense 28040 Madrid, Spain
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)-signaling pathways involved in differentiation and in
mitogenesis in fetal 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-related genes such as fatty acid synthase, malic enzyme,
glycerol 3-phosphate dehydrogenase, and acetylcoenzyme A carboxylase
induced by IGF-I was totally prevented in the presence of IGF-I and any
of those inhibitors, resulting in a marked decrease of the cytoplasmic
lipid content. Moreover, the expression of the thermogenic marker
uncoupling protein induced by IGF-I was also down-regulated in the
presence of wortmannin/LY294002. IGF-I-induced adipogenic- and
thermogenic-related gene expression was only partly inhibited by the
p70S6k inhibitor rapamycin. In addition,
pretreatment of brown adipocytes with either wortmannin or LY294002,
but not with rapamycin, blocked protein kinase C 
activation by
IGF-I. In contrast, IGF-I-induced fetal brown adipocyte proliferation
was PI 3-kinase-independent. Our results show for the first time an
essential requirement of PI 3-kinase in the IGF-I-signaling pathways
leading to fetal brown adipocyte differentiation, but not leading to
mitogenesis. In addition, protein kinase C seems to be a signaling
molecule also involved in the IGF-I differentiation pathways downstream
from PI 3-kinase.
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