Role of PPARγ in Regulating Adipocyte Differentiation and Insulin‐Responsive Glucose Uptake

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Abstract
Adipocyte differentiation is regulated by at least two families of transcription factors, CCAAT/enhancer binding proteins (C/EBPs) and peroxisome proliferator-activated receptors (PPARs). Induction of PPARγ gene transcription during the differentiation of preadipocytes into adipocytes in vitro occurs following an initial phase of cell proliferation and requires a direct involvement of C/EBPβ, C/EBPδ, and glucocorticoids. Ectopic expression of PPARγ in non-adipogenic, Swiss 3T3 fibroblasts promotes their conversion into adipocytes as indicated by the accumulation of lipid droplets and the induction of C/EBPα, aP2, insulin-responsive aminopeptidase (IRAP), and glucose transporter 4 (GLUT4) expression. These PPARγ-expressing Swiss cells also exhibit a high level of insulin-responsive glucose uptake that is comparable to that expressed in 3T3-L1 adipocytes. In contrast, PPARγ-expressing NIH-3T3 fibroblasts, despite similar lipid accumulation, adipocyte morphology, and aP2 expression, do not synthesize C/EBPα and fail to acquire insulin sensitivity. In Swiss 3T3 cells ectopically expressing PPARγ, the development of insulin-responsive glucose uptake correlates with C/EBPα expression. Furthermore, ectopic expression of C/EBPα in NIH-3T3 cells induces PPARγ expression and adipogenesis, but also restores insulin-sensitive glucose transport. These results suggest that although PPARγ is sufficient to trigger the adipogenic program, C/EBPα is required for establishment of insulin-sensitive glucose transport in adipocytes.