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Department of Pediatrics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
¹ Department of Biochemistry, Graduate School of Dentistry, Osaka University, 1-8 Yamadaoka, Suita, Osaka 565-0871, Japan
² Department of Biochemistry, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan

(Requests for offprints should be addressed to K Ozono; Email: keioz{at}ped.med.osaka-u.ac.jp)

Growth hormone-deficient (GHD) patients show a decreased number of adipocytes, which is normalized by GH replacement, indicating an adipogenic effect of GH. However, the precise mechanisms underlying this effect remain to be clarified. In this study, we investigated the adipogenic effect of GH. GH stimulated MDI (3-isobutyl-1-methylxanthine, dexamethasone, and insulin)-induced adipogenesis of 3T3-L1 cells with early induction of peroxisome proliferator-activated receptors (PPAR)2 expression. This adipogenic effect of GH was suppressed by overexpression of Stat5A mutant (Stat5A-Y694F), a transcriptional suppressor for the GH–Stat5A/5B signaling pathway, with the reduction of PPAR2 expression. Next, we investigated the relationship between Stat5A/5B and CCAAT/enhancer binding protein (C/EBP)ß/ orPPAR in 3T3-L1 cells. Stat5A/5B stimulated C/EBPß- and C/EBP-induced adipogenesis with enhancement of PPAR2 expression. In addition, Stat5A/5B enhanced the transcriptional activity of C/EBPß/ in the PPAR gene promoter. Furthermore, Stat5A/5B stimulated PPAR-induced adipogenesis and enhanced the transcriptional activity of PPAR. These results suggest that the GH–Stat5A/5B signaling pathway stimulates adipogenesis in cooperation with C/EBPß/ and PPAR. To completely understand the effect of GH, cDNA microarray analysis was performed to screen genes affected by GH during MDI-induced adipogenesis. Among 4277 genes, 18 and 19 genes were up- and down-regulated respectively. cDNA microarray analysis also indicated the up-regulation of PPAR and the modulation of expression of genes coding for growth factors or growth factor receptors, suggesting that GH stimulates adipogenesis in association with the modulation of cell growth. Thus, the GH–Stat5A/B signaling pathway stimulates adipogenesis through two distinct steps. In addition, cDNA microarray data provide us the further insights underlying the adipogenic effect of GH.