Characterization of the inhibitory effect of growth hormone on primary preadipocyte differentiation.
GH exerts adipogenic activity in several preadipocyte cell lines, whereas in primary rat preadipocytes, GH has an antiadipogenic activity. To better understand the molecular mechanism involved in adipocyte differentiation, the expression of adipocyte-specific genes was analyzed in differentiating preadipocytes in response to GH. We found that the expression of both adipocyte determination and differentiation factor 1 (ADD1) and peroxisome proliferator activated receptor gamma(PPARgamma) was induced in preadipocytes during differentiation. In the presence of GH, which markedly inhibited triglyceride accumulation, no reduction in the expression level of ADD1 was observed in response to GH, whereas there was a 50% reduction in the expression of PPARgamma. The DNA binding activity of the PPARgamma/retinoid X receptor-alpha(RXRalpha) to the ARE7 element from the aP2 gene was also reduced by approximately 50% in response to GH. GH inhibited the expression of late markers of adipocyte differentiation, fatty acid synthase, aP2, and hormone-sensitive lipase by 70-80%. The antiadipogenic effect of GH was not affected by the mitogen-activated protein (MAP) kinase/ extracellular-regulated protein (ERK) kinase inhibitor PD 98059, indicating that the mitogen-activated protein kinase pathway was not involved in GH inhibition of preadipocyte differentiation. The expression of preadipocyte factor-1/fetal antigen 1 was decreased during differentiation, and GH treatment prevented this down-regulation of Pref1/FA1. A possible role for Pref-1/FA1 in mediating the antiadipogenic effect of GH was indicated by the observation that FA1 inhibited differentiation as effectively as GH. These data suggest that GH exerts its inhibitory activity in adipocyte differentiation at a step after the induction of ADD1 but before the induction of genes required for terminal differentiation.
Hansen
L H
LH
Hagedorn Research Institute, Gentofte, Denmark.
Madsen
B
B
Teisner
B
B
Nielsen
J H
JH
Billestrup
N
N
D017667:Adipocytes / Q000187:drug effects*; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins; D002135:Calcium-Binding Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000235:genetics; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006023:Glycoproteins / Q000235:genetics / Q000494:pharmacology; D013006:Growth Hormone / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects / Q000235:genetics; D018996:Myelin P2 Protein / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins / Q000187:drug effects / Q000235:genetics; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000235:genetics; D012097:Repressor Proteins / Q000187:drug effects / Q000235:genetics; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics
D022762:CCAAT-Enhancer-Binding Proteins; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C512925:Dlk1 protein, mouse; C512923:Dlk1 protein, rat; C490174:Fabp7 protein, rat; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005419:Flavonoids; D006023:Glycoproteins; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D018996:Myelin P2 Protein; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D015240:Phorbol 12,13-Dibutyrate; D013006:Growth Hormone; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one