The role of signal transducer and activator of transcription 5 in the inhibitory effects of GH on adipocyte differentiation

TY - JOUR

T1 - The role of signal transducer and activator of transcription 5 in the inhibitory effects of GH on adipocyte differentiation

AU - Richter, H E

AU - Albrektsen, T

AU - Billestrup, Nils

PY - 2003/4

Y1 - 2003/4

N2 - GH inhibits primary rat preadipocyte differentiation and expression of late genes required for terminal differentiation. Here we show that GH-mediated inhibition of fatty acid-binding protein aP2 gene expression correlates with the activation of the Janus kinase-2/signal transducer and activator of transcription (STAT)-5 signalling pathway. Within minutes of treatment, GH induced the tyrosine phosphorylation, nuclear localization and DNA binding of STAT5. Importantly, there was no evidence that STAT5 acted via an interaction with peroxisome proliferator-activated receptor gamma. To further understand the mechanism of STAT5 action, we reconstituted the inhibition of aP2 in a non-adipogenic cell line. Using this system, we showed that the ability of GH to inhibit a 520 bp aP2 reporter was largely dependent upon the presence of either STAT5A or STAT5B. Mutant analysis confirmed that the tyrosine phosphorylation of STAT5 was essential for this signalling. However, STAT5's C-terminal transactivation domain was fully dispensable for this inhibition. Taken together, these data confirm a key regulatory role of STAT5 in adipose tIssue and point to STAT5 as the repressing modulator of GH-mediated inhibition in primary preadipocytes.

AB - GH inhibits primary rat preadipocyte differentiation and expression of late genes required for terminal differentiation. Here we show that GH-mediated inhibition of fatty acid-binding protein aP2 gene expression correlates with the activation of the Janus kinase-2/signal transducer and activator of transcription (STAT)-5 signalling pathway. Within minutes of treatment, GH induced the tyrosine phosphorylation, nuclear localization and DNA binding of STAT5. Importantly, there was no evidence that STAT5 acted via an interaction with peroxisome proliferator-activated receptor gamma. To further understand the mechanism of STAT5 action, we reconstituted the inhibition of aP2 in a non-adipogenic cell line. Using this system, we showed that the ability of GH to inhibit a 520 bp aP2 reporter was largely dependent upon the presence of either STAT5A or STAT5B. Mutant analysis confirmed that the tyrosine phosphorylation of STAT5 was essential for this signalling. However, STAT5's C-terminal transactivation domain was fully dispensable for this inhibition. Taken together, these data confirm a key regulatory role of STAT5 in adipose tIssue and point to STAT5 as the repressing modulator of GH-mediated inhibition in primary preadipocytes.

KW - Adipocytes

KW - Animals

KW - Carrier Proteins

KW - Cell Differentiation

KW - Cells, Cultured

KW - DNA-Binding Proteins

KW - Fatty Acid-Binding Proteins

KW - Gene Expression Regulation

KW - Genes, Reporter

KW - Growth Hormone

KW - Humans

KW - Janus Kinase 2

KW - Milk Proteins

KW - Nuclear Proteins

KW - Phosphorylation

KW - Promoter Regions, Genetic

KW - Protein Isoforms

KW - Protein-Tyrosine Kinases

KW - Proto-Oncogene Proteins

KW - RNA, Messenger

KW - Rats

KW - Receptors, Cytoplasmic and Nuclear

KW - STAT5 Transcription Factor

KW - Signal Transduction

KW - Trans-Activators

KW - Transcription Factors

KW - Tumor Suppressor Proteins

KW - Tyrosine

M3 - Journal article

C2 - 12683938

SN - 0952-5041

VL - 30

SP - 139

EP - 150

JO - Journal of Molecular Endocrinology

JF - Journal of Molecular Endocrinology

IS - 2

ER -