TY - JOUR

T1 - SOCS-3 is involved in the downregulation of the acute insulin-like effects of growth hormone in rat adipocytes by inhibition of Jak2/IRS-1 signaling

AU - Ridderstråle, M

AU - Amstrup, J

AU - Hilton, D J

AU - Billestrup, Nils

AU - Tornqvist, H

PY - 2003/3

Y1 - 2003/3

N2 - One of the long-term effects of growth hormone (GH) in adipocytes is to maintain a state of refractoriness to insulin-like effects, a refractoriness which otherwise declines within a few hours of GH starvation. Here, we examined differences in GH signaling and the possible role for the recently identified family of suppressors of cytokine signaling (SOCS) proteins in the transition between the refractory and the responsive states in rat adipocytes. The ability of GH to stimulate lipogenesis and tyrosine phosphorylation of the GH receptor (GHR), Janus kinase 2 (Jak2), insulin receptor substrate-1 (IRS-1) and -2 (IRS-2) was greatly reduced in refractory as compared to responsive primary rat adipocytes. However, phosphorylation of Signal Transducer and Activator of Transcription 5 (Stat5) was not affected. SOCS-3 and CIS mRNA levels were significantly higher in refractory compared to responsive cells and could be induced by GH, whereas the level of SOCS-2 mRNA was unchanged. With overexpression of GHR, Jak2 and IRS-1 along with each of these SOCS proteins in human A293 cells, we could demonstrate that both SOCS-1 and SOCS-3 completely inhibited the GH-stimulated tyrosine phosphorylation of IRS-1, whereas SOCS-2 and CIS did not. Our data suggest that GH induces refractoriness to the insulin-like effects in a negative-feedback manner by inhibiting GH-induced GHR/Jak2/IRS-1/IRS-2 phosphorylation through upregulation of SOCS-3, which almost completely blocks Jak2 activation.

AB - One of the long-term effects of growth hormone (GH) in adipocytes is to maintain a state of refractoriness to insulin-like effects, a refractoriness which otherwise declines within a few hours of GH starvation. Here, we examined differences in GH signaling and the possible role for the recently identified family of suppressors of cytokine signaling (SOCS) proteins in the transition between the refractory and the responsive states in rat adipocytes. The ability of GH to stimulate lipogenesis and tyrosine phosphorylation of the GH receptor (GHR), Janus kinase 2 (Jak2), insulin receptor substrate-1 (IRS-1) and -2 (IRS-2) was greatly reduced in refractory as compared to responsive primary rat adipocytes. However, phosphorylation of Signal Transducer and Activator of Transcription 5 (Stat5) was not affected. SOCS-3 and CIS mRNA levels were significantly higher in refractory compared to responsive cells and could be induced by GH, whereas the level of SOCS-2 mRNA was unchanged. With overexpression of GHR, Jak2 and IRS-1 along with each of these SOCS proteins in human A293 cells, we could demonstrate that both SOCS-1 and SOCS-3 completely inhibited the GH-stimulated tyrosine phosphorylation of IRS-1, whereas SOCS-2 and CIS did not. Our data suggest that GH induces refractoriness to the insulin-like effects in a negative-feedback manner by inhibiting GH-induced GHR/Jak2/IRS-1/IRS-2 phosphorylation through upregulation of SOCS-3, which almost completely blocks Jak2 activation.

KW - Adipocytes

KW - Animals

KW - Carrier Proteins

KW - DNA-Binding Proteins

KW - Embryo, Mammalian

KW - Feedback, Physiological

KW - Gene Expression

KW - Growth Hormone

KW - Humans

KW - Immediate-Early Proteins

KW - Insulin

KW - Insulin Receptor Substrate Proteins

KW - Intracellular Signaling Peptides and Proteins

KW - Janus Kinase 2

KW - Kidney

KW - Lipids

KW - Male

KW - Milk Proteins

KW - Phosphoproteins

KW - Phosphorylation

KW - Protein-Tyrosine Kinases

KW - Proteins

KW - Proto-Oncogene Proteins

KW - RNA, Messenger

KW - Rats

KW - Rats, Sprague-Dawley

KW - Receptors, Somatotropin

KW - Repressor Proteins

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - STAT5 Transcription Factor

KW - Signal Transduction

KW - Suppressor of Cytokine Signaling Proteins

KW - Trans-Activators

KW - Transcription Factors

KW - Transfection

KW - Tyrosine

U2 - 10.1055/s-2003-39077

DO - 10.1055/s-2003-39077

M3 - Journal article

C2 - 12734778

VL - 35

SP - 169

EP - 177

JO - Hormone and Metabolic Research. Supplement

JF - Hormone and Metabolic Research. Supplement

SN - 0170-5903

IS - 3

ER -