Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adipocytes / chemistry
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Adipocytes / drug effects*
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Adipocytes / metabolism
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Animals
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Carrier Proteins / genetics
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Carrier Proteins / physiology
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DNA-Binding Proteins / metabolism
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Embryo, Mammalian
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Feedback, Physiological
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Gene Expression
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Growth Hormone / pharmacology*
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Humans
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Immediate-Early Proteins / genetics
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Insulin / pharmacology*
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Insulin Receptor Substrate Proteins
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Intracellular Signaling Peptides and Proteins*
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Janus Kinase 2
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Kidney
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Lipids / biosynthesis
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Male
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Milk Proteins*
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Phosphoproteins / antagonists & inhibitors*
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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Phosphorylation
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism
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Proteins / genetics
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Proteins / physiology*
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Proto-Oncogene Proteins*
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RNA, Messenger / analysis
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Rats
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Rats, Sprague-Dawley
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Receptors, Somatotropin / metabolism
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Repressor Proteins*
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Reverse Transcriptase Polymerase Chain Reaction
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STAT5 Transcription Factor
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Signal Transduction
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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Trans-Activators / metabolism
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Transcription Factors*
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Transfection
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Tyrosine / metabolism
Substances
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Carrier Proteins
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DNA-Binding Proteins
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IRS1 protein, human
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IRS2 protein, human
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Immediate-Early Proteins
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Insulin
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Insulin Receptor Substrate Proteins
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Intracellular Signaling Peptides and Proteins
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Irs1 protein, rat
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Irs2 protein, rat
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Lipids
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Milk Proteins
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Phosphoproteins
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Proteins
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Proto-Oncogene Proteins
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RNA, Messenger
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Receptors, Somatotropin
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Repressor Proteins
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SOCS1 protein, human
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SOCS2 protein, human
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SOCS3 protein, human
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STAT5 Transcription Factor
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Socs1 protein, rat
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Socs2 protein, rat
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Socs3 protein, rat
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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Trans-Activators
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Transcription Factors
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cytokine inducible SH2-containing protein
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Tyrosine
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Growth Hormone
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Protein-Tyrosine Kinases
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JAK2 protein, human
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Jak2 protein, rat
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Janus Kinase 2