Activation of SOCS-3 by resistin.
Resistin is an adipocyte hormone that modulates glucose homeostasis. Here we show that in 3T3-L1 adipocytes, resistin attenuates multiple effects of insulin, including insulin receptor (IR) phosphorylation, IR substrate 1 (IRS-1) phosphorylation, phosphatidylinositol-3-kinase (PI3K) activation, phosphatidylinositol triphosphate production, and activation of protein kinase B/Akt. Remarkably, resistin treatment markedly induces the gene expression of suppressor of cytokine signaling 3 (SOCS-3), a known inhibitor of insulin signaling. The 50% effective dose for resistin induction of SOCS-3 is approximately 20 ng/ml, close to levels of resistin in serum. Association of SOCS-3 protein with the IR is also increased by resistin. Inhibition of SOCS function prevented resistin from antagonizing insulin action in adipocytes. SOCS-3 induction is the first cellular effect of resistin that is independent of insulin and is a likely mediator of resistin's inhibitory effect on insulin signaling in adipocytes.
Steppan
Claire M
CM
Pfizer Inc., PRGD, MS220-3145, Eastern Point Rd., Groton, CT 06340, USA. claire.m.steppan@pfizer.com
Wang
Juan
J
Whiteman
Eileen L
EL
Birnbaum
Morris J
MJ
Lazar
Mitchell A
MA
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology*; D006729:Hormones, Ectopic / Q000008:administration & dosage / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000502:physiology*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011972:Receptor, Insulin / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D052243:Resistin; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors / Q000378:metabolism*
D006729:Hormones, Ectopic; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011972:Receptor, Insulin; D012097:Repressor Proteins; D052243:Resistin; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; C526295:Irs1 protein, mouse; C499623:Retn protein, mouse; C106644:SOCS3 protein, human