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

M. Ridderstråle; J. Amstrup; D. J. Hilton; N. Billestrup; H. Tornqvist

doi:10.1055/s-2003-39077

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2003; 35(3): 169-177
DOI: 10.1055/s-2003-39077

Original Basic

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

M. Ridderstråle ¹ , J. Amstrup ² , D. J. Hilton ³ , N. Billestrup ^2, ⁴ , H. Tornqvist ^1, ^2, ⁵

¹ Department of Endocrinology, Lund University, Wallenberg Laboratory, University Hospital Malmö, Malmö, Sweden
² Hagedorn Research Institute, Gentofte, Denmark
³ The Walter and Eliza Hall Institute, Victoria, Australia
⁴ Present address: Steno Hospital, Niels Steensens Vej 2, 2820 Gentofte, Denmark
⁵ Present address: Diabetes Biology, Novo Allé, Novo Nordisk A/S, 2880 Bagsværd, Denmark

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.

Key words

Phosphorylation - Lipogenesis - STAT 5 - Transient Expression - A293 Cells

Full Text

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Dr. M. Ridderstråle

Dept of Endocrinology · Wallenberg Laboratory · University Hospital Malmö

20502 Malmö · Sweden

Phone: + 46 (40) 337215

Fax: + 46 (40) 337042

Email: martin.ridderstrale@endo.mas.lu.se