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

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

References

• 1 Isaksson O GP, Edén S, Jansson J O. Mode of action of pituitary growth hormone on target cells.  Ann Rev Physiol. 1985;  47 483-499
• 2 Press M. Growth hormone and metabolism.  Diabetes Metab Rev. 1988;  4 391-414
• 3 Davidson M. Effect of growth hormone on carbohydrate and lipid metabolism.  Endocr Rev. 1987;  8 115-131
• 4 Wabitsch M, Hauner H, Heinze E, Teller W. In vitro effects of growth hormone in adipose tissue.  Acta Paediatr Suppl. 1994;  83 48-53
• 5 Wabitsch M, Heinze E, Hauner H, Shymko R M, Teller W M, de Meyts P. Ilondo M. Biological effects of human growth hormone in rat adipocyte precursor and newly differentiated adipocytes in primary culture.  Metabolism. 1996;  45 34-42
• 6 Edén S, Schwartz J, Kostyo J L. Effects of preincubation on the ability of rat adipocytes to bind and response to growth hormone.  Endocrinology. 1982;  111 1505-1512
• 7 Eriksson H, Ridderstråle M, Tornqvist H. Tyrosin phosphorylation of the growth hormone (GH) receptor and Janus tyrosine kinase-2 is involved in the insulin-like effects of GH in primary rat adipocytes.  Endocrinology. 1995;  136 5093-5101
• 8 Ridderstråle M, Degerman E, Tornqvist H. Growth hormone stimulates the tyrosine phosphorylation of the insulin receptor substrate-1 and its association with phosphatidylinositol 3-kinase in primary adipocytes.  J Biol Chem. 1995;  270 3471-3474
• 9 Souza S C, Frick G P, Yip R, Lobo R B, Tai L R, Goodman H M. Growth hormone stimulates tyrosine phosphorylation of insulin receptor substrate-1.  J Biol Chem. 1994;  269 30 085-30 088
• 10 Ridderstråle M, Tornqvist H. PI-3-kinase inhibitor wortmannin blocks the insulin-like effects of growth hormone in isolated rat adipocytes.  Biochem Biophys Res Commun. 1994;  203 306-310
• 11 Fain J N. Studies on the role of RNA and protein synthesis in the lipolytic action of growth hormone in isolated fat cells.  Adv Enzyme Regul. 1967;  5 39-51
• 12 Fain J N, Saperstein R. The involvement of RNA synthesis and cyclic AMP in the activation of fat cell lipolysis by growth hormone and glucocorticoids.  Horm Metab Res. 1970;  2 20-27
• 13 Campbell G S, Pang L, Miyasaka T, Saltiel A R, Carter-Su C. Stimulation by growth hormone of MAP kinase activity in 3T3-F442A fibroblasts.  J Biol Chem. 1992;  267 6074-6080
• 14 Winston L A, Bertics P J. Growth hormone stimulates the tyrosine phosphorylation of 42- and 45-kDa ERK-related proteins.  J Biol Chem. 1992;  267 4747-4751
• 15 Anderson N G. Growth hormone activates mitogen-activated protein kinase and S6 kinase and promotes intracellular tyrosine phosphorylation in 3T3-F442A preadipocytes.  Biochem J. 1992;  284 649-652
• 16 Schindler C, Darnell J E. Transcriptional responses to polypeptide ligands: the JAK-STAT pathway.  Annu Rev Biochem. 1995;  64 621-651
• 17 Carter-Su C, Schwartz J, Smit L S. Molecular mechanism of growth hormone action.  Ann Rev Physiol. 1996;  58 187-207
• 18 Ridderstråle M, Groop L. Differential phosphorylation of Janus kinase 2, Stat5A and Stat5B in response to growth hormone in primary rat adipocytes.  Mol Cell Endocrinol. 2001;  183 49-54
• 19 Goodman H M. Separation of early and late responses of adipose tissue to growth hormone.  Endocrinology. 1981;  109 120-129
• 20 Schwartz Y, Yamaguchi H, Goodman H M. Growth hormone increases intracellular free calcium in rat adipocytes: correlation with actions on carbohydrate metabolism.  Endocrinology. 1992;  131 772-778
• 21 Starr R, Willson T A, Viney E M, Murray L J, Rayner J R, Jenkins B J, Gonda T J, Alexander W S, Metcalf D, Nicola N A, Hilton D J. A family of cytokine-inducible inhibitors of signalling.  Nature. 1997;  387 917-921
• 22 Endo T A, Masuhara M, Tokouchi M, Suzuki R, Sakamoto H, Mitsui K, Matsumoto A, Tanimura S, Ohtsubo M, Misawa H, Miyazaki T, Leonor N, Taniguchi T, Fujita T, Kanakura Y, Komiya S, Yoshimura A. A new protein containing an SH2 domain that inhibits JAK kinases.  Nature. 1997;  387 921-924
• 23 Auernhammer C J, Melmed S. The central role of OSCS-3 in integrating the neuro-immunoendocrine interface.  J Clin Invest. 2001;  108 1735-1740
• 24 Adams T E, Hansen J A, Starr R, Nicola N A, Hilton D J, Billestrup N. Growth hormone preferentially induces the rapid, transient expression of SOCS-3, a novel inhibitor of cytokine receptor signaling.  J Biol Chem. 1998;  273 1285-1287
• 25 Favre H, Benhamou A, Finidori J, Kelly P A, Edery M. Dual effects of suppressor of cytokine signaling (SOCS-2) on growth hormone signal transduction.  FEBS Lett. 1999;  453 63-66
• 26 Ram P A, Waxman D J. SOCS/CIS protein inhibition of growth hormone-stimulated STAT5 signaling by mutiple mechanisms.  J Biol Chem. 1999;  274 35 553-35 561
• 27 Rodbell M. Metabolism of isolated fat cells.  J Biol Chem. 1964;  239 375-380
• 28 Moody A J, Stan M A, Stan M, Glieman J. A simple free fat cell bioassay for insulin.  Horm Metab Res. 1974;  6 12-16
• 29 Chen C, Okayama H. High-efficiency transformation of mammalian cells by plasmid DNA.  Mol Cell Biol. 1987;  7 2745-2752
• 30 Gorman C M, Gies D, McCray G, Huang M. The human cytomegalovirus major immediate early promoter can be trans-activated by adenovirus early proteins.  Virology. 1989;  171 377-385
• 31 Jensen J, Serup P, Karlsen C, Nielsen T F, Madsen O D. mRNA profiling of rat islet tumors reveals nkx 6.1 as a beta-cell-specific homeodomain transcription factor.  J Biol Chem. 1996;  271 18 749-18 758
• 32 Ridderstråle M, Tornqvist H. Effects of tyrosine kinase inhibitors on tyrosine phosphorylations and the insulin-like effects in response to human growth hormone in isolated rat adipocytes.  Endocrinology. 1996;  137 4650-4656
• 33 Tamemoto H, Kadowaki T, Tobe K, Yagi T, Sakura H, Hayakawa T, Terauchi Y, Ueki K, Kaburagi Y, Satoh S, Sekihara H, Yoshioka S, Horikoshi H, Furuta Y, Ikawa Y, Kasuga M, Yazaki Y, Aizawa S. Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1.  Nature. 1994;  372 182-186
• 34 Araki E, Lipes M A, Patti M E, Bruning J C, Haag B, Johnson R S, Kahn C R. Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene.  Nature. 1994;  372 186-190
• 35 Sun X J, Wang L M, Zhang Y T, Yenush L, Myers M G, Glasheen E, Lane W S, Pierce J H, White M F. Role of IRS-2 in insulin and cytokine signalling.  Nature. 1995;  377 173-177
• 36 Lavan B E, Lane W S, Lienhard G E. The 60-kDa phosphotyrosine protein in insulin-treated adipocytes is a new member of the insulin receptor substrate family.  J Biol Chem. 1997;  272 11 439-11 443
• 37 Argetsinger L S, Norstedt G, Billestrup N, White M F, Carter-Su C. Growth hormone, interferon-gamma, and leukemia inhibitory factor utilize insulin receptor substrate-2 in intracellular signaling.  J Biol Chem. 1996;  271 29 415-29 421
• 38 Chow J C, Ling P R, Qu Z, Laviola L, Ciccarone A, Bistrian B R, Smith R J. Growth hormone stimulates tyrosine phosphorylation of JAK2 and STAT5, but not insulin receptor substrate-1 or SHC proteins in liver and skeletal muscle of normal rats in vivo.  Endocrinology. 1996;  137 2880-2886
• 39 Yamauchi T, Kaburagi Y, Ueki K, Tsuji Y, Stark G R, Kerr I M, Tsushima T, Akanuma Y, Komuro I, Tobe K, Yazaki Y, Kadowaki T. Growth hormone and prolactin stimulate tyrosine phosphorylation of insulin receptor substrate-1, -2, and -3, their association with p85 phosphatidylinositol 3-kinase (PI3-kinase), and concomitantly PI3-kinase activation via JAK2 kinase.  J Biol Chem. 1998;  273 15 719-15 726
• 40 Thirone A C, Carvalho C R, Saad M J. Growth hormone stimulates the tyrosine kinase activity of JAK2 and induces tyrosine phosphorylation of insulin receptor substrates and Shc in rat tissues.  Endocrinology. 1999;  140 55-62
• 41 Villanueva-Peñacarrillo M L, Márquez L, González N, Díaz-Miguel M, Valverde I. Effect of GLP-1 on lipid metabolism in human adipocytes.  Horm Metab Res. 2001;  33 73-77
• 42 Lobie P E, Mertani H, Morel G, Moralesbustos O, Norstedt G, Waters M J. Receptor-mediated nuclear translocation of growth hormone.  J Biol Chem. 1994;  269 21 330-21 339
• 43 Lobie P E, Wood T JJ, Chen C M, Waters M J, Norstedt G. Nuclear translocation and anchorage of the growth hormone receptor.  J Biol Chem. 1994;  269 31 735-31 746
• 44 Argetsinger L S, Campbell G S, Yang X, Witthuhn B A, Silvennoinen O, Ihle J N, Carter-Su C. Identification of JAK2 as a growth hormone receptor-associated tyrosine kinase.  Cell. 1993;  74 237-244
• 45 Johnston J A, Kawamura M, Kirken R A, Chen Y, Blake T B, Shibuya K, Ortaldo J R, Mcvicar D W, O'Shea J J. Phosphorylation and activation of the Jak-3 Janus kinase in response to interleukin-2.  Nature. 1994;  370 151-153
• 46 Smit L S, Meyer D J, Billestrup N, Norstedt G, Schwartz J, Carter-Su C. The role of the growth hormone (GH) receptor and JAK1 and JAK2 kinases in the activation of Stats 1, 3 and 5 by GH.  Mol Endocrinol. 1996;  10 519-533
• 47 Han Y L, Leaman D W, Watling D, Rogers N C, Groner B, Kerr I M, Wood W I, Stark G R. Participation of JAK and STAT proteins in growth hormone-induced signaling.  J Biol Chem. 1996;  271 5947-5952
• 48 Carter-Su C, Smit L S. Signaling via JAK tyrosine kinases: growth hormone receptor as a model system.  Recent Prog Horm Res. 1998;  53 61-82
• 49 Zhu T, Goh E L, Lobie P E. Growth hormone stimulates the tyrosine phosphorylation and association of p125 focal adhesion kinase (FAK) with JAK2. Fak is not required for Stat-mediated transcription.  J Biol Chem. 1998;  273 10 682-10 689
• 50 Zhu T, Goh E LK, LeRoith D, Lobie P E. Growth hormone stimulates the formation of a multiprotein signaling complex involving p130(Cas) and CrkII. Resultant activation of c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK).  J Biol Chem. 1998;  273 33 864-33 875
• 51 Silva C M, Lu H, Day R N. Characterization and cloning of STAT5 from IM-9 cells and its activation by growth hormone.  Mol Endocrinol. 1996;  10 508-518
• 52 Ilondo M M, Damholt A B, Cunningham B A, Wells J A, Demeyts P, Shymko R M. Receptor dimerization determines the effects of growth hormone in primary rat adipocytes and cultured human IM-9 lymphocytes.  Endocrinology. 1994;  134 2397-2403
• 53 Bousquet C, Susini C, Melmed S. Inhibitory roles for SHP-1 and SOCS-3 following pituitary proopiomelanocortin induction by leukemia inhibitory factor.  J Clin Invest. 1999;  104 1277-1285
• 54 Bjorbaeck C, El-Haschimi K, Frantz J D, Flier J S. The role of SOCS-3 in leptin signaling and leptin resistance.  J Biol Chem. 1999;  274 30 059-30 065
• 55 Pezet A, Favre H, Kelly P A, Edery M. Inhibition and restoration of prolactin signal transduction by suppressors of cytokine signaling.  J Biol Chem. 1999;  274 24 497-24 502
• 56 Siewert E, Muller-Esterl W, Starr R, Heinrich P C, Schaper F. Different protein turnover of interleukin-6-type cytokine signalling components.  Eur J Biochem. 1999;  265 251-257
• 57 Sotiropoulos A, Perrotapplanat M, Dinerstein H, Pallier A, Postelvinay M C, Finidori J, Kelly P A. Distinct cytoplasmic regions of the growth hormone receptor are required for activation of JAK2, mitogen-activated protein kinase, and transcription.  Endocrinology. 1994;  135 1292-1298
• 58 Vanderkuur J A, Wang X Y, Zhang L Y, Campbell G S, Allevato G, Billestrup N, Norstedt G, Carter-Su C. Domains of the growth hormone receptor required for association and activation of JAK2 tyrosine kinase.  J Biol Chem. 1994;  269 21 709-21 717
• 59 Frank S J, Gilliland G, Kraft A S, Arnold C S. Interaction of the growth hormone receptor cytoplasmic domain with the JAK2 tyrosine kinase.  Endocrinology. 1994;  135 2228-2239
• 60 Yip R G, Goodman H M. Growth hormone and dexamethasone stimulate lipolysis and activate adenylyl cyclase in rat adipocytes by selectively shifting Gi alpha2 to lower density membrane fractions.  Endocrinology. 1999;  140 1219-1227