Insulin resistance-inducing cytokines differentially regulate SOCS mRNA expression via growth factor- and Jak/Stat-signaling pathways in 3T3-L1 adipocytes.

Various cytokines, including tumor necrosis factor (TNF) alpha, growth hormone (GH) and interleukin (IL)-6, induce insulin resistance. Recently, it was demonstrated that induction of suppressor of cytokine signaling (SOCS)-3 by TNFalpha and GH is an important mechanism by which these cytokines impair insulin sensitivity. The current study investigated in 3T3-L1 adipocytes whether TNFalpha and GH also upregulate SOCS-1 and SOCS-6, which have both been shown to inhibit insulin signaling potently, and whether IL-6 might alter synthesis of SOCS-1, -3 and -6. Interestingly, 10 ng/ml TNFalpha, 500 ng/ml GH and 30 ng/ml IL-6 induced SOCS-1 mRNA time-dependently with maximal stimulation detectable after 8 h of TNFalpha and 1 h of GH and IL-6 addition respectively. Furthermore, TNFalpha and GH caused sustained upregulation of SOCS-1 for up to 24 h, whereas stimulation by IL-6 was only transient, with SOCS-1 mRNA returning to basal levels 2 h after effector addition. Induction of SOCS-1 was dose-dependent, and significant stimulation was detectable at concentrations as low as 3 ng/ml TNFalpha, 50 ng/ml GH and 10 ng/ml IL-6. Furthermore, stimulation experiments and studies using pharmacologic inhibitors suggested that the positive effect of TNFalpha, GH and IL-6 on SOCS-1 mRNA is, at least in part, mediated by Janus kinase (Jak) 2. Finally, SOCS-3 expression was dose- and time-dependently induced by IL-6, at least in part via Jak2, but none of the cytokines affected SOCS-6 expression. Taken together, our results show a differential regulation of SOCS mRNA by insulin resistance-inducing hormones, and suggest that SOCS-1, as well as SOCS-3, may be an important intracellular mediator of insulin resistance in fat cells and a potential pharmacologic target for the treatment of impaired insulin sensitivity.

[1]  L. Mandarino,et al.  Effects of Growth Hormone on Insulin Action in Man: Mechanisms of Insulin Resistance, Impaired Suppression of Glucose Production, and Impaired Stimulation of Glucose Utilization , 1982, Diabetes.

[2]  P. Cryer,et al.  Pathogenesis of the dawn phenomenon in patients with insulin-dependent diabetes mellitus. Accelerated glucose production and impaired glucose utilization due to nocturnal surges in growth hormone secretion. , 1985, The New England journal of medicine.

[3]  B. Beaufrère,et al.  Insulin resistance in acromegaly: defects in both hepatic and extrahepatic insulin action. , 1986, The American journal of physiology.

[4]  K. Yasukawa,et al.  IL-6-induced homodimerization of gp130 and associated activation of a tyrosine kinase. , 1993, Science.

[5]  B. Spiegelman,et al.  Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. , 1993, Science.

[6]  J. Luo,et al.  Endocrine and carbohydrate responses to interleukin-6 in vivo. , 1994, Circulatory shock.

[7]  M. Ridderstråle,et al.  Growth Hormone Stimulates the Tyrosine Phosphorylation of the Insulin Receptor Substrate-1 and Its Association with Phosphatidylinositol 3-Kinase in Primary Adipocytes (*) , 1995, The Journal of Biological Chemistry.

[8]  T. Mustelin,et al.  Constitutive activation of a slowly migrating isoform of Stat3 in mycosis fungoides: tyrphostin AG490 inhibits Stat3 activation and growth of mycosis fungoides tumor cell lines. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[9]  J. Stephens,et al.  Tumor necrosis factor-alpha-induced insulin resistance in 3T3-L1 adipocytes is accompanied by a loss of insulin receptor substrate-1 and GLUT4 expression without a loss of insulin receptor-mediated signal transduction. , 1997, The Journal of biological chemistry.

[10]  D. Papanicolaou,et al.  Dose-dependent effects of recombinant human interleukin-6 on glucose regulation. , 1997, The Journal of clinical endocrinology and metabolism.

[11]  J. S. Elmendorf,et al.  Growth hormone-induced insulin resistance: role of the insulin receptor, IRS-1, GLUT-1, and GLUT-4. , 1997, The American journal of physiology.

[12]  L. Velloso,et al.  Effect of chronic growth hormone treatment on insulin signal transduction in rat tissues , 1997, Molecular and Cellular Endocrinology.

[13]  S. Akira,et al.  Structure and function of a new STAT-induced STAT inhibitor , 1997, Nature.

[14]  J. Stephens,et al.  Tumor Necrosis Factor-α-induced Insulin Resistance in 3T3-L1 Adipocytes Is Accompanied by a Loss of Insulin Receptor Substrate-1 and GLUT4 Expression without a Loss of Insulin Receptor-mediated Signal Transduction* , 1997, The Journal of Biological Chemistry.

[15]  Warren S. Alexander,et al.  A family of cytokine-inducible inhibitors of signalling , 1997, Nature.

[16]  Takaho A. Endo,et al.  A new protein containing an SH2 domain that inhibits JAK kinases , 1997, Nature.

[17]  P. Clayton,et al.  Growth hormone stimulation of the mitogen-activated protein kinase pathway is cell type specific. , 1998, Endocrinology.

[18]  P. Heinrich,et al.  Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. , 1998, The Biochemical journal.

[19]  L. Pfeffer,et al.  Induction of Jak/STAT signaling by activation of the type 1 TNF receptor. , 1998, Journal of immunology.

[20]  J. Klein,et al.  β3-Adrenergic Stimulation Differentially Inhibits Insulin Signaling and Decreases Insulin-induced Glucose Uptake in Brown Adipocytes* , 1999, The Journal of Biological Chemistry.

[21]  G. Hotamisligil.  The role of TNFalpha and TNF receptors in obesity and insulin resistance. , 1999, Journal of internal medicine.

[22]  J. Flier,et al.  The Role of SOCS-3 in Leptin Signaling and Leptin Resistance* , 1999, The Journal of Biological Chemistry.

[23]  G. Hotamisligil.  The role of TNFα and TNF receptors in obesity and insulin resistance , 1999 .

[24]  J. Klein,et al.  Essential Role of Insulin Receptor Substrate-2 in Insulin Stimulation of Glut4 Translocation and Glucose Uptake in Brown Adipocytes* , 2000, The Journal of Biological Chemistry.

[25]  S. Kalra,et al.  Leptin resistance of adipocytes in obesity: role of suppressors of cytokine signaling. , 2000, Biochemical and biophysical research communications.

[26]  E. Van Obberghen,et al.  SOCS-3 Is an Insulin-induced Negative Regulator of Insulin Signaling* , 2000, The Journal of Biological Chemistry.

[27]  J. Engelman,et al.  Tumor Necrosis Factor α-Mediated Insulin Resistance, but Not Dedifferentiation, Is Abrogated by MEK1/2 Inhibitors in 3T3-L1 Adipocytes , 2000 .

[28]  S. Matthaei,et al.  Pathophysiology and pharmacological treatment of insulin resistance. , 2000, Endocrine reviews.

[29]  J. Engelman,et al.  Tumor necrosis factor alpha-mediated insulin resistance, but not dedifferentiation, is abrogated by MEK1/2 inhibitors in 3T3-L1 adipocytes. , 2000, Molecular endocrinology.

[30]  T. Sasaoka,et al.  Growth hormone induces cellular insulin resistance by uncoupling phosphatidylinositol 3-kinase and its downstream signals in 3T3-L1 adipocytes. , 2001, Diabetes.

[31]  R. Paschke,et al.  Adiponectin gene expression is inhibited by β‐adrenergic stimulation via protein kinase A in 3T3‐L1 adipocytes , 2001, FEBS letters.

[32]  S. Frank.  Growth hormone signalling and its regulation: preventing too much of a good thing. , 2001, Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society.

[33]  J. Manson,et al.  C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. , 2001, JAMA.

[34]  R. Paschke,et al.  Plasma levels of tumor necrosis factor-alpha, angiotensin II, growth hormone, and IGF-I are not elevated in insulin-resistant obese individuals with impaired glucose tolerance. , 2001, Diabetes care.

[35]  M. Ridderstråle,et al.  Differential phosphorylation of Janus kinase 2, Stat5A and Stat5B in response to growth hormone in primary rat adipocytes , 2001, Molecular and Cellular Endocrinology.

[36]  M. Benito,et al.  TNF-alpha inhibits UCP-1 expression in brown adipocytes via ERKs. Opposite effect of p38MAPK. , 2001, FEBS letters.

[37]  J. Klein,et al.  Essential Role of Insulin Receptor Substrate 1 in Differentiation of Brown Adipocytes , 2001, Molecular and Cellular Biology.

[38]  S. Cameron,et al.  Suppressors of Cytokine Signaling-1 and -6 Associate with and Inhibit the Insulin Receptor , 2001, The Journal of Biological Chemistry.

[39]  R. Paschke,et al.  Isoproterenol inhibits resistin gene expression through a GS‐protein‐coupled pathway in 3T3‐L1 adipocytes , 2001, FEBS letters.

[40]  E. Van Obberghen,et al.  SOCS-3 Inhibits Insulin Signaling and Is Up-regulated in Response to Tumor Necrosis Factor-α in the Adipose Tissue of Obese Mice* , 2001, The Journal of Biological Chemistry.

[41]  Bruce M. Spiegelman,et al.  Obesity and the Regulation of Energy Balance , 2001, Cell.

[42]  R. Mooney,et al.  Interleukin-6 induces cellular insulin resistance in hepatocytes. , 2002, Diabetes.

[43]  Jiandie D. Lin,et al.  Peroxisome proliferator-activated receptor gamma coactivator 1beta (PGC-1beta ), a novel PGC-1-related transcription coactivator associated with host cell factor. , 2002, The Journal of biological chemistry.

[44]  M. White,et al.  SOCS-1 and SOCS-3 Block Insulin Signaling by Ubiquitin-mediated Degradation of IRS1 and IRS2* , 2002, The Journal of Biological Chemistry.

[45]  Jiandie D. Lin,et al.  Peroxisome Proliferator-activated Receptor γ Coactivator 1β (PGC-1β), A Novel PGC-1-related Transcription Coactivator Associated with Host Cell Factor* , 2002, The Journal of Biological Chemistry.

[46]  T. Zimmers,et al.  Suppressor of Cytokine Signaling-3 (SOCS-3), a Potential Mediator of Interleukin-6-dependent Insulin Resistance in Hepatocytes* , 2003, The Journal of Biological Chemistry.

[47]  U. Smith,et al.  Interleukin-6 (IL-6) Induces Insulin Resistance in 3T3-L1 Adipocytes and Is, Like IL-8 and Tumor Necrosis Factor-α, Overexpressed in Human Fat Cells from Insulin-resistant Subjects* , 2003, Journal of Biological Chemistry.