SOCS-3 Inhibits Insulin Signaling and Is Up-regulated in Response to Tumor Necrosis Factor-α in the Adipose Tissue of Obese Mice

Abstract

SOCS (suppressor of cytokine signaling) proteins are inhibitors of cytokine signaling involved in negative feedback loops. We have recently shown that insulin increases SOCS-3 mRNA expression in 3T3-L1 adipocytes. When expressed, SOCS-3 binds to phosphorylated Tyr960 of the insulin receptor and prevents Stat 5B activation by insulin. Here we show that in COS-7 cells SOCS-3 decreases insulin-induced insulin receptor substrate 1 (IRS-1) tyrosine phosphorylation and its association with p85, a regulatory subunit of phosphatidylinositol-3 kinase. This mechanism points to a function of SOCS-3 in insulin resistance. Interestingly, SOCS-3 expression was found to be increased in the adipose tissue of obese mice, but not in the liver and muscle of these animals. Two polypeptides known to be elevated during obesity, insulin and tumor necrosis factor-α (TNF-α), induce SOCS-3 mRNA expression in mice. Insulin induces a transient expression of SOCS-3 in the liver, muscle, and the white adipose tissue (WAT). Strikingly, TNF-α induced a sustained SOCS-3 expression, essentially in the WAT. Moreover, transgenic ob/ob mice lacking both TNF receptors have a pronounced decrease in SOCS-3 expression in the WAT compared with ob/ob mice, providing genetic evidence for a function of this cytokine in obesity-induced SOCS-3 expression. As SOCS-3 appears as a TNF-α target gene that is elevated during obesity, and as SOCS-3 antagonizes insulin-induced IRS-1 tyrosine phosphorylation, we suggest that it is a player in the development of insulin resistance. SOCS (suppressor of cytokine signaling) proteins are inhibitors of cytokine signaling involved in negative feedback loops. We have recently shown that insulin increases SOCS-3 mRNA expression in 3T3-L1 adipocytes. When expressed, SOCS-3 binds to phosphorylated Tyr960 of the insulin receptor and prevents Stat 5B activation by insulin. Here we show that in COS-7 cells SOCS-3 decreases insulin-induced insulin receptor substrate 1 (IRS-1) tyrosine phosphorylation and its association with p85, a regulatory subunit of phosphatidylinositol-3 kinase. This mechanism points to a function of SOCS-3 in insulin resistance. Interestingly, SOCS-3 expression was found to be increased in the adipose tissue of obese mice, but not in the liver and muscle of these animals. Two polypeptides known to be elevated during obesity, insulin and tumor necrosis factor-α (TNF-α), induce SOCS-3 mRNA expression in mice. Insulin induces a transient expression of SOCS-3 in the liver, muscle, and the white adipose tissue (WAT). Strikingly, TNF-α induced a sustained SOCS-3 expression, essentially in the WAT. Moreover, transgenic ob/ob mice lacking both TNF receptors have a pronounced decrease in SOCS-3 expression in the WAT compared with ob/ob mice, providing genetic evidence for a function of this cytokine in obesity-induced SOCS-3 expression. As SOCS-3 appears as a TNF-α target gene that is elevated during obesity, and as SOCS-3 antagonizes insulin-induced IRS-1 tyrosine phosphorylation, we suggest that it is a player in the development of insulin resistance. phosphatidylinositol 3-kinase suppressor of cytokine signaling insulin receptor substrate Src homology collagen signal transducer and activator of transcription tumor necrosis factor-α white adipose tissue Based on population studies, type 2 diabetes is now considered as an epidemic disease affecting almost 150 million people worldwide. It results from a diminished biological response of tissues to insulin, termed insulin resistance, and the failure of increased insulin secretion to compensate for this resistance. Its progression parallels that of obesity. Indeed, association between insulin resistance and obesity has been recognized for decades (1Spiegelman B.M. Flier J.S. Cell. 2001; 104: 531-543Abstract Full Text Full Text PDF PubMed Scopus (1942) Google Scholar). However, the molecular basis linking these two syndromes is not yet clearly defined. In humans the concentration of several circulating molecules, such as glucose, free fatty acids, and insulin, as well as the levels of TNF-α in animal models, are increased during obesity, and these molecules have been proposed to play a role in the development of insulin resistance (2Saltiel A.R. Cell. 2001; 104: 517-529Abstract Full Text Full Text PDF PubMed Scopus (572) Google Scholar, 3Sethi J.K. Hotamisligil G.S. Semin. Cell Dev. Biol. 1999; 10: 19-29Crossref PubMed Scopus (360) Google Scholar). At the cellular level, a general decrease in insulin signaling is observed and defects occur via several mechanisms (4Kahn B.B. Flier J.S. J. Clin. Invest. 2000; 106: 473-481Crossref PubMed Scopus (2462) Google Scholar). First, the insulin receptor tyrosine kinase activity is diminished (2Saltiel A.R. Cell. 2001; 104: 517-529Abstract Full Text Full Text PDF PubMed Scopus (572) Google Scholar). Moreover, the coupling of the insulin receptor substrates with the insulin receptor is impaired (2Saltiel A.R. Cell. 2001; 104: 517-529Abstract Full Text Full Text PDF PubMed Scopus (572) Google Scholar). As a consequence, all the signaling events downstream of the insulin receptor are defective, leading to decreased cellular responses. Several hypotheses, which are not mutually exclusive, have been proposed to explain these defects (4Kahn B.B. Flier J.S. J. Clin. Invest. 2000; 106: 473-481Crossref PubMed Scopus (2462) Google Scholar). Among them the following have been reported: (i) a decrease in the expression of key molecules such as the insulin receptor and GLUT 4 (5Kahn B.B. Cell. 1998; 92: 593-596Abstract Full Text Full Text PDF PubMed Scopus (374) Google Scholar), (ii) an increased expression of the phosphotyrosine phosphatases LAR and PTP-1B, potentially involved in the dephosphorylation of the insulin receptor and IRS-1 (6Goldstein B.J. Ahmad F. Ding W. Li P.M. Zhang W.R. Mol. Cell. Biochem. 1998; 182: 91-99Crossref PubMed Scopus (173) Google Scholar), and (iii) serine phosphorylation of the insulin receptor by certain protein kinase C isoforms (7Bossenmaier B. Mosthaf L. Mischak H. Ullrich A. Häring H.U. Diabetologia. 1997; 40: 863-866Crossref PubMed Scopus (96) Google Scholar, 8Itani S.I. Zhou Q. Pories W.J. MacDonald K.G. Dohm G.L. Diabetes. 2000; 49: 1353-1358Crossref PubMed Scopus (184) Google Scholar) and of IRS-1 by several serine kinases such as MAPK (mitogen-activated protein kinase), TOR (target of rapamycin), PI3K,1 and Jnk (Jun N-terminal kinase) (9De Fea K. Roth R.A. J. Biol. Chem. 1997; 272: 31400-31406Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar, 10Ozes O.N. Akca H. Mayo L.D. Gustin J.A. Maehama T. Dixon J.E. Donner D.B. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 4640-4645Crossref PubMed Scopus (326) Google Scholar, 11Tanti J.-F. Grémeaux T. Van Obberghen E. Le Marchand-Brustel Y. J. Biol. Chem. 1994; 269: 6051-6057Abstract Full Text PDF PubMed Google Scholar, 12Rui L. Aguirre V. Kim J.K. Shulman G.I. Lee A. Corbould A. Dunaif A. White M.F. J. Clin. Invest. 2001; 107: 181-189Crossref PubMed Scopus (486) Google Scholar). The serine phosphorylation of IRS-1 results in diminished insulin receptor tyrosine kinase activity and coupling of IRS-1 with the insulin receptor. However, due to the complexity of the insulin resistance syndrome, it is anticipated that other mechanisms are involved, which are likely to act in concert. Recently, a new class of inhibitory molecules, the SOCS (suppressor of cytokine signaling) proteins, has been identified (13Starr 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. Nature. 1997; 387: 921-924Crossref PubMed Scopus (1805) Google Scholar, 14Endo T.A. Masuhara M. Yokouchi 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. Nature. 1997; 387: 921-924Crossref PubMed Scopus (1230) Google Scholar, 15Naka T. Narazaki M. Hirata M. Matsumoto T. Minamoto S. Aono A. Nishimoto N. Kajita T. Taga T. Yoshizaki K. Akira S. Kishimoto T. Nature. 1997; 387: 921-924Crossref PubMed Scopus (1135) Google Scholar). The SOCS protein family consists presently of eight members that all contain a central SH2 domain and a conserved C-terminal domain, the SOCS box (16Hilton D.J. Richardson R.T. Alexander W.S. Viney E.M. Willson T.A. Sprigg N.S. Starr R. Nicholson S.E. Metcalf D. Nicola N.A. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 114-119Crossref PubMed Scopus (618) Google Scholar). SOCS proteins are induced by several cytokines, in various tissues, in a cytokine- and tissue-specific manner. Once induced, they are involved in negative feedback loops leading to decreased cytokine signaling. Different mechanisms allow the SOCS to modulate the cytokine-activated Jak/Stat pathway (17Krebs D.L. Hilton D.J. J. Cell Sci. 2000; 113: 2813-2819Crossref PubMed Google Scholar). They can either bind to Jak and inhibit their tyrosine kinase activity (14Endo T.A. Masuhara M. Yokouchi 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. Nature. 1997; 387: 921-924Crossref PubMed Scopus (1230) Google Scholar) or bind to the cytoplasmic tail of the receptors, thus preventing Stat binding and activation (18Matsumoto A. Masuhara M. Mitsui K. Yokouchi M. Ohtsubo M. Misawa H. Miyajima A. Yoshimura A. Blood. 1997; 89: 3148-3154Crossref PubMed Google Scholar). By their ability to be rapidly induced and to efficiently inhibit Jak/Stat pathway, SOCS proteins are potent modulators of cytokine physiology in vivo. This is illustrated by the marked phenotype of the knock-out mice. Indeed, the SOCS-3 knock-out is embryonic lethal for reasons still under debate (19Marine J.C. McKay C. Wang D. Topham D.J. Parganas E. Nakajima H. Pendeville H. Yasukawa H. Sasaki A. Yoshimura A. Ihle J.N. Cell. 1999; 98: 617-627Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar, 20Roberts A.W. Robb L. Rakar S. Hartley L. Cluse L. Nicola N.A. Metcalf D. Hilton D.J. Alexander W.S. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 9324-9329Crossref PubMed Scopus (257) Google Scholar), and SOCS-1-invalidated mice die rapidly after birth (21Naka T. Matsumoto T. Narazaki M. Fujimoto M. Morita Y. Ohsawa Y. Saito H. Nagasawa T. Uchiyama Y. Kishimoto T. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 15577-15582Crossref PubMed Scopus (259) Google Scholar, 22Marine J.C. Topham D.J. McKay C. Wang D. Parganas E. Stravopodis D. Yoshimura A. Ihle J.N. Cell. 1999; 98: 609-616Abstract Full Text Full Text PDF PubMed Scopus (451) Google Scholar, 23Alexander W.S. Starr R. Fenner J.E. Scott C.L. Handman E. Sprigg N.S. Corbin J.E. Cornish A.L. Darwiche R. Owczarek C.M. Kay T.W. Nicola N.A. Hertzog P.J. Metcalf D. Hilton D.J. Cell. 1999; 98: 597-608Abstract Full Text Full Text PDF PubMed Scopus (652) Google Scholar), while SOCS-2-deficient mice have an increased body size (24Metcalf D. Greenhalgh C. Viney E. Willson T. Starr R. Nicola N. Hilton D. Alexander W. Nature. 2000; 405: 1069-1073Crossref PubMed Scopus (406) Google Scholar). Although the SOCS were originally described in cytokine signaling pathways, we have shown recently that they also belong to the insulin signaling circuitry (25Emanuelli B. Peraldi C. D. Hilton D. Van Obberghen E. J. Biol. Chem. 2000; Full Text Full Text PDF Scopus Google Scholar). Indeed, insulin increases SOCS-3 mRNA expression in 3T3-L1 adipocytes. When expressed, SOCS-3 is in the under insulin we found that it to the it with the insulin receptor. SOCS-3 binds to phosphotyrosine of the insulin the and are not observed in cells an insulin receptor on this show that SOCS-3 binds its SH2 domain to this receptor This association results in a with Stat 5B to bind to the insulin thus preventing the activation of the transcription by insulin. Interestingly, this also to the binding for of the insulin receptor Here we SOCS-3 be considered as a general of insulin signaling pathways, and we its in insulin resistance. We show that SOCS-3 expression insulin-induced tyrosine phosphorylation of IRS-1 and its association with p85, a regulatory subunit of Moreover, SOCS-3 expression was found to be increased in the white adipose tissue of obese animals. Interestingly, which has been proposed to play a role in the insulin observed in obesity, induces SOCS-3 expression in the WAT. compared with ob/ob mice, a pronounced decrease in SOCS-3 expression was observed in the WAT of transgenic ob/ob mice of TNF-α signaling. This that a known to be involved in the insulin of obese is in for an of SOCS-3 expression in the WAT of obese and that SOCS-3 is an of insulin signaling. The insulin receptor from A. and the insulin receptor substrate 1 from M. were in COS-7 were in with were by the as described in T. E. and were in the were from IRS-1 and insulin receptor for were in insulin receptor and were from and were and or not with insulin for were in and in were with various under and protein or to from and were by to and with various under were with protein and proteins were by or by a and or were and on was with a mice were and with a or insulin were or 4 after In a of mice were with TNF-α Le 4 or with were or after mice, mice, and were from They were or of the and the obese mice In muscle, liver, and were for ob/ob mice were and as described Hotamisligil G.S. Nature. 1997; PubMed Scopus Google Scholar, Hotamisligil G.S. 1998; PubMed Google Scholar). mice and their ob/ob were of for from tissues was with the to the of was by on and to SOCS-3 was as The was by with the and with the to a was as an for and were in were in and by or by a and or We have shown that SOCS-3 the insulin-induced of Stat 5B (25Emanuelli B. Peraldi C. D. Hilton D. Van Obberghen E. J. Biol. Chem. 2000; Full Text Full Text PDF Scopus Google Scholar). We that this was the of a between SOCS-3 and Stat 5B to bind to the phosphorylated Tyr960 of the insulin receptor. As substrates of the insulin such as bind to this to phosphorylation by the insulin we SOCS-3 with IRS-1 tyrosine phosphorylation in response to insulin. COS-7 cells were with the insulin receptor or IRS-1 and with were or not with insulin for and The insulin receptor and IRS-1 were and by an levels of and SOCS-3 were in As shown in expression of SOCS-3 decreased the insulin-induced tyrosine phosphorylation of IRS-1 by these the decrease of IRS-1 or of insulin receptor expression. However, expression of to a decrease in both insulin receptor and IRS-1 proteins not As described SOCS-3 expression not the insulin receptor tyrosine kinase activity (25Emanuelli B. Peraldi C. D. Hilton D. Van Obberghen E. J. Biol. Chem. 2000; Full Text Full Text PDF Scopus Google Y. T. Fujimoto M. H. Morita Y. Narazaki M. K. H. R. Uchiyama Y. Akira S. Kishimoto T. J. 2001; PubMed Scopus Google Scholar). Once phosphorylated on tyrosine by the insulin IRS-1 a for proteins, such as the regulatory subunit of As SOCS-3 expression decreased insulin-induced tyrosine phosphorylation of we it the association between IRS-1 and COS-7 cells were with the insulin receptor or IRS-1 and with of were with insulin for and IRS-1 was and the were by an and an levels for IRS-1 and SOCS-3 were on As the decrease in the insulin-induced tyrosine phosphorylation of IRS-1 SOCS-3 expression is with a of association between and As SOCS-3 appears as an of insulin we its expression during obesity, a known to be with insulin resistance. muscle, and from ob/ob or mice or their were were and by SOCS-3 as a As illustrated in SOCS-3 mRNA expression was increased and in the WAT of and ob/ob mice, compared with their By SOCS-3 mRNA was not in the muscle and the liver of either the obese or the animals. that SOCS-3 is in the WAT of obese animals. is with and with an of TNF-α in WAT. we in mice the of these two polypeptides on SOCS-3 mRNA expression. We have that in insulin increases SOCS-3 mRNA expression. Here we SOCS-3 mRNA expression in insulin target tissues of with the mice were and either with a or with insulin. were or 4 after and the liver, and were were and by SOCS-3 mRNA expression was increased or after 2 in WAT and muscle, and in the liver 1 after In these tissues, the expression was sustained for 1 and to levels 2 after We the of TNF-α on SOCS-3 expression in mice were either with a or with were or after and the liver, and WAT were were and by As shown in SOCS-3 mRNA expression was increased in WAT following TNF-α This was observed 1 after was sustained for diminished after of and to levels after not TNF-α also induced SOCS-3 mRNA expression in muscle and in the liver, the of this to be and transient in the WAT. Indeed, SOCS-3 mRNA 2 after and to levels in these tissues 4 of As both TNF-α and SOCS-3 are elevated in the WAT of obese and as we found that TNF-α induces SOCS-3 in we TNF-α was involved in the increased expression of SOCS-3 in obese mice. we SOCS-3 expression in ob/ob mice of the two known TNF receptors, ob/ob mice Hotamisligil G.S. Nature. 1997; PubMed Scopus Google Scholar). were from WAT from ob/ob and ob/ob and by As the of TNF-α signaling was with a decrease in SOCS-3 mRNA expression. This genetic of of TNF-α signaling that the in SOCS-3 expression observed in ob/ob mice is to The insulin receptor its biological tyrosine phosphorylation of several them the and Stat This phosphorylation is on a coupling between the insulin receptor and its The coupling can be for the between phosphorylated tyrosine of the insulin receptor and the phosphotyrosine binding of and M.F. J.N. V. T.J. Ullrich A. Cell. Full Text PDF PubMed Scopus Google Scholar, T. E. L. A. White M.F. Miyazaki M. Lee J. S.E. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) or with the SH2 domain of Stat 5B D. C. S. Van Obberghen E. J. Biochem. 1997; PubMed Scopus Google Scholar, J. R.A. Wang Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus Google Scholar). The coupling insulin can also be the domain of D.J. S. H. J. L. White M.F. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). homology bind to in proteins or to that substrates to insulin receptors D.J. Wang J. H. D. H. White M.F. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). As a consequence, molecular the coupling between the insulin receptor and its substrates to a decrease in the tyrosine phosphorylation of the Recently, we have that SOCS-3 be considered as such a which is to the between the insulin receptor and of its Stat 5B (25Emanuelli B. Peraldi C. D. Hilton D. Van Obberghen E. J. Biol. Chem. 2000; Full Text Full Text PDF Scopus Google Scholar). Indeed, SOCS-3 expression insulin-induced binding activity of Stat a between Stat 5B and SOCS-3 for binding to the insulin receptor We have the of SOCS-3 on insulin signaling by SOCS-3 with the tyrosine phosphorylation of the key insulin receptor Indeed, Stat 5B in the of insulin target D. S. J. Van Obberghen E. 2000; PubMed Scopus Google Scholar), its with and is to several cellular by insulin such as protein and and gene expression M.F. Mol. Cell. Biochem. 1998; 182: PubMed Scopus Google Scholar). Stat 5B and IRS-1 with the insulin receptor the of SOCS-3 on IRS-1 tyrosine phosphorylation Indeed, Stat 5B and SOCS-3 bind to the insulin receptor their SH2 domain, while IRS-1 its the of and SH2 for the association with are likely to be in the of S.E. Chem. Biol. 1997; PubMed Scopus Google Scholar), they not the binding SH2 domain is to with and in the of the a domain is anticipated to bind but is in the C of the Moreover, IRS-1 a domain, which has been proposed to play a role in insulin-induced IRS-1 phosphorylation in cells L. J. White M.F. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Here we show that SOCS-3 expression insulin-induced tyrosine phosphorylation of IRS-1 and its association with these results and studies, it that the binding of SOCS-3 to Tyr960 prevents the coupling of IRS-1 with the insulin receptor both its and we suggest that SOCS-3 is a potent of insulin signaling. This is of we that SOCS-3 expression is increased in several with insulin resistance. At two have a function of the SOCS in insulin resistance. R.A. J. S. N. Y. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar) that and inhibit insulin-induced activation of kinase and of Based on in with insulin receptor and the suggest that these SOCS inhibit insulin receptor tyrosine kinase However, they not a of insulin receptor tyrosine phosphorylation, and IRS-1 phosphorylation was not role for in the of has been proposed by Y. T. Fujimoto M. H. Morita Y. Narazaki M. K. H. R. Uchiyama Y. Akira S. Kishimoto T. J. 2001; PubMed Scopus Google Scholar). They that insulin was increased in mice. In they show that and SOCS-3 to a inhibit insulin-induced tyrosine phosphorylation of They suggest that this is to a decrease in Jak This have it evidence for a role of in the of insulin However, can that the it is that of the insulin-induced tyrosine phosphorylation of IRS-1 is due to the insulin receptor of a between SOCS-3 and IRS-1 to bind to the insulin receptor with a for the observed decrease in IRS-1 tyrosine is in tissues, and induced, its expression is transient not the in which insulin resistance Here we show that SOCS-3 expression is increased in the WAT of obese mice. was observed in muscle in with a in the liver V. J. R. C. M. 1999; PubMed Scopus Google Scholar). It is to that this SOCS-3 expression in the development of insulin resistance in the we show that sustained SOCS-3 expression is insulin signaling. Interestingly, an obesity-induced of SOCS-3 mRNA expression has also been to occur in the of obese mice, and it has been proposed that this is involved in resistance C. J.K. S.E. Flier J.S. Mol. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). In obese an of and SOCS-3 mRNA in the adipose tissue has also been observed Zhou T. Lee Y. W. Biochem. 2000; PubMed Scopus Google Scholar). Among other is known to be elevated during obesity. We have that insulin to SOCS-3 mRNA expression in 3T3-L1 and we have proposed that this was to Stat 5B activation (25Emanuelli B. Peraldi C. D. Hilton D. Van Obberghen E. J. Biol. Chem. 2000; Full Text Full Text PDF Scopus Google Scholar). Recently, results were in by C.L. Le M. Wang J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). We that SOCS-3 is an gene in However, insulin-induced SOCS-3 expression is not to as it is observed in the muscle, liver, and WAT. Moreover, the in SOCS-3 expression was This that is not the leading of the increased expression of SOCS-3 during obesity. has also been with an increased expression of TNF-α in the WAT G.S. N.S. B.M. PubMed Scopus Google Scholar). Several have illustrated the role of TNF-α in insulin resistance in while its to insulin resistance in humans is J.K. Hotamisligil G.S. Semin. Cell Dev. Biol. 1999; 10: 19-29Crossref PubMed Scopus (360) Google B. Mol. Cell. Biochem. 1998; 182: PubMed Scopus Google Scholar). We show in that in mice with TNF-α SOCS-3 mRNA expression is induced in This is pronounced and sustained in the WAT compared with liver and the molecular mechanisms leading to SOCS-3 expression in response to TNF-α have not been SOCS transcription is induced by activation of transcription of the Stat family (17Krebs D.L. Hilton D.J. J. Cell Sci. 2000; 113: 2813-2819Crossref PubMed Google Scholar). Although TNF-α has been shown to certain Stat to D. Donner D.B. J. 1998; Google Scholar), it is likely that the of TNF-α on SOCS-3 expression is Indeed, two that TNF-α induces SOCS-3 expression in the liver F. B. J. 2001; PubMed Scopus Google Scholar, J.S. L. F. J. A. N. J. Clin. Invest. 2001; 107: PubMed Scopus Google Scholar), but not in and in it was that other cytokines, induced by were for SOCS-3 expression. were with transgenic mice lacking on the of this on TNF-α of SOCS-3 in the liver F. B. J. 2001; PubMed Scopus Google Scholar, J.S. L. F. J. A. N. J. Clin. Invest. 2001; 107: PubMed Scopus Google Scholar). At this we that a mechanism TNF-α explain the increased SOCS-3 expression observed in WAT of obese mice. this we SOCS-3 expression in ob/ob mice and in ob/ob transgenic mice in both and the two known receptors for It has been that these transgenic mice have a insulin compared with their Hotamisligil G.S. Nature. 1997; PubMed Scopus Google Scholar, Hotamisligil G.S. 1998; PubMed Google Scholar). We found a pronounced decrease in SOCS-3 expression in obese mice lacking TNF-α signaling. genetic evidence the that the elevated levels of SOCS-3 expression found in obesity is to increased TNF-α expression. Several molecular mechanisms have been proposed to explain insulin resistance. Although the they all an role of IRS-1 phosphorylation on serine to be for the decrease in insulin signaling J.K. Hotamisligil G.S. Semin. Cell Dev. Biol. 1999; 10: 19-29Crossref PubMed Scopus (360) Google Scholar, B. Mol. Cell. Biochem. 1998; 182: PubMed Scopus Google Scholar). SOCS-3 expression a identified for this cytokine to the cellular to insulin. results show that SOCS-3 insulin signaling. Moreover, evidence of increased SOCS-3 expression in with insulin resistance to that SOCS-3 in the development of this of SOCS-3 be not the but also in the central these SOCS-3 in insulin resistance and SOCS-3 a recognized molecular target for the of insulin resistance. We are to and for the We for with the animals.