{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T23:52:38Z","timestamp":1770508358980,"version":"3.49.0"},"reference-count":36,"publisher":"American Diabetes Association","issue":"3","content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2007,3,1]]},"abstract":"<jats:p>Pioglitazone is widely used for the treatment of diabetic patients with insulin resistance. The mechanism of pioglitazone to improve insulin sensitivity is not fully understood. Recent studies have shown that the induction of suppressor of cytokine signaling 3 (SOCS3) is related to the development of insulin resistance. Here, we examined whether the insulin-sensitizing effect of pioglitazone affects the SOCS induction. In db\/db mice and high-fat\u2013fed mice, expression of SOCS3 mRNA in fat tissue was increased compared with that in lean control mice, and pioglitazone suppressed SOCS3 levels. In 3T3-L1 adipocytes, mediators of insulin resistance such as tumor necrosis factor-\u03b1 (TNF-\u03b1), interleukin-6, growth hormone, and insulin increased SOCS3 expression, which was partially inhibited by pioglitazone. The ability of pioglitazone to suppress SOCS3 induction by TNF-\u03b1 was greatly augmented by peroxisome proliferator\u2013activated receptor \u03b3 overexpression. SOCS3 overexpression and tyrphostin AG490, a Janus kinase 2 inhibitor, or dominant-negative STAT3 expression partially inhibited adiponectin secretion and was accompanied by decreased STAT3 phosphorylation. Conversely, pioglitazone increased adiponectin secretion and STAT3 phosphorylation in fat tissue of db\/db mice and in 3T3-L1 adipocytes. These results suggest that pioglitazone exerts its effect to improve whole-body insulin sensitivity in part through the suppression of SOCS3, which is associated with the increase in STAT3 phosphorylation and adiponectin production in fat tissue.<\/jats:p>","DOI":"10.2337\/db06-1039","type":"journal-article","created":{"date-parts":[[2007,2,27]],"date-time":"2007-02-27T18:14:43Z","timestamp":1172600083000},"page":"795-803","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":53,"title":["Effects of Pioglitazone on Suppressor of Cytokine Signaling 3 Expression"],"prefix":"10.2337","volume":"56","author":[{"given":"Yukiko","family":"Kanatani","sequence":"first","affiliation":[{"name":"The First Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isao","family":"Usui","sequence":"additional","affiliation":[{"name":"The First Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ken","family":"Ishizuka","sequence":"additional","affiliation":[{"name":"The First Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Agussalim","family":"Bukhari","sequence":"additional","affiliation":[{"name":"The First Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shiho","family":"Fujisaka","sequence":"additional","affiliation":[{"name":"The First Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masaharu","family":"Urakaze","sequence":"additional","affiliation":[{"name":"The First Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tetsuro","family":"Haruta","sequence":"additional","affiliation":[{"name":"The First Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tadamitsu","family":"Kishimoto","sequence":"additional","affiliation":[{"name":"Osaka University Graduate School of Frontier Bioscience, Osaka, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tetsuji","family":"Naka","sequence":"additional","affiliation":[{"name":"Laboratory for Immune Signal, National Institute of Biomedical Innovation, Osaka, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masashi","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"The First Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1167","reference":[{"key":"2022031210482422500_R1","doi-asserted-by":"crossref","unstructured":"Kahn BB, Flier JS: Obesity and insulin resistance. J Clin Invest\u2008106: 473\u2013481,2000","DOI":"10.1172\/JCI10842"},{"key":"2022031210482422500_R2","doi-asserted-by":"crossref","unstructured":"Mokdad AH, Ford ES, Bowman BA, Dietz WH, Vinicor F, Bales VS, Marks JS: Prevalence of obesity, diabetes, and obesity-related health risk factors,2001. JAMA\u2008289: 76\u201379, 2003","DOI":"10.1001\/jama.289.1.76"},{"key":"2022031210482422500_R3","doi-asserted-by":"crossref","unstructured":"Spiegelman BM, Flier JS: Obesity and the regulation of energy balance. Cell\u2008104: 531\u2013543,2001","DOI":"10.1016\/S0092-8674(01)00240-9"},{"key":"2022031210482422500_R4","doi-asserted-by":"crossref","unstructured":"Aguirre V, Uchida T, Yenush L, Davis R, White MF: The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307). J Biol Chem\u2008275: 9047\u20139054,2000","DOI":"10.1074\/jbc.275.12.9047"},{"key":"2022031210482422500_R5","doi-asserted-by":"crossref","unstructured":"Gao Z, Hwang D, Bataille F, Lefevre M, York D, Quon MJ, Ye J: Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex. J Biol Chem\u2008277: 48115\u201348121,2002","DOI":"10.1074\/jbc.M209459200"},{"key":"2022031210482422500_R6","doi-asserted-by":"crossref","unstructured":"Gao Z, Zuberi A, Quon MJ, Dong Z, Ye J: Aspirin inhibits serine phosphorylation of insulin receptor substrate 1 in tumor necrosis factor-treated cells through targeting multiple serine kinases. J Biol Chem\u2008278: 24944\u201324950,2003","DOI":"10.1074\/jbc.M300423200"},{"key":"2022031210482422500_R7","doi-asserted-by":"crossref","unstructured":"Haruta T, Uno T, Kawahara J, Takano A, Egawa K, Sharma PM, Olefsky JM, Kobayashi M: A rapamycin-sensitive pathway down-regulates insulin signaling via phosphorylation and proteasomal degradation of insulin receptor substrate-1. Mol Endocrinol\u200814: 783\u2013794,2000","DOI":"10.1210\/mend.14.6.0446"},{"key":"2022031210482422500_R8","doi-asserted-by":"crossref","unstructured":"Rui L, Yuan M, Frantz D, Shoelson S, White MF: SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. J Biol Chem\u2008277: 42394\u201342398,2002","DOI":"10.1074\/jbc.C200444200"},{"key":"2022031210482422500_R9","doi-asserted-by":"crossref","unstructured":"Ueki K, Kondo T, Kahn CR: Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms. Mol Cell Biol\u200824: 5434\u20135446,2004","DOI":"10.1128\/MCB.24.12.5434-5446.2004"},{"key":"2022031210482422500_R10","doi-asserted-by":"crossref","unstructured":"Ueki K, Kondo T, Tseng YH, Kahn CR: Central role of suppressors of cytokine signaling proteins in hepatic steatosis, insulin resistance, and the metabolic syndrome in the mouse. Proc Natl Acad Sci U S A\u2008101: 10422\u201310427,2004","DOI":"10.1073\/pnas.0402511101"},{"key":"2022031210482422500_R11","doi-asserted-by":"crossref","unstructured":"Endo TA, 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: A new protein containing an SH2 domain that inhibits JAK kinases. Nature\u2008387: 921\u2013924,1997","DOI":"10.1038\/43213"},{"key":"2022031210482422500_R12","doi-asserted-by":"crossref","unstructured":"Naka T, Narazaki M, Hirata M, Matsumoto T, Minamoto S, Aono A, Nishimoto N, Kajita T, Taga T, Yoshizaki K, Akira S, Kishimoto T: Structure and function of a new STAT-induced STAT inhibitor. Nature\u2008387: 924\u2013929,1997","DOI":"10.1038\/43219"},{"key":"2022031210482422500_R13","doi-asserted-by":"crossref","unstructured":"Starr R, Willson TA, Viney EM, Murray LJ, Rayner JR, Jenkins BJ, Gonda TJ, Alexander WS, Metcalf D, Nicola NA, Hilton DJ: A family of cytokine-inducible inhibitors of signalling. Nature\u2008387: 917\u2013921,1997","DOI":"10.1038\/43206"},{"key":"2022031210482422500_R14","doi-asserted-by":"crossref","unstructured":"Emanuelli B, Peraldi P, Filloux C, Chavey C, Freidinger K, Hilton DJ, Hotamisligil GS, Van Obberghen E: SOCS-3 inhibits insulin signaling and is up-regulated in response to tumor necrosis factor-alpha in the adipose tissue of obese mice. J Biol Chem\u2008276: 47944\u201347949,2001","DOI":"10.1074\/jbc.M104602200"},{"key":"2022031210482422500_R15","doi-asserted-by":"crossref","unstructured":"Emanuelli B, Peraldi P, Filloux C, Sawka-Verhelle D, Hilton D, Van Obberghen E: SOCS-3 is an insulin-induced negative regulator of insulin signaling. J Biol Chem\u2008275: 15985\u201315991,2000","DOI":"10.1074\/jbc.275.21.15985"},{"key":"2022031210482422500_R16","doi-asserted-by":"crossref","unstructured":"Shi H, Tzameli I, Bjorbaek C, Flier JS: Suppressor of cytokine signaling 3 is a physiological regulator of adipocyte insulin signaling. J Biol Chem\u2008279: 34733\u201334740,2004","DOI":"10.1074\/jbc.M403886200"},{"key":"2022031210482422500_R17","doi-asserted-by":"crossref","unstructured":"Shi H, Cave B, Inouye K, Bjorbaek C, Flier JS: Overexpression of suppressor of cytokine signaling 3 in adipose tissue causes local but not systemic insulin resistance. Diabetes\u200855: 699\u2013707,2006","DOI":"10.2337\/diabetes.55.03.06.db05-0841"},{"key":"2022031210482422500_R18","doi-asserted-by":"crossref","unstructured":"Jamieson E, Chong MM, Steinberg GR, Jovanovska V, Fam BC, Bullen DV, Chen Y, Kemp BE, Proietto J, Kay TW, Andrikopoulos S: Socs1 deficiency enhances hepatic insulin signaling. J Biol Chem\u2008280: 31516\u201331521,2005","DOI":"10.1074\/jbc.M502163200"},{"key":"2022031210482422500_R19","doi-asserted-by":"crossref","unstructured":"Kawazoe Y, Naka T, Fujimoto M, Kohzaki H, Morita Y, Narazaki M, Okumura K, Saitoh H, Nakagawa R, Uchiyama Y, Akira S, Kishimoto T: Signal transducer and activator of transcription (STAT)-induced STAT inhibitor 1 (SSI-1)\/suppressor of cytokine signaling 1 (SOCS1) inhibits insulin signal transduction pathway through modulating insulin receptor substrate 1 (IRS-1) phosphorylation. J Exp Med\u2008193: 263\u2013269,2001","DOI":"10.1084\/jem.193.2.263"},{"key":"2022031210482422500_R20","doi-asserted-by":"crossref","unstructured":"Mayerson AB, Hundal RS, Dufour S, Lebon V, Befroy D, Cline GW, Enocksson S, Inzucchi SE, Shulman GI, Petersen KF: The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes. Diabetes\u200851: 797\u2013802,2002","DOI":"10.2337\/diabetes.51.3.797"},{"key":"2022031210482422500_R21","doi-asserted-by":"crossref","unstructured":"Yki-Jarvinen H: Thiazolidinediones. N Engl J Med\u2008351: 1106\u20131118,2004","DOI":"10.1056\/NEJMra041001"},{"key":"2022031210482422500_R22","doi-asserted-by":"crossref","unstructured":"Maeda N, Takahashi M, Funahashi T, Kihara S, Nishizawa H, Kishida K, Nagaretani H, Matsuda M, Komuro R, Ouchi N, Kuriyama H, Hotta K, Nakamura T, Shimomura I, Matsuzawa Y: PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes\u200850: 2094\u20132099,2001","DOI":"10.2337\/diabetes.50.9.2094"},{"key":"2022031210482422500_R23","doi-asserted-by":"crossref","unstructured":"Okuno A, Tamemoto H, Tobe K, Ueki K, Mori Y, Iwamoto K, Umesono K, Akanuma Y, Fujiwara T, Horikoshi H, Yazaki Y, Kadowaki T: Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats. J Clin Invest\u2008101: 1354\u20131361,1998","DOI":"10.1172\/JCI1235"},{"key":"2022031210482422500_R24","doi-asserted-by":"crossref","unstructured":"Iwata M, Haruta T, Usui I, Takata Y, Takano A, Uno T, Kawahara J, Ueno E, Sasaoka T, Ishibashi O, Kobayashi M: Pioglitazone ameliorates tumor necrosis factor-alpha-induced insulin resistance by a mechanism independent of adipogenic activity of peroxisome proliferator\u2013activated receptor-\u03b3. Diabetes\u200850: 1083\u20131092,2001","DOI":"10.2337\/diabetes.50.5.1083"},{"key":"2022031210482422500_R25","doi-asserted-by":"crossref","unstructured":"Kunisada K, Tone E, Fujio Y, Matsui H, Yamauchi-Takihara K, Kishimoto T: Activation of gp130 transduces hypertrophic signals via STAT3 in cardiac myocytes. Circulation\u200898: 346\u2013352,1998","DOI":"10.1161\/01.CIR.98.4.346"},{"key":"2022031210482422500_R26","doi-asserted-by":"crossref","unstructured":"Chick WL, Lavine RL, Like AA: Studies in the diabetic mutant mouse. V. Glucose tolerance in mice homozygous and heterozygous for the diabetes (db) gene. Diabetologia\u20086: 257\u2013262,1970","DOI":"10.1007\/BF01212235"},{"key":"2022031210482422500_R27","doi-asserted-by":"crossref","unstructured":"Pajvani UB, Hawkins M, Combs TP, Rajala MW, Doebber T, Berger JP, Wagner JA, Wu M, Knopps A, Xiang AH, Utzschneider KM, Kahn SE, Olefsky JM, Buchanan TA, Scherer PE: Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity. J Biol Chem\u2008279: 12152\u201312162,2004","DOI":"10.1074\/jbc.M311113200"},{"key":"2022031210482422500_R28","doi-asserted-by":"crossref","unstructured":"Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA: An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem\u2008270: 12953\u201312956,1995","DOI":"10.1074\/jbc.270.22.12953"},{"key":"2022031210482422500_R29","doi-asserted-by":"crossref","unstructured":"Fasshauer M, Kralisch S, Klier M, Lossner U, Bluher M, Klein J, Paschke R: Insulin resistance-inducing cytokines differentially regulate SOCS mRNA expression via growth factor- and Jak\/Stat-signaling pathways in 3T3\u2013L1 adipocytes. J Endocrinol\u2008181: 129\u2013138,2004","DOI":"10.1677\/joe.0.1810129"},{"key":"2022031210482422500_R30","doi-asserted-by":"crossref","unstructured":"Iwaki M, Matsuda M, Maeda N, Funahashi T, Matsuzawa Y, Makishima M, Shimomura I: Induction of adiponectin, a fat-derived antidiabetic and antiatherogenic factor, by nuclear receptors. Diabetes\u200852: 1655\u20131663,2003","DOI":"10.2337\/diabetes.52.7.1655"},{"key":"2022031210482422500_R31","doi-asserted-by":"crossref","unstructured":"Park SK, Oh SY, Lee MY, Yoon S, Kim KS, Kim JW: CCAAT\/enhancer binding protein and nuclear factor-Y regulate adiponectin gene expression in adipose tissue. Diabetes\u200853: 2757\u20132766,2004","DOI":"10.2337\/diabetes.53.11.2757"},{"key":"2022031210482422500_R32","doi-asserted-by":"crossref","unstructured":"Seo JB, Moon HM, Noh MJ, Lee YS, Jeong HW, Yoo EJ, Kim WS, Park J, Youn BS, Kim JW, Park SD, Kim JB: Adipocyte determination- and differentiation-dependent factor 1\/sterol regulatory element-binding protein 1c regulates mouse adiponectin expression. J Biol Chem\u2008279: 22108\u201322117,2004","DOI":"10.1074\/jbc.M400238200"},{"key":"2022031210482422500_R33","doi-asserted-by":"crossref","unstructured":"Howard JK, Cave BJ, Oksanen LJ, Tzameli I, Bjorbaek C, Flier JS: Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3. Nat Med\u200810: 734\u2013738,2004","DOI":"10.1038\/nm1072"},{"key":"2022031210482422500_R34","doi-asserted-by":"crossref","unstructured":"Mori H, Hanada R, Hanada T, Aki D, Mashima R, Nishinakamura H, Torisu T, Chien KR, Yasukawa H, Yoshimura A: Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity. Nat Med\u200810: 739\u2013743,2004","DOI":"10.1038\/nm1071"},{"key":"2022031210482422500_R35","doi-asserted-by":"crossref","unstructured":"Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K: Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest\u2008116: 1784\u20131792,2006","DOI":"10.1172\/JCI29126"},{"key":"2022031210482422500_R36","doi-asserted-by":"crossref","unstructured":"Kubota N, Terauchi Y, Kubota T, Kumagai H, Itoh S, Satoh H, Yano W, Ogata H, Tokuyama K, Takamoto I, Mineyama T, Ishikawa M, Moroi M, Sugi K, Yamauchi T, Ueki K, Tobe K, Noda T, Nagai R, Kadowaki T: Pioglitazone ameliorates insulin resistance and diabetes by both adiponectin-dependent and -independent pathways. J Biol Chem\u2008281: 8748\u20138755,2006","DOI":"10.1074\/jbc.M505649200"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/56\/3\/795\/663418\/zdb00307000795.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/56\/3\/795\/663418\/zdb00307000795.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T16:09:09Z","timestamp":1667405349000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/56\/3\/795\/15175\/Effects-of-Pioglitazone-on-Suppressor-of-Cytokine"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,3,1]]},"references-count":36,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2007,3,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db06-1039","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2007,3,1]]}}}