SOCS, inflammation, and metabolism

Kyoko Inagaki-Ohara, Akihiko Yoshimura


Obesity is characterized by the development of low-grade chronic inflammation, which is a contributing factor in defective energy metabolism. A hallmark of metabolic dysregulation, obesity is a life-style disease that contributes to diabetes, hypertension, and dyslipidemia. Further, recent studies warn that obesity can be a risk factor for certain cancers and exacerbates infectious diseases. This association is called the “metabolic domino”. Suppressor of cytokine signaling (SOCS) proteins are negative feedback regulators of cytokine and hormone signaling mediated by the JAK-STAT signaling pathway. SOCS proteins regulate cell-cell communication through JAK-STAT-dependent cytokines and signaling by Toll-like receptors (TLRs) and they may be influenced by dietary factors such as fatty acids and glucose. In this review, we focus on the role of the JAK-STAT-SOCS signaling cascade in metabolic disorder and obesity-related diseases.


SOCS; obesity; cancer; leptin; insulin


Al-Qassab H, Smith MA, Irvine EE, Guillermet-Guibert J, Claret M, Choudhury AI, Selman C, Piipari K, Clements M, Lingard S, Chandarana K, Bell JD, Barsh GS, Smith AJ, Batterham RL, Ashford ML, Vanhaesebroeck B & Withers DJ 2009 Dominant role of the p110beta isoform of PI3K over p110alpha in energy homeostasis regulation by POMC and AgRP neurons. Cell Metab 10 343-354

Bäckhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, Semenkovich CF & Gordon JI 2004 The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci U S A 101 15718-15723

Backhed F, Manchester JK, Semenkovich CF & Gordon JI 2007 Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci U S A, 104 979-984

Bado A, Levasseur S, Attoub S, Kermorgant S, Laigneau JP, Bortoluzzi MN, Moizo L, Lehy T, Guerre-Millo M, Le Marchand-Brustel Y & Lewin MJ 1998 The stomach is a source of leptin. Nature 394 790-793

Banks AS, Davis SM, Bates SH & Myers MG Jr 2000 Activation of downstream signals by the long form of the leptin receptor. J Biol Chem 275 14563-14572

Bence KK, Delibegovic M, Xue B, Gorgun CZ, Hotamisligil GS, Neel BG & Kahn BB 2006 Neuronal PTP1B regulates body weight, adiposity and leptin action. Nat Med 12 917-924

Bjorbaek C, Elmquist JK, Frantz JD, Shoelson SE & Flier JS 1998. Identification of SOCS-3 as a potential mediator of central leptin resistance. Mol Cell 1 619-625

Bluestone JA, Herold K & Eisenbarth G 2010 Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature 464 1293-1300

Briancon N, McNay DE, Maratos-Flier E & Flier JS 2010 Combined neural inactivation of suppressor of cytokine signaling-3 and protein-tyrosine phosphatase-1B reveals additive, synergistic, and factor specific roles in the regulation of body energy balance. Diabetes 59 3074-3084

Bruun C, Heding PE, Rønn SG, Frobøse H, Rhodes CJ, Mandrup-Poulsen T & Billestrup N 2009 Suppressor of cytokine signalling-3 inhibits Tumor necrosis factor-alpha induced apoptosis and signalling in beta cells. Mol Cell Endocrinol 311 32-38

Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM & Burcelin R 2008 Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 57 1470-1481

Cani PD & Delzenne NM 2009 The role of the gut microbiota in energy metabolism and metabolic disease. Curr Pharm Des 15 1546-1558

Chakraborty S, Zawieja S, Wang W, Zawieja DC & Muthuchamy M 2010. Lymphatic system: a vital link between metabolic syndrome and inflammation. Ann N Y Acad Sci 1207 E94-102

Cho Y, Lee DH, Oh HS, Seo JY, Lee DH, Kim N, Jeong SH, Kim JW, Hwang JH, Park YS, Lee SH, Shin CM, Jo HJ, Jung HC, Yoon YB & Song IS 2012 Higher prevalence of obesity in gastric cardia adenocarcinoma compared to gastric noncardia adenocarcinoma. Dig Dis Sci 57 2687-2692

del Campo JA, Lopez RA & Romero-Gomez M 2010 Insulin resistance and response to antiviral therapy in chronic hepatitis C: mechanisms and management. Dig Dis 28 285-293

Deopurkar R, Ghanim H, Friedman J, Abuaysheh S, Sia CL, Mohanty P, Viswanathan P, Chaudhuri A & Dandona P 2010 Differential effects of cream, glucose, and orange juice on inflammation, endotoxin, and the expression of Toll-like receptor-4 and suppressor of cytokine signaling-3. Diabetes Care 33 991-997

Eckburg PB1, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, Gill SR, Nelson KE & Relman DA 2005 Diversity of the human intestinal microbial flora Science 308 1635-1638

Elchebly M, Payette P, Michaliszyn E, Cromlish W, Collins S, Loy AL, Normandin D, Cheng A, Himms-Hagen J, Chan CC, Ramachandran C, Gresser MJ, Tremblay ML & Kennedy BP 1999 Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science 283 1544-1548

Emanuelli B, Macotela Y, Boucher J & Ronald Kahn C 2008 SOCS-1 deficiency does not prevent diet-induced insulin resistance. Biochem Biophys Res Commun 377 447-452

Emanuelli B, Peraldi P, Filloux C, Chavey C, Freidinger K, Hilton DJ, Hotamisligil GS & Van Obberghen E 2001 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 276 47944-47949

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 1997 A new protein containing an SH2 domain that inhibits JAK kinases. Nature 387 921-924

Feldman DE, Chen C, Punj V, Tsukamoto H & Machida K 2012 Pluripotency factor-mediated expression of the leptin receptor (OB-R) links obesity to oncogenesis through tumor-initiating stem cells. Proc Natl Acad Sci U S A 109 829-834

Friedman JM & Halaas JL 1998 Leptin and the regulation of body weight in mammals. Nature 395 763-770

Garofalo C, Koda M, Cascio S, Sulkowska M, Kanczuga-Koda L, Golaszewska J, Russo A, Sulkowski S & Surmacz E 2006 Increased expression of leptin and the leptin receptor as a marker of breast cancer progression: possible role of obesity-related stimuli. Clin Cancer Res 12 1447-1453

Gautron L & Elmquist JK 2011 Sixteen years and counting: an update on leptin in energy balance. J Clin Invest 121 2087-2093

Ghanim H, Abuaysheh S, Sia CL, Korzeniewski K, Chaudhuri A, Fernandez-Real JM & Dandona P 2009 Increase in plasma endotoxin concentrations and the expression of Toll-like receptors and suppressor of cytokine signaling-3 in mononuclear cells after a high-fat, high-carbohydrate meal: implications for insulin resistance. Diabetes Care 32 2281-2287

Grant L, Shearer KD, Czopek A, Lees EK, Owen C, Agouni A, Workman J, Martin-Granados C, Forrester JV, Wilson HM, Mody N & Delibegovic M 2014 Myeloid-cell protein tyrosine phosphatase-1B deficiency in mice protects against high fat diet and lipopolysaccharide-induced inflammation, hyperinsulinemia, and endotoxemia through an IL-10 STAT3-dependent mechanism. Diabetes 63 456-470

Gravaghi C, Bo J, Laperle KM, Quimby F, Kucherlapati R, Edelmann W & Lamprecht SA 2008 Obesity enhances gastrointestinal tumorigenesis in Apc-mutant mice. Int J Obes (Lond) 32 1716-1719

Gregor MF & Hotamisligil GS 2011 Inflammatory mechanisms in obesity. Annu Rev Immunol 29 415-445

Hoda MR, Keely SJ, Bertelsen LS, Junger WG, Dharmasena D & Barrett KE 2007 Leptin acts as a mitogenic and antiapoptotic factor for colonic cancer cells. Br J Surg 94 346-354

Howard JK, Cave BJ, Oksanen LJ, Tzameli I, Bjorbaek C & Flier JS 2004 Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3. Nat Med 10 734-738

Howard JK & Flier JS 2006 Attenuation of leptin and insulin signaling by SOCS proteins. Trends Endocrinol Metab 17 365-371

Inagaki-Ohara K, Kondo T, Ito M & Yoshimura A 2013 SOCS, inflammation, and cancer. JAKSTAT 2 e24053

Inagaki-Ohara K, Mayuzumi H, Kato S, Minokoshi Y, Otsubo T, Kawamura YI, Dohi T, Matsuzaki G & Yoshimura A 2014 Enhancement of leptin receptor signaling by SOCS3 deficiency induces development of gastric tumors in mice. Oncogene 33 74-84

Jamieson E, Chong MM, Steinberg GR, Jovanovska V, Fam BC, Bullen DV, Chen Y, Kemp BE, Proietto J, Kay TW & Andrikopoulos S 2005 Socs1 deficiency enhances hepatic insulin signaling. J Biol Chem 280 31516-31521

Karlsson EA, Sheridan PA & Beck MA 2010 Diet-induced obesity in mice reduces the maintenance of influenza-specific CD8+ memory T cells. J Nutr 140 1691-1697

Kershaw NJ, Murphy JM, Liau NP, Varghese LN, Laktyushin A, Whitlock EL, Lucet IS, Nicola NA & Babon JJ 2013 SOCS3 binds specific receptor-JAK complexes to control cytokine signaling by direct kinase inhibition. Nat Struct Mol Biol 20 469-476 Kievit P, Howard JK, Badman MK, Balthasar N, Coppari R, Mori H, Lee CE, Elmquist JK, Yoshimura A & Flier JS 2006 Enhanced leptin sensitivity and improved glucose homeostasis in mice lacking suppressor of cytokine signaling-3 in POMC-expressing cells. Cell Metab 4 123-132

Kim JJ & Sears DD 2010 TLR4 and Insulin Resistance. Gastroenterol Res Pract 212563

Koike K, Tsutsumi T, Miyoshi H, Shinzawa S, Shintani Y, Fujie H, Yotsuyanagi H & Moriya K 2008 Molecular basis for the synergy between alcohol and hepatitis C virus in hepatocarcinogenesis. J Gastroenterol Hepatol 23 S87-91

La Cava A & Matarese G 2004. The weight of leptin in immunity Nat Rev Immunol 4 371-379

Lebrun P & Van Obberghen E 2008 SOCS proteins causing trouble in insulin action. Acta Physiol (Oxf) 192 29-36

Lee JY, Plakidas A, Lee WH, Heikkinen A, Chanmugam P, Bray G & Hwang DH 2003 Differential modulation of Toll-like receptors by fatty acids: preferential inhibition by n-3 polyunsaturated fatty acids. J Lipid Res 44 479-486

Lee JY, Sohn KH, Rhee SH & Hwang D 2001 Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4. J Biol Chem 276 16683-16689

Ley RE, Turnbaugh PJ, Klein S & Gordon JI 2006 Microbial ecology: human gut microbes associated with obesity. Nature 444 1022-1023

Louie JK, Acosta M, Samuel MC, Schechter R, Vugia DJ, Harriman K, Matyas BT & California Pandemic (H1N1) Working Group 2011 A novel risk factor for a novel virus: obesity and 2009 pandemic influenza A (H1N1). Clin Infect Dis 52 301-312

Maccio A & Madeddu C 2011 Obesity, inflammation, and postmenopausal breast cancer: therapeutic implications. ScientificWorldJournal 11 2020-2036

Macciò A, Madeddu C, Gramignano G, Mulas C, Floris C, Massa D, Astara G, Chessa P & Mantovani G 2010 Correlation of body mass index and leptin with tumor size and stage of disease in hormone-dependent postmenopausal breast cancer: preliminary results and therapeutic implications. J Mol Med (Berl) 88 677-686

Medzhitov R 2001 Toll-like receptors and innate immunity. Nat Rev Immunol 1 135-145

Miyamoto H, Moriishi K, Moriya K, Murata S, Tanaka K, Suzuki T, Miyamura T, Koike K & Matsuura Y 2007. Involvement of the PA28gamma-dependent pathway in insulin resistance induced by hepatitis C virus core protein. J Virol 81 1727-1735

Morgan OW, Bramley A, Fowlkes A, Freedman DS, Taylor TH, Gargiullo P, Belay B, Jain S, Cox C, Kamimoto L, Fiore A, Finelli L, Olsen SJ & Fry AM 2010 Morbid obesity as a risk factor for hospitalization and death due to 2009 pandemic influenza A(H1N1) disease. PLoS One 5 e9694

Mori H, Hanada R, Hanada T, Aki D, Mashima R, Nishinakamura H, Torisu T, Chien KR, Yasukawa H & Yoshimura A 2004 Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to dietinduced obesity. Nat Med 10 739-743

Mori H, Shichita T, Yu Q, Yoshida R, Hashimoto M, Okamoto F, Torisu T, Nakaya M, Kobayashi T, Takaesu G & Yoshimura A 2007 Suppression of SOCS3 expression in the pancreatic beta-cell leads to resistance to type 1 diabetes. Biochem Biophys Res Commun 359 952-958

O'Doherty MG, Freedman ND, Hollenbeck AR, Schatzkin A & Abnet CC 2012 A prospective cohort study of obesity and risk of oesophageal and gastric adenocarcinoma in the NIH-AARP Diet and Health Study. Gut 61 1261-1268

Ogata H, Kobayashi T, Chinen T, Takaki H, Sanada T, Minoda Y, Koga K, Takaesu G, Maehara Y, Iida M & Yoshimura A 2006. Deletion of the SOCS3 gene in liver parenchymal cells promotes hepatitis-induced hepatocarcinogenesis. Gastroenterology 131 179-193

Owen C, Czopek A, Agouni A, Grant L, Judson R, Lees EK, Mcilroy GD, Göransson O, Welch A, Bence KK, Kahn BB, Neel BG, Mody N & Delibegović M 2012. Adipocyte-specific protein tyrosine phosphatase 1B deletion increases lipogenesis, adipocyte cell size and is a minor regulator of glucose homeostasis. PLoS One 7 e32700

Park EJ, Lee JH, Yu GY, He G, Ali SR, Holzer RG, Osterreicher CH, Takahashi H & Karin M 2010 Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 140 197-208

Pascarella S, Clement S, Guilloux K, Conzelmann S, Penin F & Negro F 2011. Effects of hepatitis C virus on suppressor of cytokine signaling mRNA levels: comparison between different genotypes and core protein sequence analysis. J Med Virol 83 1005-1015

Piessevaux J, Lavens D, Peelman F & Tavernier J 2008 The many faces of the SOCS box. Cytokine Growth Factor Rev 19 371-381

Reed AS, Unger EK, Olofsson LE, Piper ML, Myers MG Jr & Xu AW 2010 Functional role of suppressor of cytokine signaling 3 upregulation in hypothalamic leptin resistance and long-term energy homeostasis. Diabetes 59 894-906

Reeves GK, Pirie K, Beral V, Green J, Spencer E, Bull D & Million Women Study Collaboration 2007 Cancer incidence and mortality in relation to body mass index in the Million Women Study: cohort study. BMJ 335 1134

Saberi M, Woods NB, de Luca C, Schenk S, Lu JC, Bandyopadhyay G, Verma IM & Olefsky JM 2009 Hematopoietic cell-specific deletion of toll-like receptor 4 ameliorates hepatic and adipose tissue insulin resistance in high-fat-fed mice. Cell Metab 10 419-429

Santillan-Benitez JG, Mendieta-Zeron H, Gomez-Olivan LM, Ordonez Quiroz A, Torres-Juarez JJ & Gonzalez-Banales JM 2014 JAK2, STAT3 and SOCS3 gene expression in women with and without breast cancer. Gene 547 70-76

Schele E, Grahnemo, L, Anesten, F, Hallen, A, Backhed F & Jansson JO 2013 The gut microbiota reduces leptin sensitivity and the expression of the obesity-suppressing neuropeptides proglucagon (Gcg) and brain-derived neurotrophic factor (Bdnf) in the central nervous system. Endocrinology 154 3643-3651

Sharma D, Wang J, Fu PP, Sharma S, Nagalingam A, Mells J, Handy J, Page AJ, Cohen C, Anania FA & Saxena NK 2010 Adiponectin antagonizes the oncogenic actions of leptin in hepatocellular carcinogenesis. Hepatology 52 1713-1722

Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H & Flier JS 2006 TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 116 3015-3025

Shimizu M, Sakai H, Shirakami Y, Yasuda Y, Kubota M, Terakura D, Baba A, Ohno T, Hara Y, Tanaka T & Moriwaki H 2011 Preventive effects of (-)-epigallocatechin gallate on diethylnitrosamine-induced liver tumorigenesis in obese and diabetic C57BL/KsJ-db/db Mice. Cancer Prev Res (Phila) 4 396-403

Starr R, Metcalf D, Elefanty AG, Brysha M, Willson TA, Nicola NA, Hilton DJ & Alexander WS 1998 Liver degeneration and lymphoid deficiencies in mice lacking suppressor of cytokine signaling-1. Proc Natl Acad Sci U S A 95 14395-14399

Suchy D, Labuzek K, Machnik G, Kozlowski M & Okopien B 2013 SOCS and diabetes--ups and downs of a turbulent relationship. Cell Biochem Funct 31 181-195.

Tanti JF, Ceppo F, Jager J & Berthou F 2012 Implication of inflammatory signaling pathways in obesity induced insulin resistance. Front Endocrinol (Lausanne) 3 181

Teran-Cabanillas E, Montalvo-Corral M, Silva-Campa E, Caire-Juvera G, Moya-Camarena SY & Hernandez J 2014 Production of interferon alpha and beta, pro-inflammatory cytokines and the expression of suppressor of cytokine signaling (SOCS) in obese subjects infected with influenza A/H1N1. Clin Nutr 33 922-926

Torisu T, Sato N, Yoshiga D, Kobayashi T, Yoshioka T, Mori H, Iida M & Yoshimura A 2007 The dual function of hepatic SOCS3 in insulin resistance in vivo. Genes Cells 12 143-154

Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER & Gordon JI 2006 An obesity associated gut microbiome with increased capacity for energy harvest. Nature 444 1027-1031

Ueki K, Kondo T & Kahn CR 2004 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 24 5434-5446

Ueki K, Kondo T, Tseng YH & Kahn CR 2004 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 101 10422-10427

Vijay-Kumar M, Aitken JD, Carvalho FA, Cullender TC, Mwangi S, Srinivasan S, Sitaraman SV, Knight R, Ley RE & Gewirtz AT 2010 Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 328 228-231

Wild S, Roglic G, Green A, Sicree R & King H 2004 Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 27 1047-1053

Wolin KY, Carson K & Colditz GA 2010 Obesity and cancer. Oncologist 15 556-565

Wunderlich CM, Hovelmeyer N & Wunderlich FT 2013 Mechanisms of chronic JAK-STAT3-SOCS3 signaling in obesity. JAKSTAT 2 e23878

Xu CX, Zhu HH & Zhu YM 2014 Diabetes and cancer: Associations, mechanisms, and implications for medical practice. World J Diabetes 5 372-380

Xu H, An H, Hou J, Han C, Wang P, Yu Y & Cao X 2008 Phosphatase PTP1B negatively regulates MyD88- and TRIF-dependent proinflammatory cytokine and type I interferon production in TLR-triggered macrophages. Mol Immunol 45 3545-3552

Yasukawa H, Misawa H, Sakamoto H, Masuhara M, Sasaki A, Wakioka T, Ohtsuka S, Imaizumi T, Matsuda T, Ihle JN & Yoshimura A 1999 The JAK-binding protein JAB inhibits Janus tyrosine kinase activity through binding in the activation loop. EMBO J 18 1309-1320

Yasukawa H, Sasaki A & Yoshimura A 2000 Negative regulation of cytokine signaling pathways. Annu Rev Immunol 18 143-164

Yoshimura A, Naka T & Kubo M 2007 SOCS proteins, cytokine signalling and immune regulation. Nat Rev Immunol 7 454-465

Yoshimura A, Suzuki M, Sakaguchi R, Hanada T & Yasukawa H 2012 SOCS, Inflammation, and Autoimmunity. Front Immunol 3 20

Zaitseva II, Hultcrantz M, Sharoyko V, Flodstrom-Tullberg M, Zaitsev SV & Berggren PO 2009 Suppressor of cytokine signaling-1 inhibits caspase activation and protects from cytokine-induced beta cell death. Cell Mol Life Sci 66 3787-3795

Zheng Q, Dunlap SM, Zhu J, Downs-Kelly E, Rich J, Hursting SD, Berger NA & Reizes O 2011 Leptin deficiency suppresses MMTV-Wnt-1 mammary tumor growth in obese mice and abrogates tumor initiating cell survival. Endocr Relat Cancer 18 491-503

Zhou X, Sun P, Lucendo-Villarin B, Angus AG, Szkolnicka D, Cameron K, Farnworth SL, Patel AH & Hay DC 2014 Modulating innate immunity improves hepatitis C virus infection and replication in stem cell-derived hepatocytes. Stem Cell Reports 3 204-214

Full Text: PDF


  • There are currently no refbacks.

Copyright © 2018 Lorem Ipsum Press