Obesity is associated with increased production of inflammatory mediators in adipose tissue, which contributes to chronic inflammation and insulin resistance. Midkine (MK) is a heparin-binding growth factor with potent proinflammatory activities. We aimed to test whether MK is associated with obesity and has a role in insulin resistance. It was found that MK was expressed in adipocytes and regulated by inflammatory modulators (TNF-α and rosiglitazone). In addition, a significant increase in MK levels was observed in adipose tissue of obese ob/ob mice as well as in serum of overweight/obese subjects when compared with their respective controls. In vitro studies further revealed that MK impaired insulin signaling in 3T3-L1 adipocytes, as indicated by reduced phosphorylation of Akt and IRS-1 and decreased translocation of glucose transporter 4 (GLUT4) to the plasma membrane in response to insulin stimulation. Moreover, MK activated the STAT3-suppressor of cytokine signaling 3 (SOCS3) pathway in adipocytes. Thus, MK is a novel adipocyte-secreted factor associated with obesity and inhibition of insulin signaling in adipocytes. It may provide a potential link between obesity and insulin resistance.
References
[1]
Franks PW, Hanson RL, Knowler WC, Sievers ML, Bennett PH, et al. (2010) Childhood obesity, other cardiovascular risk factors, and premature death. N Engl J Med 362: 485–493. doi: 10.1056/nejmoa0904130
[2]
Shang X, Li J, Tao Q, Li J, Li X, et al. (2013) Educational Level, Obesity and Incidence of Diabetes among Chinese Adult Men and Women Aged 18–59 Years Old: An 11-Year Follow-Up Study. PLoS One 8: e66479. doi: 10.1371/journal.pone.0066479
[3]
Waki H, Tontonoz P (2007) Endocrine functions of adipose tissue. Annu Rev Pathol 2: 31–56. doi: 10.1146/annurev.pathol.2.010506.091859
[4]
Galic S, Oakhill JS, Steinberg GR (2010) Adipose tissue as an endocrine organ. Mol Cell Endocrinol 316: 129–139. doi: 10.1016/j.mce.2009.08.018
[5]
Maury E, Brichard SM (2010) Adipokine dysregulation, adipose tissue inflammation and metabolic syndrome. Mol Cell Endocrinol 314: 1–16. doi: 10.1016/j.mce.2009.07.031
[6]
Tilg H, Moschen AR (2006) Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 6: 772–783. doi: 10.1038/nri1937
[7]
Ouchi N, Parker JL, Lugus JJ, Walsh K (2011) Adipokines in inflammation and metabolic disease. Nat Rev Immunol 11: 85–97. doi: 10.1038/nri2921
[8]
Kadomatsu K, Kishida S, Tsubota S (2013) The heparin-binding growth factor midkine: the biological activities and candidate receptors. J Biochem 153: 511–521. doi: 10.1093/jb/mvt035
[9]
Kadomatsu K, Tomomura M, Muramatsu T (1988) cDNA cloning and sequencing of a new gene intensely expressed in early differentiation stages of embryonal carcinoma cells and in mid-gestation period of mouse embryogenesis. Biochem Biophys Res Commun 151: 1312–1318. doi: 10.1016/s0006-291x(88)80505-9
[10]
Muramatsu T (1993) Midkine (MK), the product of a retinoic acid responsive gene, and pleiotrophin constitute a new protein family regulating growth and differentiation. Int J Dev Biol 37: 183–188.
[11]
Weckbach LT, Groesser L, Borgolte J, Pagel JI, Pogoda F, et al. (2012) Midkine acts as proangiogenic cytokine in hypoxia-induced angiogenesis. Am J Physiol Heart Circ Physiol 303: H429–438. doi: 10.1152/ajpheart.00934.2011
[12]
Sueyoshi T, Jono H, Shinriki S, Ota K, Ota T, et al. (2012) Therapeutic approaches targeting midkine suppress tumor growth and lung metastasis in osteosarcoma. Cancer Lett 316: 23–30. doi: 10.1016/j.canlet.2011.10.013
[13]
Michikawa M, Kikuchi S, Muramatsu H, Muramatsu T, Kim SU (1993) Retinoic acid responsive gene product, midkine, has neurotrophic functions for mouse spinal cord and dorsal root ganglion neurons in culture. J Neurosci Res 35: 530–539. doi: 10.1002/jnr.490350509
[14]
Weckbach LT, Muramatsu T, Walzog B (2011) Midkine in inflammation. ScientificWorldJournal 11: 2491–2505. doi: 10.1100/2011/517152
[15]
Takada T, Toriyama K, Muramatsu H, Song XJ, Torii S, et al. (1997) Midkine, a retinoic acid-inducible heparin-binding cytokine in inflammatory responses: chemotactic activity to neutrophils and association with inflammatory synovitis. J Biochem 122: 453–458. doi: 10.1093/oxfordjournals.jbchem.a021773
[16]
Horiba M, Kadomatsu K, Nakamura E, Muramatsu H, Ikematsu S, et al. (2000) Neointima formation in a restenosis model is suppressed in midkine-deficient mice. J Clin Invest 105: 489–495. doi: 10.1172/jci7208
[17]
Wang J, Takeuchi H, Sonobe Y, Jin S, Mizuno T, et al. (2008) Inhibition of midkine alleviates experimental autoimmune encephalomyelitis through the expansion of regulatory T cell population. Proc Natl Acad Sci U S A 105: 3915–3920. doi: 10.1073/pnas.0709592105
[18]
Maruyama K, Muramatsu H, Ishiguro N, Muramatsu T (2004) Midkine, a heparin-binding growth factor, is fundamentally involved in the pathogenesis of rheumatoid arthritis. Arthritis Rheum 50: 1420–1429. doi: 10.1002/art.20175
[19]
Krzystek-Korpacka M, Neubauer K, Matusiewicz M (2010) Circulating midkine in Crohn’s disease: clinical implications. Inflamm Bowel Dis 16: 208–215. doi: 10.1002/ibd.21011
[20]
Krzystek-Korpacka M, Neubauer K, Matusiewicz M (2009) Clinical relevance of circulating midkine in ulcerative colitis. Clin Chem Lab Med 47: 1085–1090. doi: 10.1515/cclm.2009.248
[21]
Cernkovich ER, Deng J, Hua K, Harp JB (2007) Midkine is an autocrine activator of signal transducer and activator of transcription 3 in 3T3-L1 cells. Endocrinology 148: 1598–1604. doi: 10.1210/en.2006-1106
[22]
Ratovitski EA, Kotzbauer PT, Milbrandt J, Lowenstein CJ, Burrow CR (1998) Midkine induces tumor cell proliferation and binds to a high affinity signaling receptor associated with JAK tyrosine kinases. J Biol Chem 273: 3654–3660. doi: 10.1074/jbc.273.6.3654
[23]
Kadomatsu K, Hagihara M, Akhter S, Fan QW, Muramatsu H, et al. (1997) Midkine induces the transformation of NIH3T3 cells. Br J Cancer 75: 354–359.
[24]
Lucas S Fau - Henze G, Henze G Fau - Schnabel D, Schnabel D Fau - Barthlen W, Barthlen W Fau - Sakuma S, Sakuma S Fau - Kurtz A, et al.. (2010) Serum levels of Midkine in children and adolescents without malignant disease.
[25]
Student AK, Hsu RY, Lane MD (1980) Induction of fatty acid synthetase synthesis in differentiating 3T3-L1 preadipocytes. J Biol Chem 255: 4745–4750.
[26]
You Z, Dong Y, Kong X, Beckett LA, Gandour-Edwards R, et al. (2008) Midkine is a NF-kappaB-inducible gene that supports prostate cancer cell survival. BMC Med Genomics 1: 6. doi: 10.1186/1755-8794-1-6
[27]
Yazihan N, Karakurt O, Ataoglu H (2008) Erythropoietin reduces lipopolysaccharide-induced cell Damage and midkine secretion in U937 human histiocytic lymphoma cells. Adv Ther 25: 502–514. doi: 10.1007/s12325-008-0055-5
[28]
Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, et al. (1996) IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science 271: 665–668. doi: 10.1126/science.271.5249.665
[29]
Delerive P, Fruchart JC, Staels B (2001) Peroxisome proliferator-activated receptors in inflammation control. J Endocrinol 169: 453–459. doi: 10.1677/joe.0.1690453
[30]
Friedman JM, Halaas JL (1998) Leptin and the regulation of body weight in mammals. Nature 395: 763–770. doi: 10.1038/27376
[31]
Stienstra R, Joosten LA, Koenen T, van Tits B, van Diepen JA, et al. (2010) The inflammasome-mediated caspase-1 activation controls adipocyte differentiation and insulin sensitivity. Cell Metab 12: 593–605. doi: 10.1016/j.cmet.2010.11.011
[32]
Kuo AH, Stoica GE, Riegel AT, Wellstein A (2007) Recruitment of insulin receptor substrate-1 and activation of NF-kappaB essential for midkine growth signaling through anaplastic lymphoma kinase. Oncogene 26: 859–869. doi: 10.1038/sj.onc.1209840
[33]
Baker RG, Hayden MS, Ghosh S (2011) NF-kappaB, inflammation, and metabolic disease. Cell Metab 13: 11–22. doi: 10.1016/j.cmet.2010.12.008
[34]
Serrano-Marco L, Rodriguez-Calvo R, El Kochairi I, Palomer X, Michalik L, et al. (2011) Activation of peroxisome proliferator-activated receptor-beta/？delta (PPAR-beta/？delta) ameliorates insulin signaling and reduces SOCS3 levels by inhibiting STAT3 in interleukin-6-stimulated adipocytes. Diabetes 60: 1990–1999. doi: 10.2337/db10-0704
[35]
Steppan CM, Wang J, Whiteman EL, Birnbaum MJ, Lazar MA (2005) Activation of SOCS-3 by resistin. Mol Cell Biol 25: 1569–1575. doi: 10.1128/mcb.25.4.1569-1575.2005
[36]
Ishizuka K, Usui I, Kanatani Y, Bukhari A, He J, et al. (2007) Chronic tumor necrosis factor-alpha treatment causes insulin resistance via insulin receptor substrate-1 serine phosphorylation and suppressor of cytokine signaling-3 induction in 3T3-L1 adipocytes. Endocrinology 148: 2994–3003. doi: 10.1210/en.2006-1702
[37]
Narita H Fau - Chen S, Chen S Fau - Komori K, Komori K Fau - Kadomatsu K, Kadomatsu K (2008) Midkine is expressed by infiltrating macrophages in in-stent restenosis in hypercholesterolemic rabbits.
[38]
Dai LC, Yao X, Wang X, Niu SQ, Zhou LF, et al. (2009) In vitro and in vivo suppression of hepatocellular carcinoma growth by midkine-antisense oligonucleotide-loaded nanoparticles. World J Gastroenterol 15: 1966–1972. doi: 10.3748/wjg.15.1966
[39]
Hotamisligil GS, Shargill NS, Spiegelman BM (1993) Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259: 87–91. doi: 10.1126/science.7678183
[40]
Olefsky JM, Glass CK (2010) Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 72: 219–246. doi: 10.1146/annurev-physiol-021909-135846
[41]
Palanivel R, Fullerton MD, Galic S, Honeyman J, Hewitt KA, et al. (2012) Reduced Socs3 expression in adipose tissue protects female mice against obesity-induced insulin resistance. Diabetologia 55: 3083–3093. doi: 10.1007/s00125-012-2665-3
[42]
Emanuelli B, Peraldi P, Filloux C, Chavey C, Freidinger K, et al. (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.
[43]
Emanuelli B, Peraldi P, Filloux C, Sawka-Verhelle D, Hilton D, et al. (2000) SOCS-3 is an insulin-induced negative regulator of insulin signaling. J Biol Chem 275: 15985–15991. doi: 10.1074/jbc.275.21.15985
[44]
Huang Y, Hoque MO, Wu F, Trink B, Sidransky D, et al. (2008) Midkine induces epithelial-mesenchymal transition through Notch2/Jak2-Stat3 signaling in human keratinocytes. Cell Cycle 7: 1613–1622. doi: 10.4161/cc.7.11.5952
[45]
Stoica GE, Kuo A, Powers C, Bowden ET, Sale EB, et al. (2002) Midkine binds to anaplastic lymphoma kinase (ALK) and acts as a growth factor for different cell types. J Biol Chem 277: 35990–35998. doi: 10.1074/jbc.m205749200
[46]
Maeda N, Ichihara-Tanaka K, Kimura T, Kadomatsu K, Muramatsu T, et al. (1999) A receptor-like protein-tyrosine phosphatase PTPzeta/RPTPbeta binds a heparin-binding growth factor midkine. Involvement of arginine 78 of midkine in the high affinity binding to PTPzeta. J Biol Chem 274: 12474–12479. doi: 10.1074/jbc.274.18.12474
[47]
Muramatsu H, Zou P, Suzuki H, Oda Y, Chen GY, et al. (2004) alpha4beta1- and alpha6beta1-integrins are functional receptors for midkine, a heparin-binding growth factor. J Cell Sci 117: 5405–5415. doi: 10.1242/jcs.01423
[48]
Chiarle R, Simmons WJ, Cai H, Dhall G, Zamo A, et al. (2005) Stat3 is required for ALK-mediated lymphomagenesis and provides a possible therapeutic target. Nat Med 11: 623–629. doi: 10.1038/nm1249
