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IL-6 induces lipolysis and mitochondrial dysfunction, but does not affect insulin-mediated glucose transport in 3T3-L1 adipocytes

  • Chenbo Ji
  • Xiaohui Chen
  • Chunlin Gao
  • Liuhong Jiao
  • Jianguo Wang
  • Guangfeng Xu
  • Hailong Fu
  • Xirong Guo
  • Yaping Zhao
Article

Abstract

Interleukin-6 (IL-6) has emerged as an important cytokine involved in the regulation of metabolism. However, the role of IL-6 in the etiology of obesity and insulin resistance is not fully understood. Mitochondria are key organelles of energy metabolism, and there is growing evidence that mitochondrial dysfunction plays a crucial role in the pathogenesis of obesity-associated insulin resistance. In this study, we determined the direct effect of IL-6 on lipolysis in adipocytes, and the effects of IL-6 on mitochondrial function were investigated. We found that cells treated with IL-6 displayed fewer lipids and an elevated glycerol release rate. Further, IL-6 treatment led to decreased mitochondrial membrane potential, decreased cellular ATP production, and increased intracellular ROS levels. The mitochondria in IL-6-treated cells became swollen and hollow with reduced or missing cristae. However, insulin-stimulated glucose transport was unaltered. PGC-1α, NRF1, and mtTFA mRNA levels were markedly increased, and the mitochondrial contents were also increased. Our results demonstrate that IL-6 can exert a direct lipolytic effect and induce mitochondrial dysfunction. However, IL-6 did not affect insulin sensitivity in adipocytes in vitro. We deduce that in these cells, enhanced mitochondrial biogenesis might play a compensatory role in glucose transport.

Keywords

IL-6 Adipocytes Lipolysis Mitochondria Insulin resistance 

References

  1. Bastard JP, Maachi M, Van Nhieu JT, Jardel C, Bruckert E, Grimaldi A, Robert JJ, Capeau J, Hainque B (2002) Adipose tissue IL-6 content correlates with resistance to insulin activation of glucose uptake both in vivo and in vitro. J Clin Endocrinol Metab 87(5):2084–2089CrossRefGoogle Scholar
  2. Bournat JC, Brown CW (2010) Mitochondrial dysfunction in obesity. Curr Opin Endocrinol Diabetes Obes 17(5):446–452CrossRefGoogle Scholar
  3. Carey AL, Steinberg GR, Macaulay SL, Thomas WG, Holmes AG, Ramm G, Prelovsek O, Hohnen-Behrens C, Watt MJ, James DE, Kemp BE, Pedersen BK, Febbraio MA (2006) Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase. Diabetes 55(10):2688–2697CrossRefGoogle Scholar
  4. Ceddia RB, Somwar R, Maida A, Fanq X, Bikopouls G, Sweeney G (2005) Globular adiponectin increases GLUT4 translocation and glucose uptake but reduces glycogen synthesis in rat skeletal muscle cells. Diabetologia 48(1):132–139CrossRefGoogle Scholar
  5. Chanseaume E, Barquissau V, Salles J, Aucouturier J, Patrac V, Giraudet C, Gryson C, Duché P, Boirie Y, Chardigny JM, Morio B (2010) Muscle mitochondrial oxidative phosphorylation activity, but not content, is altered with abdominal obesity in sedentary men: synergism with changes in insulin sensitivity. J Clin Endocrinol Metab 95(6):2948–2956CrossRefGoogle Scholar
  6. Choo HJ, Kim JH, Kwon OB, Lee CS, Mun JY, Han SS, Yoon YS, Yoon G, Choi KM, Ko YG (2006) Mitochondria are impaired in the adipocytes of type 2 diabetic mice. Diabetologia 49(4):784–791CrossRefGoogle Scholar
  7. Chow LS, Greenlund LJ, Asmann YW, Short KR, McCrady SK, Levine JA, Nair KS (2007) Impact of endurance training on murine spontaneous activity, muscle mitochondrial DNA abundance, gene transcripts, and function. J Appl Physiol 102(3):1078–1089CrossRefGoogle Scholar
  8. Franckhauser S, Elias I, Rotter Sopasakis V, Ferré T, Nagaev I, Andersson CX, Agudo J, Ruberte J, Bosch F, Smith U (2008) Overexpression of Il6 leads to hyperinsulinaemia, liver inflammation and reduced body weight in mice. Diabetologia 51(7):1306–1316CrossRefGoogle Scholar
  9. Fried SK, Bunkin DA, Greenberg AS (1998) Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid. J Clin Endocrinol Metab 83(3):847–850CrossRefGoogle Scholar
  10. Green A, Rumberger JM, Stuart CA, Ruhoff MS (2004) Stimulation of lipolysis by tumor necrosis factor-alpha in 3T3-L1 adipocytes is glucose dependent: implications for long-term regulation of lipolysis. Diabetes 53(1):74–81CrossRefGoogle Scholar
  11. Højlund K, Mogensen M, Sahlin K, Beck-Nielsen H (2008) Mitochondrial dysfunction in type 2 diabetes and obesity. Endocrinol Metab Clin North Am 37(3):713–731CrossRefGoogle Scholar
  12. Kelly DP, Scarpulla RC (2004) Transcriptional regulatory circuits controlling mitochondrial biogenesis and function. Genes Dev 18(4):357–368CrossRefGoogle Scholar
  13. Kim JA, Wei Y, Sowers JR (2008) Role of mitochondrial dysfunction in insulin resistance. Circ Res 102(4):401–414CrossRefGoogle Scholar
  14. Koves TR, Ussher JR, Noland RC, Slentz D, Mosedale M, Ilkayeva O, Bain J, Stevens R, Dyck JR, Newgard CB, Lopaschuk GD, Muoio DM (2008) Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab 7(1):45–56CrossRefGoogle Scholar
  15. Lyngsø D, Simonsen L, Bülow J (2002) Interleukin-6 production in human subcutaneous abdominal adipose tissue: the effect of exercise. J Physiol 543(Pt 1):373–378CrossRefGoogle Scholar
  16. Mohamed-Ali V, Goodrick S, Rawesh A, Katz DR, Miles JM, Yudkin JS, Klein S, Coppack SW (1997) Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. J Clin Endocrinol Metab 82(12):4196–4200CrossRefGoogle Scholar
  17. Muoio DM, Koves TR (2007) Skeletal muscle adaptation to fatty acid depends on coordinated actions of the PPARs and PGC1 alpha: implications for metabolic disease. Appl Physiol Nutr Metab 32(5):874–883CrossRefGoogle Scholar
  18. Patti ME, Corvera S (2010) The role of mitochondria in the pathogenesis of type 2 diabetes. Endocr Rev 31(3):364–395CrossRefGoogle Scholar
  19. Pedersen BK, Fischer CP (2007) Beneficial health effects of exercise—the role of IL-6 as a myokine. Trends Pharmacol Sci 28(4):152–156CrossRefGoogle Scholar
  20. Rong JX, Qiu Y, Hansen MK, Zhu L, Zhang V, Xie M, Okamoto Y, Mattie MD, Higashiyama H, Asano S, Strum JC, Ryan TE (2007) Adipose mitochondrial biogenesis is suppressed in db/db and high-fat diet–fed mice and improved by rosiglitazone. Diabetes 56(7):1751–1760CrossRefGoogle Scholar
  21. Rotter V, Nagaev I, Smith U (2003) Interleukin-6 (IL-6) induces insulin resistance in 3T3-L1 adipocytes and is, like IL-8 and tumor necrosis factor-alpha, overexpressed in human fat cells from insulin-resistant subjects. J Biol Chem 278(46):45777–45784CrossRefGoogle Scholar
  22. Roytblat L, Rachinsky M, Fisher A, Greemberg L, Shapira Y, Douvdevani A, Gelman S (2000) Raised interleukin-6 levels in obese patients. Obes Res 8(9):673–675CrossRefGoogle Scholar
  23. Schrauwen P, Hesselink MK (2004) Oxidative capacity, lipotoxicity, and mitochondrial damage in type 2 diabetes. Diabetes 53(6):1412–1417CrossRefGoogle Scholar
  24. Sopasakis VR, Sandqvist M, Gustafson B, Hammarstedt A, Schmelz M, Yang X, Jansson PA, Smith U (2004) High local concentrations and effects on differentiation implicate interleukin-6 as a paracrine regulator. Obes Res 12(3):454–460CrossRefGoogle Scholar
  25. Spiegelman BM (2007) Transcriptional control of mitochondrial energy metabolism through the PGC1 coactivators. Novartis Found Symp 287:60–63, discussion 63–69CrossRefGoogle Scholar
  26. Stouthard JM, Oude Elferink RP, Sauerwein HP (1996) Interleukin-6 enhances glucose transport in 3T3-L1 adipocytes. Biochem Biophys Res Commun 220(2):241–245CrossRefGoogle Scholar
  27. Student AK, Hsu RY, Lane MD (1980) Induction of fatty acid synthetase synthesis in differentiating 3T3-L1 preadipocytes. J Biol Chem 255(10):4745–4750Google Scholar
  28. van Hall G, Steensberg A, Sacchetti M, Fischer C, Keller C, Schjerling P, Hiscock N, Møller K, Saltin B, Febbraio MA, Pedersen BK (2003) Interleukin-6 stimulates lipolysis and fat oxidation in humans. J Clin Endocrinol Metab 88(7):3005–3010CrossRefGoogle Scholar
  29. Vozarova B, Weyer C, Hanson K, Tataranni PA, Bogardus C, Pratley RE (2001) Circulating interleukin-6 in relation to adiposity, insulin action, and insulin secretion. Obes Res 9(7):414–417CrossRefGoogle Scholar
  30. Wallenius V, Wallenius K, Ahrén B, Rudling M, Carlsten H, Dickson SL, Ohlsson C, Jansson JO (2002) Interleukin-6-deficient mice develop mature-onset obesity. Nat Med 8(1):75–79CrossRefGoogle Scholar
  31. Wilson-Fritch L, Nicoloro S, Chouinard M, Lazar MA, Chui PC, Leszyk J, Straubhaar J, Czech MP, Corvera S (2004) Mitochondrial remodeling in adipose tissue associated with obesity and treatment with rosiglitazone. J Clin Invest 114(9):1281–1289Google Scholar
  32. Wojtczak L, Schönfeld P (1993) Effect of fatty acids on energy coupling processes in mitochondria. Biochim Biophys Acta 1183(1):41–57CrossRefGoogle Scholar
  33. Wolsk E, Mygind H, Grøndahl TS, Pedersen BK, van Hall G (2010) IL-6 selectively stimulates fat metabolism in human skeletal muscle. Am J Physiol Endocrinol Metab 299(5):E832–E840CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Chenbo Ji
    • 1
    • 2
  • Xiaohui Chen
    • 2
  • Chunlin Gao
    • 3
  • Liuhong Jiao
    • 4
  • Jianguo Wang
    • 4
  • Guangfeng Xu
    • 4
  • Hailong Fu
    • 4
  • Xirong Guo
    • 1
    • 2
  • Yaping Zhao
    • 4
  1. 1.Department of PediatricsNanjing Maternal and Child Health Hospital of Nanjing Medical UniversityNanjingChina
  2. 2.Institute of PediatricsNanjing Medical UniversityNanjingChina
  3. 3.Department of PediatricsJinling HospitalNanjingChina
  4. 4.Department of Clinical LaboratoryThe 82nd Hospital of the People’s Liberation ArmyHuaianChina

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