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The role of complement system in adipose tissue-related inflammation

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Abstract

As the common factor linking adipose tissue to the metabolic context of obesity, insulin resistance and atherosclerosis are associated with a low-grade chronic inflammatory status, to which the complement system is an important contributor. Adipose tissue synthesizes complement proteins and is a target of complement activation. C3a-desArg/acylation-stimulating protein stimulates lipogenesis and affects lipid metabolism. The C3a receptor and C5aR are involved in the development of adipocytes’ insulin resistance through macrophage infiltration and the activation of adipose tissue. The terminal complement pathway has been found to be instrumental in promoting hyperglycemia-associated tissue damage, which is characteristic of the major vascular complications of diabetes mellitus and diabetic ketoacidosis. As a mediator of the effects of the terminal complement complex C5b-9, RGC-32 has an impact on energy expenditure as well as lipid and glucose metabolic homeostasis. All of this evidence, taken together, indicates an important role for complement activation in metabolic diseases.

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Abbreviations

MAC:

Membrane attack complex

AT:

Adipose tissue

DIO:

Diet-induced obesity

DM:

Diabetes mellitus

TG:

Triglyceride body

BMI:

Mass index

SMC:

Smooth muscle cells

KO:

Knockout

MBL:

Mannose binding lectin

GCCD59:

Glycated CD59

DKA:

Diabetic ketoacidosis

ASP:

Acylation-stimulating protein

HFD:

High-fat diet

C5L2:

C5-like receptor 2

References

  1. Niculescu F, Niculescu T, Rus H. C5b-9 terminal complement complex assembly on apoptotic cells in human arterial wall with atherosclerosis. Exp Mol Pathol. 2004;76:17–23.

    Article  CAS  PubMed  Google Scholar 

  2. Ricklin D, Hajishengallis G, Yang K, Lambris JD. Complement: a key system for immune surveillance and homeostasis. Nat Immunol. 2010;11:785–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Vlaicu SI, Tatomir A, Rus V, Mekala AP, Mircea PA, et al. The role of complement activation in atherogenesis: the first 40 years. Immunol Res. 2015;. doi:10.1007/s12026-015-8669-6.

    Google Scholar 

  4. Dunkelberger JR, Song WC. Complement and its role in innate and adaptive immune responses. Cell Res. 2010;20:34–50.

    Article  CAS  PubMed  Google Scholar 

  5. Cole DS, Morgan BP. Beyond lysis: how complement influences cell fate. Clin Sci (Lond). 2003;104:455–66.

    Article  CAS  Google Scholar 

  6. Niculescu F, Rus H. The role of complement activation in atherosclerosis. Immunol Res. 2004;30:73–80.

    Article  CAS  PubMed  Google Scholar 

  7. Vlaicu SI, Tegla CA, Cudrici CD, Danoff J, Madani H, et al. Role of C5b-9 complement complex and response gene to complement-32 (RGC-32) in cancer. Immunol Res. 2013;56:109–21.

    Article  CAS  PubMed  Google Scholar 

  8. Hu VW, Esser AF, Podack ER, Wisnieski BJ. The membrane attack mechanism of complement: photolabeling reveals insertion of terminal proteins into target membrane. J Immunol. 1981;127:380–6.

    CAS  PubMed  Google Scholar 

  9. Laine RO, Esser AF. Detection of refolding conformers of complement protein C9 during insertion into membranes. Nature. 1989;341:63–5.

    Article  CAS  PubMed  Google Scholar 

  10. Podack ER, Tschopp J. Polymerization of the ninth component of complement (C9): formation of poly(C9) with a tubular ultrastructure resembling the membrane attack complex of complement. Proc Natl Acad Sci USA. 1982;79:574–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Tschopp J, Podack ER, Muller-Eberhard HJ. The membrane attack complex of complement: C5b-8 complex as accelerator of C9 polymerization. J Immunol. 1985;134:495–9.

    CAS  PubMed  Google Scholar 

  12. Whitlow MB, Ramm LE, Mayer MM. Penetration of C8 and C9 in the C5b-9 complex across the erythrocyte membrane into the cytoplasmic space. J Biol Chem. 1985;260:998–1005.

    CAS  PubMed  Google Scholar 

  13. Tegla CA, Cudrici C, Patel S, Trippe R 3rd, Rus V, et al. Membrane attack by complement: the assembly and biology of terminal complement complexes. Immunol Res. 2011;51:45–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Alexopoulos N, Katritsis D, Raggi P. Visceral adipose tissue as a source of inflammation and promoter of atherosclerosis. Atherosclerosis. 2014;233:104–12.

    Article  CAS  PubMed  Google Scholar 

  15. Richardson VR, Smith KA, Carter AM. Adipose tissue inflammation: feeding the development of type 2 diabetes mellitus. Immunobiology. 2013;218:1497–504.

    Article  CAS  PubMed  Google Scholar 

  16. Cianflone K, Maslowska M. Differentiation-induced production of ASP in human adipocytes. Eur J Clin Invest. 1995;25:817–25.

    Article  CAS  PubMed  Google Scholar 

  17. Phieler J, Garcia-Martin R, Lambris JD, Chavakis T. The role of the complement system in metabolic organs and metabolic diseases. Semin Immunol. 2013;25:47–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sissons JG, West RJ, Fallows J, Williams DG, Boucher BJ, et al. The complement abnormalities of lipodystrophy. N Engl J Med. 1976;294:461–5.

    Article  CAS  PubMed  Google Scholar 

  19. McLean RH, Hoefnagel D. Partial lipodystrophy and familial C3 deficiency. Hum Hered. 1980;30:149–54.

    Article  CAS  PubMed  Google Scholar 

  20. White RT, Damm D, Hancock N, Rosen BS, Lowell BB, et al. Human adipsin is identical to complement factor D and is expressed at high levels in adipose tissue. J Biol Chem. 1992;267:9210–3.

    CAS  PubMed  Google Scholar 

  21. Choy LN, Rosen BS, Spiegelman BM. Adipsin and an endogenous pathway of complement from adipose cells. J Biol Chem. 1992;267:12736–41.

    CAS  PubMed  Google Scholar 

  22. Peake PW, O’Grady S, Pussell BA, Charlesworth JA. Detection and quantification of the control proteins of the alternative pathway of complement in 3T3-L1 adipocytes. Eur J Clin Invest. 1997;27:922–7.

    Article  CAS  PubMed  Google Scholar 

  23. Mathieson PW, Wurzner R, Oliveria DB, Lachmann PJ, Peters DK. Complement-mediated adipocyte lysis by nephritic factor sera. J Exp Med. 1993;177:1827–31.

    Article  CAS  PubMed  Google Scholar 

  24. Barbu A, Hamad OA, Lind L, Ekdahl KN, Nilsson B. The role of complement factor C3 in lipid metabolism. Mol Immunol. 2015;67:101–7.

    Article  CAS  PubMed  Google Scholar 

  25. Gauvreau D, Roy C, Tom FQ, Lu H, Miegueu P, et al. A new effector of lipid metabolism: complement factor properdin. Mol Immunol. 2012;51:73–81.

    Article  CAS  PubMed  Google Scholar 

  26. Hertle E, van Greevenbroek MM, Stehouwer CD. Complement C3: an emerging risk factor in cardiometabolic disease. Diabetologia. 2012;55:881–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. MacLaren RE, Cui W, Lu H, Simard S, Cianflone K. Association of adipocyte genes with ASP expression: a microarray analysis of subcutaneous and omental adipose tissue in morbidly obese subjects. BMC Med Genomics. 2010;3:3.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Moreno-Navarrete JM, Martinez-Barricarte R, Catalan V, Sabater M, Gomez-Ambrosi J, et al. Complement factor H is expressed in adipose tissue in association with insulin resistance. Diabetes. 2010;59:200–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gabrielsson BG, Johansson JM, Lonn M, Jernas M, Olbers T, et al. High expression of complement components in omental adipose tissue in obese men. Obes Res. 2003;11:699–708.

    Article  CAS  PubMed  Google Scholar 

  30. Gupta A, Rezvani R, Lapointe M, Poursharifi P, Marceau P, et al. Downregulation of complement C3 and C3aR expression in subcutaneous adipose tissue in obese women. PLoS ONE. 2014;9:e95478.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Hillian AD, McMullen MR, Sebastian BM, Roychowdhury S, Kashyap SR, et al. Mice lacking C1q are protected from high fat diet-induced hepatic insulin resistance and impaired glucose homeostasis. J Biol Chem. 2013;288:22565–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Diawara MR, Hue C, Wilder SP, Venteclef N, Aron-Wisnewsky J, et al. Adaptive expression of microRNA-125a in adipose tissue in response to obesity in mice and men. PLoS ONE. 2014;9:e91375.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. van Greevenbroek MM, Ghosh S, van der Kallen CJ, Brouwers MC, Schalkwijk CG, et al. Up-regulation of the complement system in subcutaneous adipocytes from nonobese, hypertriglyceridemic subjects is associated with adipocyte insulin resistance. J Clin Endocrinol Metab. 2012;97:4742–52.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Cero C, Vostrikov VV, Verardi R, Severini C, Gopinath T, et al. The TLQP-21 peptide activates the G-protein-coupled receptor C3aR1 via a folding-upon-binding mechanism. Structure. 2014;22:1744–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lim J, Iyer A, Suen JY, Seow V, Reid RC, et al. C5aR and C3aR antagonists each inhibit diet-induced obesity, metabolic dysfunction, and adipocyte and macrophage signaling. Faseb J. 2013;27:822–31.

    Article  CAS  PubMed  Google Scholar 

  36. Mamane Y, Chung Chan C, Lavallee G, Morin N, Xu LJ, et al. The C3a anaphylatoxin receptor is a key mediator of insulin resistance and functions by modulating adipose tissue macrophage infiltration and activation. Diabetes. 2009;58:2006–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Schaffler A, Scholmerich J. Innate immunity and adipose tissue biology. Trends Immunol. 2010;31:228–35.

    Article  PubMed  CAS  Google Scholar 

  38. Blogowski W, Budkowska M, Salata D, Serwin K, Dolegowska B, et al. Clinical analysis of selected complement-derived molecules in human adipose tissue. J Transl Med. 2013;11:11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Phieler J, Chung KJ, Chatzigeorgiou A, Klotzsche-von Ameln A, Garcia-Martin R, et al. The complement anaphylatoxin C5a receptor contributes to obese adipose tissue inflammation and insulin resistance. J Immunol. 2013;191:4367–74.

    Article  CAS  PubMed  Google Scholar 

  40. Zhang J, Wright W, Bernlohr DA, Cushman SW, Chen X. Alterations of the classic pathway of complement in adipose tissue of obesity and insulin resistance. Am J Physiol Endocrinol Metab. 2007;292:E1433–40.

    Article  CAS  PubMed  Google Scholar 

  41. Fraser DA, Laust AK, Nelson EL, Tenner AJ. C1q differentially modulates phagocytosis and cytokine responses during ingestion of apoptotic cells by human monocytes, macrophages, and dendritic cells. J Immunol. 2009;183:6175–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Alkhouri N, Gornicka A, Berk MP, Thapaliya S, Dixon LJ, et al. Adipocyte apoptosis, a link between obesity, insulin resistance, and hepatic steatosis. J Biol Chem. 2010;285:3428–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Cianflone K, Zakarian R, Couillard C, Delplanque B, Despres JP, et al. Fasting acylation-stimulating protein is predictive of postprandial triglyceride clearance. J Lipid Res. 2004;45:124–31.

    Article  CAS  PubMed  Google Scholar 

  44. MacLaren R, Cui W, Cianflone K. Adipokines and the immune system: an adipocentric view. Adv Exp Med Biol. 2008;632:1–21.

    Article  CAS  PubMed  Google Scholar 

  45. Maslowska M, Sniderman AD, Germinario R, Cianflone K. ASP stimulates glucose transport in cultured human adipocytes. Int J Obes Relat Metab Disord. 1997;21:261–6.

    Article  CAS  PubMed  Google Scholar 

  46. Murray I, Sniderman AD, Cianflone K. Enhanced triglyceride clearance with intraperitoneal human acylation stimulating protein in C57BL/6 mice. Am J Physiol. 1999;277:E474–80.

    CAS  PubMed  Google Scholar 

  47. Murray I, Sniderman AD, Cianflone K. Mice lacking acylation stimulating protein (ASP) have delayed postprandial triglyceride clearance. J Lipid Res. 1999;40:1671–6.

    CAS  PubMed  Google Scholar 

  48. Badea TC, Niculescu FI, Soane L, Shin ML, Rus H. Molecular cloning and characterization of RGC-32, a novel gene induced by complement activation in oligodendrocytes. J Biol Chem. 1998;273:26977–81.

    Article  CAS  PubMed  Google Scholar 

  49. Badea T, Niculescu F, Soane L, Fosbrink M, Sorana H, et al. RGC-32 increases p34CDC2 kinase activity and entry of aortic smooth muscle cells into S-phase. J Biol Chem. 2002;277:502–8.

    Article  CAS  PubMed  Google Scholar 

  50. Tegla CA, Cudrici CD, Nguyen V, Danoff J, Kruszewski AM, et al. RGC-32 is a novel regulator of the T-lymphocyte cell cycle. Exp Mol Pathol. 2015;98:328–37.

    Article  CAS  PubMed  Google Scholar 

  51. Vlaicu SI, Cudrici C, Ito T, Fosbrink M, Tegla CA, et al. Role of response gene to complement 32 in diseases. Arch Immunol Ther Exp (Warsz). 2008;56:115–22.

    Article  CAS  Google Scholar 

  52. Wang JN, Shi N, Xie WB, Guo X, Chen SY. Response gene to complement 32 promotes vascular lesion formation through stimulation of smooth muscle cell proliferation and migration. Arterioscler Thromb Vasc Biol. 2011;31:e19–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Fosbrink M, Cudrici C, Tegla CA, Soloviova K, Ito T, et al. Response gene to complement 32 is required for C5b-9 induced cell cycle activation in endothelial cells. Exp Mol Pathol. 2009;86:87–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Cui XB, Guo X, Chen SY. Response gene to complement 32 deficiency causes impaired placental angiogenesis in mice. Cardiovasc Res. 2013;99:632–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Guo S, Philbrick MJ, An X, Xu M, Wu J. Response gene to complement 32 (RGC-32) in endothelial cells is induced by glucose and helpful to maintain glucose homeostasis. Int J Clin Exp Med. 2014;7:2541–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Cui XB, Luan JN, Ye J, Chen SY. RGC32 deficiency protects against high-fat diet-induced obesity and insulin resistance in mice. J Endocrinol. 2015;224:127–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Ghosh P, Sahoo R, Vaidya A, Chorev M, Halperin JA. Role of complement and complement regulatory proteins in the complications of diabetes. Endocr Rev. 2015;36:272–88.

    Article  CAS  PubMed  Google Scholar 

  58. Guan LZ, Tong Q, Xu J. Elevated serum levels of mannose-binding lectin and diabetic nephropathy in type 2 diabetes. PLoS ONE. 2015;10:e0119699.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Geng P, Ding Y, Qiu L, Lu Y. Serum mannose-binding lectin is a strong biomarker of diabetic retinopathy in chinese patients with diabetes. Diabetes Care. 2015;38:868–75.

    Article  CAS  PubMed  Google Scholar 

  60. Hovind P, Hansen TK, Tarnow L, Thiel S, Steffensen R, et al. Mannose-binding lectin as a predictor of microalbuminuria in type 1 diabetes: an inception cohort study. Diabetes. 2005;54:1523–7.

    Article  CAS  PubMed  Google Scholar 

  61. Jenny L, Ajjan R, King R, Thiel S, Schroeder V. Plasma levels of mannan-binding lectin-associated serine proteases MASP-1 and MASP-2 are elevated in type 1 diabetes and correlate with glycaemic control. Clin Exp Immunol. 2015;180:227–32.

    Article  CAS  PubMed  Google Scholar 

  62. Vlaicu R, Niculescu F, Rus HG, Cristea A. Immunohistochemical localization of the terminal C5b-9 complement complex in human aortic fibrous plaque. Atherosclerosis. 1985;57:163–77.

    Article  CAS  PubMed  Google Scholar 

  63. Niculescu F, Hugo F, Rus HG, Vlaicu R, Bhakdi S. Quantitative evaluation of the terminal C5b-9 complement complex by ELISA in human atherosclerotic arteries. Clin Exp Immunol. 1987;69:477–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Niculescu F, Rus HG, Vlaicu R. Activation of the human terminal complement pathway in atherosclerosis. Clin Immunol Immunopathol. 1987;45:147–55.

    Article  CAS  PubMed  Google Scholar 

  65. Rus HG, Niculescu F, Constantinescu E, Cristea A, Vlaicu R. Immunoelectron-microscopic localization of the terminal C5b-9 complement complex in human atherosclerotic fibrous plaque. Atherosclerosis. 1986;61:35–42.

    Article  CAS  PubMed  Google Scholar 

  66. Rus HG, Niculescu F, Porutiu D, Ghiurca V, Vlaicu R. Cells carrying C5b-9 complement complexes in human atherosclerotic wall. Immunol Lett. 1989;20:305–10.

    Article  CAS  PubMed  Google Scholar 

  67. Niculescu F, Badea T, Rus H. Sublytic C5b-9 induces proliferation of human aortic smooth muscle cells: role of mitogen activated protein kinase and phosphatidylinositol 3-kinase. Atherosclerosis. 1999;142:47–56.

    Article  CAS  PubMed  Google Scholar 

  68. Fosbrink M, Niculescu F, Rus V, Shin ML, Rus H. C5b-9-induced endothelial cell proliferation and migration are dependent on Akt inactivation of forkhead transcription factor FOXO1. J Biol Chem. 2006;281:19009–18.

    Article  CAS  PubMed  Google Scholar 

  69. Vasil KE, Magro CM. Cutaneous vascular deposition of C5b-9 and its role as a diagnostic adjunct in the setting of diabetes mellitus and porphyria cutanea tarda. J Am Acad Dermatol. 2007;56:96–104.

    Article  PubMed  Google Scholar 

  70. Falk RJ, Sisson SP, Dalmasso AP, Kim Y, Michael AF, et al. Ultrastructural localization of the membrane attack complex of complement in human renal tissues. Am J Kidney Dis. 1987;9:121–8.

    Article  CAS  PubMed  Google Scholar 

  71. Gerl VB, Bohl J, Pitz S, Stoffelns B, Pfeiffer N, et al. Extensive deposits of complement C3d and C5b-9 in the choriocapillaris of eyes of patients with diabetic retinopathy. Invest Ophthalmol Vis Sci. 2002;43:1104–8.

    PubMed  Google Scholar 

  72. Rosoklija GB, Dwork AJ, Younger DS, Karlikaya G, Latov N, et al. Local activation of the complement system in endoneurial microvessels of diabetic neuropathy. Acta Neuropathol. 2000;99:55–62.

    Article  CAS  PubMed  Google Scholar 

  73. Mellbin LG, Bjerre M, Thiel S, Hansen TK. Complement activation and prognosis in patients with type 2 diabetes and myocardial infarction: a report from the DIGAMI 2 trial. Diabetes Care. 2012;35:911–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Qin X, Goldfine A, Krumrei N, Grubissich L, Acosta J, et al. Glycation inactivation of the complement regulatory protein CD59: a possible role in the pathogenesis of the vascular complications of human diabetes. Diabetes. 2004;53:2653–61.

    Article  CAS  PubMed  Google Scholar 

  75. Acosta J, Hettinga J, Fluckiger R, Krumrei N, Goldfine A, et al. Molecular basis for a link between complement and the vascular complications of diabetes. Proc Natl Acad Sci USA. 2000;97:5450–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Ghosh P, Vaidya A, Sahoo R, Goldfine A, Herring N, et al. Glycation of the complement regulatory protein CD59 is a novel biomarker for glucose handling in humans. J Clin Endocrinol Metab. 2014;99:E999–1006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Krus U, King BC, Nagaraj V, Gandasi NR, Sjolander J, et al. The complement inhibitor CD59 regulates insulin secretion by modulating exocytotic events. Cell Metab. 2014;19:883–90.

    Article  CAS  PubMed  Google Scholar 

  78. Hoffman WH, Cudrici CD, Zafranskaia E, Rus H. Complement activation in diabetic ketoacidosis brains. Exp Mol Pathol. 2006;80:283–8.

    Article  CAS  PubMed  Google Scholar 

  79. Jerath RS, Burek CL, Hoffman WH, Passmore GG. Complement activation in diabetic ketoacidosis and its treatment. Clin Immunol. 2005;116:11–7.

    Article  CAS  PubMed  Google Scholar 

  80. Niculescu F, Soane L, Badea T, Shin M, Rus H. Tyrosine phosphorylation and activation of Janus kinase 1 and STAT3 by sublytic C5b-9 complement complex in aortic endothelial cells. Immunopharmacology. 1999;42:187–93.

    Article  CAS  PubMed  Google Scholar 

  81. Benzaquen LR, Nicholson-Weller A, Halperin JA. Terminal complement proteins C5b-9 release basic fibroblast growth factor and platelet-derived growth factor from endothelial cells. J Exp Med. 1994;179:985–92.

    Article  CAS  PubMed  Google Scholar 

  82. Halperin JA, Taratuska A, Nicholson-Weller A. Terminal complement complex C5b-9 stimulates mitogenesis in 3T3 cells. J Clin Invest. 1993;91:1974–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Saleh J, Al-Wardy N, Farhan H, Al-Khanbashi M, Cianflone K. Acylation stimulating protein: a female lipogenic factor? Obes Rev. 2011;12:440–8.

    Article  CAS  PubMed  Google Scholar 

  84. Yasruel Z, Cianflone K, Sniderman AD, Rosenbloom M, Walsh M, et al. Effect of acylation stimulating protein on the triacylglycerol synthetic pathway of human adipose tissue. Lipids. 1991;26:495–9.

    Article  CAS  PubMed  Google Scholar 

  85. Cianflone K, Maslowska M, Sniderman AD. Acylation stimulating protein (ASP), an adipocyte autocrine: new directions. Semin Cell Dev Biol. 1999;10:31–41.

    Article  CAS  PubMed  Google Scholar 

  86. Murray I, Havel PJ, Sniderman AD, Cianflone K. Reduced body weight, adipose tissue, and leptin levels despite increased energy intake in female mice lacking acylation-stimulating protein. Endocrinology. 2000;141:1041–9.

    CAS  PubMed  Google Scholar 

  87. Murray I, Sniderman AD, Havel PJ, Cianflone K. Acylation stimulating protein (ASP) deficiency alters postprandial and adipose tissue metabolism in male mice. J Biol Chem. 1999;274:36219–25.

    Article  CAS  PubMed  Google Scholar 

  88. Xia Z, Stanhope KL, Digitale E, Simion OM, Chen L, et al. Acylation-stimulating protein (ASP)/complement C3adesArg deficiency results in increased energy expenditure in mice. J Biol Chem. 2004;279:4051–7.

    Article  CAS  PubMed  Google Scholar 

  89. Schadt EE, Lamb J, Yang X, Zhu J, Edwards S, et al. An integrative genomics approach to infer causal associations between gene expression and disease. Nat Genet. 2005;37:710–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Munkonda MN, Lapointe M, Miegueu P, Roy C, Gauvreau D, et al. Recombinant acylation stimulating protein administration to C3-/- mice increases insulin resistance via adipocyte inflammatory mechanisms. PLoS ONE. 2012;7:e46883.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Fisette A, Lapointe M, Cianflone K. Obesity-inducing diet promotes acylation stimulating protein resistance. Biochem Biophys Res Commun. 2013;437:403–7.

    Article  CAS  PubMed  Google Scholar 

  92. Paglialunga S, Schrauwen P, Roy C, Moonen-Kornips E, Lu H, et al. Reduced adipose tissue triglyceride synthesis and increased muscle fatty acid oxidation in C5L2 knockout mice. J Endocrinol. 2007;194:293–304.

    Article  CAS  PubMed  Google Scholar 

  93. Cerf ME. Beta cell dysfunction and insulin resistance. Front Endocrinol (Lausanne). 2013;4:37.

    Google Scholar 

  94. Lo JC, Ljubicic S, Leibiger B, Kern M, Leibiger IB, et al. Adipsin is an adipokine that improves beta cell function in diabetes. Cell. 2014;158:41–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Cianflone K, Lu H, Smith J, Yu W, Wang H. Adiponectin, acylation stimulating protein and complement C3 are altered in obesity in very young children. Clin Endocrinol (Oxf). 2005;62:567–72.

    Article  CAS  Google Scholar 

  96. Engström G, Hedblad B, Eriksson K-F, Janzon L, Lindgärde F. Complement C3 is a risk factor for the development of diabetes: a population-based cohort study. Diabetes. 2005;54:570–5.

    Article  PubMed  Google Scholar 

  97. Engstrom G, Hedblad B, Janzon L, Lindgarde F. Weight gain in relation to plasma levels of complement factor 3: results from a population-based cohort study. Diabetologia. 2005;48:2525–31.

    Article  CAS  PubMed  Google Scholar 

  98. Nilsson B, Hamad OA, Ahlstrom H, Kullberg J, Johansson L, et al. C3 and C4 are strongly related to adipose tissue variables and cardiovascular risk factors. Eur J Clin Invest. 2014;44:587–96.

    Article  CAS  PubMed  Google Scholar 

  99. Onat A, Uyarel H, Hergenc G, Karabulut A, Albayrak S, et al. Determinants and definition of abdominal obesity as related to risk of diabetes, metabolic syndrome and coronary disease in Turkish men: a prospective cohort study. Atherosclerosis. 2007;191:182–90.

    Article  CAS  PubMed  Google Scholar 

  100. Qin X, Lu Y, Yang X, Peng Q, Wang J, et al. Determination of reference intervals for serum complement C3 and C4 levels in Chinese Han ethnic males. Clin Lab. 2014;60:775–81.

    CAS  PubMed  Google Scholar 

  101. Warnberg J, Nova E, Moreno LA, Romeo J, Mesana MI, et al. Inflammatory proteins are related to total and abdominal adiposity in a healthy adolescent population: the AVENA Study. Am J Clin Nutr. 2006;84:505–12.

    CAS  PubMed  Google Scholar 

  102. Hernandez-Mijares A, Jarabo-Bueno MM, Lopez-Ruiz A, Sola-Izquierdo E, Morillas-Arino C, et al. Levels of C3 in patients with severe, morbid and extreme obesity: its relationship to insulin resistance and different cardiovascular risk factors. Int J Obes (Lond). 2007;31:927–32.

    Article  CAS  Google Scholar 

  103. Oberbach A, Bluher M, Wirth H, Till H, Kovacs P, et al. Combined proteomic and metabolomic profiling of serum reveals association of the complement system with obesity and identifies novel markers of body fat mass changes. J Proteome Res. 2011;10:4769–88.

    Article  CAS  PubMed  Google Scholar 

  104. Sleddering MA, Markvoort AJ, Dharuri HK, Jeyakar S, Snel M, et al. Proteomic analysis in type 2 diabetes patients before and after a very low calorie diet reveals potential disease state and intervention specific biomarkers. PLoS ONE. 2014;9:e112835.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Nestvold TK, Nielsen EW, Ludviksen JK, Fure H, Landsem A, et al. Lifestyle changes followed by bariatric surgery lower inflammatory markers and the cardiovascular risk factors C3 and C4. Metab Syndr Relat Disord. 2015;13:29–35.

    Article  CAS  PubMed  Google Scholar 

  106. Wlazlo N, van Greevenbroek MM, Ferreira I, Jansen EJ, Feskens EJ, et al. Low-grade inflammation and insulin resistance independently explain substantial parts of the association between body fat and serum C3: the CODAM study. Metabolism. 2012;61:1787–96.

    Article  CAS  PubMed  Google Scholar 

  107. Phillips CM, Kesse-Guyot E, Ahluwalia N, McManus R, Hercberg S, et al. Dietary fat, abdominal obesity and smoking modulate the relationship between plasma complement component 3 concentrations and metabolic syndrome risk. Atherosclerosis. 2012;220:513–9.

    Article  CAS  PubMed  Google Scholar 

  108. Wlazlo N, van Greevenbroek MM, Ferreira I, Feskens EJ, van der Kallen CJ, et al. Complement factor 3 is associated with insulin resistance and with incident type 2 diabetes over a 7-year follow-up period: the CODAM Study. Diabetes Care. 2014;37:1900–9.

    Article  CAS  PubMed  Google Scholar 

  109. De Pergola G, Tartagni M, Bartolomeo N, Bruno I, Masiello M, et al. Possible direct influence of complement 3 in decreasing insulin sensitivity in a cohort of overweight and obese subjects. Endocr Metab Immune Disord Drug Targets. 2013;13:301–5.

    Article  PubMed  CAS  Google Scholar 

  110. Muscari A, Antonelli S, Bianchi G, Cavrini G, Dapporto S, et al. Serum C3 is a stronger inflammatory marker of insulin resistance than C-reactive protein, leukocyte count, and erythrocyte sedimentation rate: comparison study in an elderly population. Diabetes Care. 2007;30:2362–8.

    Article  CAS  PubMed  Google Scholar 

  111. Muscari A, Bozzoli C, Puddu GM, Sangiorgi Z, Dormi A, et al. Association of serum C3 levels with the risk of myocardial infarction. Am J Med. 1995;98:357–64.

    Article  CAS  PubMed  Google Scholar 

  112. Vidigal Fde C, Ribeiro AQ, Babio N, Salas-Salvado J, Bressan J. Prevalence of metabolic syndrome and pre-metabolic syndrome in health professionals: LATINMETS Brazil study. Diabetol Metab Syndr. 2015;7:6.

    Article  PubMed  CAS  Google Scholar 

  113. Onat A, Can G, Rezvani R, Cianflone K. Complement C3 and cleavage products in cardiometabolic risk. Clin Chim Acta. 2011;412:1171–9.

    Article  CAS  PubMed  Google Scholar 

  114. Van Harmelen V, Reynisdottir S, Cianflone K, Degerman E, Hoffstedt J, et al. Mechanisms involved in the regulation of free fatty acid release from isolated human fat cells by acylation-stimulating protein and insulin. J Biol Chem. 1999;274:18243–51.

    Article  PubMed  Google Scholar 

  115. Ahren B, Havel PJ, Pacini G, Cianflone K. Acylation stimulating protein stimulates insulin secretion. Int J Obes Relat Metab Disord. 2003;27:1037–43.

    Article  CAS  PubMed  Google Scholar 

  116. Saleh J, Wahab RA, Farhan H, Al-Amri I, Cianflone K. Plasma levels of acylation-stimulating protein are strongly predicted by waist/hip ratio and correlate with decreased LDL size in men. ISRN Obes. 2013;2013:342802.

    PubMed  PubMed Central  Google Scholar 

  117. Yang Y, Lu HL, Zhang J, Yu HY, Wang HW, et al. Relationships among acylation stimulating protein, adiponectin and complement C3 in lean vs obese type 2 diabetes. Int J Obes (Lond). 2006;30:439–46.

    Article  CAS  Google Scholar 

  118. Cianflone K, Zhang XJ, Genest J Jr, Sniderman A. Plasma acylation-stimulating protein in coronary artery disease. Arterioscler Thromb Vasc Biol. 1997;17:1239–44.

    CAS  PubMed  Google Scholar 

  119. Weyer C, Pratley RE. Fasting and postprandial plasma concentrations of acylation-stimulation protein (ASP) in lean and obese Pima Indians compared to Caucasians. Obes Res. 1999;7:444–52.

    Article  CAS  PubMed  Google Scholar 

  120. Wamba PC, Mi J, Zhao XY, Zhang MX, Wen Y, et al. Acylation stimulating protein but not complement C3 associates with metabolic syndrome components in Chinese children and adolescents. Eur J Endocrinol. 2008;159:781–90.

    Article  CAS  PubMed  Google Scholar 

  121. Fujita T, Hemmi S, Kajiwara M, Yabuki M, Fuke Y, et al. Complement-mediated chronic inflammation is associated with diabetic microvascular complication. Diabetes Metab Res Rev. 2013;29:220–6.

    Article  CAS  PubMed  Google Scholar 

  122. Somani R, Richardson VR, Standeven KF, Grant PJ, Carter AM. Elevated properdin and enhanced complement activation in first-degree relatives of South Asian subjects with type 2 diabetes. Diabetes Care. 2012;35:894–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Uza G, Cristea A, Cucuianu MP. Increased level of the complement C3 protein in endogenous hypertriglyceridemia. J Clin Lab Immunol. 1982;8:101–5.

    CAS  PubMed  Google Scholar 

  124. Vaisar T, Pennathur S, Green PS, Gharib SA, Hoofnagle AN, et al. Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL. J Clin Invest. 2007;117:746–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

We thank Dr. Deborah McClellan for editing this manuscript. This work was supported in part by a Veterans Administration Merit Award BX001458 (to H.R.). Dr. Sonia Vlaicu’s work was partially supported by POSDRU Grant No. 159/1.5/S/138776 with the title: “Model colaborativ institutional pentru translatarea cercetarii stiintifice biomedicale in practica clinica—TRANSCENT” and by the internal Grant No. 1495/8/28.01.2014 financed by “Iuliu Hatieganu” University of Medicine and Pharmacy of Cluj-Napoca, Romania.

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Authors and Affiliations

  1. Department of Neurology, University of Maryland, School of Medicine, 655 W Baltimore St, BRB 12-033, Baltimore, MD, 21201, USA

    Sonia I. Vlaicu, Alexandru Tatomir, Dallas Boodhoo & Horea Rus

  2. Department of Internal Medicine, “Iuliu Haţieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania

    Sonia I. Vlaicu & Petru A. Mircea

  3. Research Service, Veterans Administration Maryland Health Care System, Baltimore, MD, USA

    Alexandru Tatomir & Horea Rus

  4. Department of Pharmacology, Toxicology and Clinical Pharmacology, “Iuliu Haţieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania

    Stefan Vesa

  5. Veterans Administration Multiple Sclerosis Center of Excellence, Baltimore, MD, USA

    Horea Rus

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  1. Sonia I. Vlaicu
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  2. Alexandru Tatomir
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Correspondence to Horea Rus.

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Vlaicu, S.I., Tatomir, A., Boodhoo, D. et al. The role of complement system in adipose tissue-related inflammation. Immunol Res 64, 653–664 (2016). https://doi.org/10.1007/s12026-015-8783-5

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