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Role of Complement and Complement‐Related Adipokines in Regulation of Energy Metabolism and Fat Storage

Jumana Saleh, Muna Al‐Maqbali, Dalia Abdel‐Hadi

10.1002/cphy.c170037

Source: Volume 9, Issue 4, October 2019

Published online: September 2019

Full Article on Wiley Online Library



Abstract

Adipose tissue releases many cytokines and inflammatory factors described as adipokines. In obesity, adipokines released from expanding adipose tissue are implicated in disease progression and metabolic dysfunction. However, mechanisms controlling the progression of adiposity and metabolic complications are not fully understood. It has been suggested that expanding fat mass and sustained release of inflammatory adipokines in adipose tissue lead to hypoxia, oxidative stress, apoptosis, and cellular damage. These changes trigger an immune response involving infiltration of adipose tissue with immune cells, complement activation and generation of factors involved in opsonization and clearance of damaged cells. Abundant evidence now indicates that adipose tissue is an active secretory source of complement and complement‐related adipokines that, in addition to their inflammatory role, contribute to the regulation of metabolic function. This article highlights advances in knowledge regarding the role of these adipokines in energy regulation of adipose tissue through modulating lipogenic and lipolytic pathways. Several adipokines will be discussed including adipsin, Factor H, properdin, C3a, Acylation‐Stimulating Protein, C1q/TNF‐related proteins, and response gene to complement‐32 (RGC‐32). Interactions between these factors will be described considering their immune‐metabolic roles in the adipose tissue microenvironment and their potential contribution to progression of adiposity and metabolic dysfunction. The differential expression and the role of complement factors in gender‐related fat partitioning will also be addressed. Identifying lipogenic adipokines and their specific autocrine/paracrine roles may provide means for adipose‐tissue‐targeted therapeutic interventions that may disrupt the vicious circle of adiposity and disease progression. © 2019 American Physiological Society. Compr Physiol 9:1411‐1429, 2019.

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Figure 1. Figure 1. The complement cascade is activated by the classical pathway, the mannose‐binding lectin (MBL) pathway, or alternative pathway. All pathways result in the cleavage of C3 and C5. C3 is cleaved by the C3 convertase enzymes, C4bC2a of the classical and MBL pathways and C3bBb of the alternative pathway. C3 convertases bind to C3b forming C5 convertase enzymes, C4bC2aC3b and C3bBbC3b. C5 convertases cleave C5 to C5a and C5b. C5b subsequently binds to C6, C7, C8, and C9, resulting in the formation of the MAC complex to form pores in the membrane of damaged or foreign‐like self‐cells promoting cell lysis. C3b opsonizes foreign and apoptotic cells, promoting phagocytosis. C3a and C5a are anaphylatoxins. Factor H downregulates the action of C3/C5 convertases. The decay‐accelerating factor (DAF) accelerates decay of C3/C5 convertases. Factor I and C4b‐binding protein (C4BP) degrade C3b. C1 esterase inhibitor (C1‐INH) inactivates C1r and C1s and compete with MASP variants for binding MBL. Properdin upregulates the alternative pathway by stabilizing the C3bBb complex.
Figure 2. Figure 2. ASP enhances triacylglycerol (TG) synthesis by activation of the following pathways: (i) Activates glucose cellular uptake by translocation of glucose transporters (GLUT) to the cell surface to provide the glycerol backbone for the synthesis of the TG molecule. (ii) Enhances FA esterification by activation of diacylglycerol‐acyltransferase (DGAT), the key enzyme in TG synthesis. (iii) Inhibits hormone‐sensitive lipase (HSL) and intracellular lipolysis.
Figure 3. Figure 3. Potential roles of adipose tissue‐released CTPRs in fat metabolism and energy‐regulation pathways as described by Seldin et al. and others 137,156,193,233.
Figure 4. Figure 4. A hypothetical scheme that summarizes potential integrated roles of complement adipokines (highlighted in blue) in the regulation of energy metabolism in the adipocyte microenvironment. C3a enhances insulin production from the pancreas, and promotes adipose tissue insulin sensitivity. C3a also acts as a precursor for the potent lipogenic factor ASP. Adipsin mediates the release of ASP from C3a, which activates PPARγ (a major adipocyte differentiation factor). PPARγ activates the release of adiponectin, which in turn stimulates lipogenesis, and acts as a protective anti‐inflammatory factor. Factor H and properdin play Counter‐regulatory roles in the activation of the alternative pathway. Many CTRPs demonstrated insulin‐like effects. The adipogenic role of CTRPs 2, 6 and 12 has been established. CTRPs 1, 5, 9, 13 and 15 showed insulin‐like effects, however their adipogenic role is yet to be determined. Conversely, CTRP 3 and 11 showed antiadipogenic effects. CTRP 3 and 12 demonstrate anti‐inflammatory effects. ASP, acylation‐stimulating protein; TG, triglyceride; FA, fatty acids; PPAR‐γ, peroxisome proliferator‐activated receptor gamma. Black arrows: activation; blunt arrows: inhibition.


Figure 1. The complement cascade is activated by the classical pathway, the mannose‐binding lectin (MBL) pathway, or alternative pathway. All pathways result in the cleavage of C3 and C5. C3 is cleaved by the C3 convertase enzymes, C4bC2a of the classical and MBL pathways and C3bBb of the alternative pathway. C3 convertases bind to C3b forming C5 convertase enzymes, C4bC2aC3b and C3bBbC3b. C5 convertases cleave C5 to C5a and C5b. C5b subsequently binds to C6, C7, C8, and C9, resulting in the formation of the MAC complex to form pores in the membrane of damaged or foreign‐like self‐cells promoting cell lysis. C3b opsonizes foreign and apoptotic cells, promoting phagocytosis. C3a and C5a are anaphylatoxins. Factor H downregulates the action of C3/C5 convertases. The decay‐accelerating factor (DAF) accelerates decay of C3/C5 convertases. Factor I and C4b‐binding protein (C4BP) degrade C3b. C1 esterase inhibitor (C1‐INH) inactivates C1r and C1s and compete with MASP variants for binding MBL. Properdin upregulates the alternative pathway by stabilizing the C3bBb complex.


Figure 2. ASP enhances triacylglycerol (TG) synthesis by activation of the following pathways: (i) Activates glucose cellular uptake by translocation of glucose transporters (GLUT) to the cell surface to provide the glycerol backbone for the synthesis of the TG molecule. (ii) Enhances FA esterification by activation of diacylglycerol‐acyltransferase (DGAT), the key enzyme in TG synthesis. (iii) Inhibits hormone‐sensitive lipase (HSL) and intracellular lipolysis.


Figure 3. Potential roles of adipose tissue‐released CTPRs in fat metabolism and energy‐regulation pathways as described by Seldin et al. and others 137,156,193,233.


Figure 4. A hypothetical scheme that summarizes potential integrated roles of complement adipokines (highlighted in blue) in the regulation of energy metabolism in the adipocyte microenvironment. C3a enhances insulin production from the pancreas, and promotes adipose tissue insulin sensitivity. C3a also acts as a precursor for the potent lipogenic factor ASP. Adipsin mediates the release of ASP from C3a, which activates PPARγ (a major adipocyte differentiation factor). PPARγ activates the release of adiponectin, which in turn stimulates lipogenesis, and acts as a protective anti‐inflammatory factor. Factor H and properdin play Counter‐regulatory roles in the activation of the alternative pathway. Many CTRPs demonstrated insulin‐like effects. The adipogenic role of CTRPs 2, 6 and 12 has been established. CTRPs 1, 5, 9, 13 and 15 showed insulin‐like effects, however their adipogenic role is yet to be determined. Conversely, CTRP 3 and 11 showed antiadipogenic effects. CTRP 3 and 12 demonstrate anti‐inflammatory effects. ASP, acylation‐stimulating protein; TG, triglyceride; FA, fatty acids; PPAR‐γ, peroxisome proliferator‐activated receptor gamma. Black arrows: activation; blunt arrows: inhibition.
References
 1. Abdul‐Ghani MA , DeFronzo RA . Pathogenesis of insulin resistance in skeletal muscle. J Biomed Biotechnol 2010: 1‐19, 2010.
 2. Al Riyami B , El‐Tahir M , Al Maskari S , Johnson EH , Saleh J . Acute effects of exogenous hormone administration on postprandial acylation stimulating protein levels in ovariectomized rats after a fat load. J Nutr Metab 2014: 510916, 2014.
 3. Albrecht EA , Chinnaiyan AM , Varambally S , Kumar‐Sinha C , Barrette TR , Sarma JV , Ward PA . C5a‐induced gene expression in human umbilical vein endothelial cells. Am J Pathol 164: 849‐859, 2004.
 4. Al‐Riyami B , Langley‐Evans S , Salter A , Saleh J . Progesterone and estrogen regulation of gene expression related to acylation stimulating protein production and function in ex vivo adipose tissue explant culture. Endocr Abstr 44: 198, 2016.
 5. Azizi M , Tadibi V , Behpour N . The effect of aerobic exercise training on β‐cell function and circulating levels of adipsin in community of obese women with type 2 diabetes mellitus. Int J Diabetes Dev Ctries 37: 298‐304, 2017.
 6. Bajic G , Yatime L , Klos A , Andersen GR . Human C3a and C3a desArg anaphylatoxins have conserved structures, in contrast to C5a and C5a desArg. Protein Sci 22: 204‐212, 2013.
 7. Baldo A , Sniderman AD , St‐Luce S , Avramoglu RK , Maslowska M , Hoang B , Monge JC , Bell A , Mulay S , Cianflone K . The adipsin‐acylation stimulating protein system and regulation of intracellular triglyceride synthesis. J Clin Invest 92: 1543‐1547, 1993.
 8. Berg AH , Combs TP , Du X , Brownlee M , Scherer PE . The adipocyte‐secreted protein Acrp30 enhances hepatic insulin action. Nat Med 7: 947‐953, 2001.
 9. Berg JM , Tymoczko JL , Stryer L . Section 22.1. Triacylglycerols are highly concentrated energy stores. In: Biochemistry (5th ed). New York: W H Freeman, 2002. https://www.ncbi.nlm.nih.gov/books/NBK22369
 10. Björntorp P . “Portal” adipose tissue as a generator of risk factors for cardiovascular disease and diabetes [Online]. Arteriosclerosis 10: 493‐496, 1990. http://www.ncbi.nlm.nih.gov/pubmed/2196039
 11. Blatt AZ , Pathan S , Ferreira VP . Properdin: A tightly regulated critical inflammatory modulator. Immunol Rev 274: 172‐190, 2016.
 12. Bulcão C , Ferreira SRG , Giuffrida FMA , Ribeiro‐Filho FF . The new adipose tissue and adipocytokines. Curr Diabetes Rev, 2006. DOI: 10.2174/157339906775473617.
 13. Cervellati F , Cervellati C , Romani A , Cremonini E , Sticozzi C , Belmonte G , Pessina F , Valacchi G . Hypoxia induces cell damage via oxidative stress in retinal epithelial cells. Free Radic Res 48: 303‐312, 2014.
 14. Charlesworth JA , Peake PW , Campbell LV , Pussell BA , O'Grady S , Tzilopoulos T . The influence of oral lipid loads on acylation stimulating protein (ASP) in healthy volunteers. Int J Obes Relat Metab Disord 22: 1096‐1102, 1998.
 15. Chen X , Xun K , Chen L , Wang Y . TNF‐α, a potent lipid metabolism regulator. Cell Biochem Funct, 2009.
 16. Chen S , Mei X , Yin A , Yin H , Cui X‐B , Chen S‐Y . Response gene to complement 32 suppresses adipose tissue thermogenic genes through inhibiting β3‐adrenergic receptor/mTORC1 signaling. FASEB J 32: 4836‐4847, 2018.
 17. Choe SS , Huh JY , Hwang IJ , Kim JI , Kim JB . Adipose tissue remodeling: Its role in energy metabolism and metabolic disorders. Front Endocrinol (Lausanne) 7: 30, 2016.
 18. Cianflone K . The ASP and C5L2 pathway: another bridge between inflammation and metabolic homeostasis. Clin Lipidol 5: 367‐377, 2010.
 19. Cianflone K , Roncari DA , Maslowska M , Baldo A , Forden J , Sniderman AD . Adipsin/acylation stimulating protein system in human adipocytes: Regulation of triacylglycerol synthesis. Biochemistry 33: 9489‐9495, 1994.
 20. Cianflone K , Zhang XJ , Genest J , Sniderman A . Plasma acylation‐stimulating protein in coronary artery disease. Arterioscler Thromb Vasc Biol 17: 1239‐1244, 1997.
 21. Cianflone K , Maslowska M , Sniderman AD . Acylation stimulating protein (ASP), an adipocyte autocrine: New directions. Semin Cell Dev Biol 10: 31‐41, 1999.
 22. Cianflone K , Xia Z , Chen LY . Critical review of acylation‐stimulating protein physiology in humans and rodents. Biochim Biophys Acta 1609: 127‐143, 2003.
 23. Cianflone K , Zakarian R , Couillard C , Delplanque B , Despres J‐P , Sniderman A . Fasting acylation‐stimulating protein is predictive of postprandial triglyceride clearance. J Lipid Res 45: 124‐131, 2004.
 24. 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) 62: 567‐572, 2005.
 25. Cleal L , Aldea T , Chau Y‐Y . Fifty shades of white: Understanding heterogeneity in white adipose stem cells. Adipocyte 6, 2017.
 26. Coelho M , Oliveira T , Fernandes R . State of the art paper biochemistry of adipose tissue: An endocrine organ. Arch Med Sci 2: 191‐200, 2013.
 27. Coimbra‐Costa D , Alva N , Duran M , Carbonell T , Rama R . Oxidative stress and apoptosis after acute respiratory hypoxia and reoxygenation in rat brain. Redox Biol 12: 216‐225, 2017.
 28. Combs TP , Wagner JA , Berger J , Doebber T , Wang W‐J , Zhang BB , Tanen M , Berg AH , O'Rahilly S , Savage DB , Chatterjee K , Weiss S , Larson PJ , Gottesdiener KM , Gertz BJ , Charron MJ , Scherer PE , Moller DE . Induction of adipocyte complement‐related protein of 30 kilodaltons by PPARgamma agonists: A potential mechanism of insulin sensitization. Endocrinology 143: 998‐1007, 2002.
 29. Combs TP , Pajvani UB , Berg AH , Lin Y , Jelicks LA , Laplante M , Nawrocki AR , Rajala MW , Parlow AF , Cheeseboro L , Ding YY , Russell RG , Lindemann D , Hartley A , Baker GRC , Obici S , Deshaies Y , Ludgate M , Rossetti L , Scherer PE . A transgenic mouse with a deletion in the collagenous domain of adiponectin displays elevated circulating adiponectin and improved insulin sensitivity. Endocrinology 145: 367‐383, 2004.
 30. Cook KS , Min HY , Johnson D , Chaplinsky RJ , Flier JS , Hunt CR , Spiegelman BM . Adipsin: A circulating serine protease homolog secreted by adipose tissue and sciatic nerve. Science 237: 402‐405, 1987.
 31. Cooke PS , Naaz A . Role of estrogens in adipocyte development and function. Exp Biol Med (Maywood) 229: 1127‐1135, 2004.
 32. Corominola H , Conner LJ , Beavers LS , Gadski RA , Johnson D , Caro JF , Rafaeloff‐Phail R . Identification of novel genes differentially expressed in omental fat of obese subjects and obese type 2 diabetic patients [Online]. Diabetes 50: 2822‐2830, 2001. http://www.ncbi.nlm.nih.gov/pubmed/11723066
 33. Cui W , Paglialunga S , Kalant D , Lu H , Roy C , Laplante M , Deshaies Y , Cianflone K . Acylation‐stimulating protein/C5L2‐neutralizing antibodies alter triglyceride metabolism in vitro and in vivo. Am J Physiol Endocrinol Metab 293: E1482‐E1491, 2007.
 34. Cui W , Lapointe M , Gauvreau D , Kalant D , Cianflone K . Recombinant C3adesArg/acylation stimulating protein (ASP) is highly bioactive: A critical evaluation of C5L2 binding and 3T3‐L1 adipocyte activation. Mol Immunol 46: 3207‐3217, 2009.
 35. Cui X‐B , Luan J‐N , Ye J , Chen S‐Y . RGC32 deficiency protects against high‐fat diet‐induced obesity and insulin resistance in mice. J Endocrinol 224: 127‐137, 2015.
 36. Czech MP , Tencerova M , Pedersen DJ , Aouadi M . Insulin signalling mechanisms for triacylglycerol storage. Diabetologia 56: 949‐964, 2013.
 37. D'Eon TM , Souza SC , Aronovitz M , Obin MS , Fried SK , Greenberg AS . Estrogen regulation of adiposity and fuel partitioning. Evidence of genomic and non‐genomic regulation of lipogenic and oxidative pathways. J Biol Chem 280: 35983‐35991, 2005.
 38. Dakin RS , Walker BR , Seckl JR , Hadoke PWF , Drake AJ . Estrogens protect male mice from obesity complications and influence glucocorticoid metabolism. Int J Obes (Lond) 39: 1539‐1547, 2015.
 39. De Pergola G . The adipose tissue metabolism: Role of testosterone and dehydroepiandrosterone. Int J Obes Relat Metab Disord 24 (Suppl 2): S59‐S63, 2000.
 40. Deng Y , Scherer PE . Adipokines as novel biomarkers and regulators of the metabolic syndrome. Ann N Y Acad Sci 1212: E1‐E19, 2010.
 41. Derosa G , Fogari E , D'Angelo A , Bianchi L , Bonaventura A , Romano D , Maffioli P . Adipocytokine levels in obese and non‐obese subjects: An observational study. Inflammation 36: 914‐920, 2013.
 42. Dimova R , Tankova T . The role of vaspin in the development of metabolic and glucose tolerance disorders and atherosclerosis. Biomed Res Int 2015: 823481, 2015.
 43. Dutheil F , Gordon BA , Naughton G , Crendal E , Courteix D , Chaplais E , Thivel D , Lac G , Benson AC . Cardiovascular risk of adipokines: A review. J Int Med Res 46: 2082‐2095, 2018.
 44. Ehrnthaller C , Ignatius A , Gebhard F , Huber‐Lang M . New insights of an old defense system: structure, function, and clinical relevance of the complement system. Mol Med 17: 317‐329, 2011.
 45. Engin A . Adipose tissue hypoxia in obesity and its impact on preadipocytes and macrophages: Hypoxia hypothesis. Adv Exp Med Biol 960: 305‐326, 2017.
 46. 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 54: 570‐575, 2005.
 47. Faraj M , Jones P , Sniderman AD , Cianflone K . Enhanced dietary fat clearance in postobese women. J Lipid Res 42: 571‐580, 2001.
 48. Faraj M , Sniderman AD , Cianflone K . ASP enhances in situ lipoprotein lipase activity by increasing fatty acid trapping in adipocytes. J Lipid Res 45: 657‐666, 2004.
 49. Fasshauer M , Blüher M . Adipokines in health and disease. Trends Pharmacol Sci 36: 461‐470, 2015.
 50. Fisette A , Lapointe M , Cianflone K . Obesity‐inducing diet promotes acylation stimulating protein resistance. Biochem Biophys Res Commun 437: 403‐407, 2013.
 51. Fisette A , Munkonda MN , Oikonomopoulou K , Paglialunga S , Lambris JD , Cianflone K . C5L2 receptor disruption enhances the development of diet‐induced insulin resistance in mice. Immunobiology 218: 127‐133, 2013.
 52. Fisette A , Poursharifi P , Oikonomopoulou K , Munkonda MN , Lapointe M , Cianflone K . Paradoxical glucose‐sensitizing yet proinflammatory effects of acute ASP administration in mice. Mediators Inflamm 2013: 713284, 2013.
 53. Flier JS , Cook KS , Usher P , Spiegelman BM . Severely impaired adipsin expression in genetic and acquired obesity. Science 237: 405‐408, 1987.
 54. Fosbrink M , Cudrici C , Niculescu F , Badea TC , David S , Shamsuddin A , Shin ML , Rus H . Overexpression of RGC‐32 in colon cancer and other tumors. Exp Mol Pathol 78: 116‐122, 2005.
 55. Fosbrink M , Cudrici C , Tegla CA , Soloviova K , Ito T , Vlaicu S , Rus V , Niculescu F , Rus H . Response gene to complement 32 is required for C5b‐9 induced cell cycle activation in endothelial cells. Exp Mol Pathol 86: 87‐94, 2009.
 56. Fu Y , Luo N , Klein RL , Garvey WT . Adiponectin promotes adipocyte differentiation, insulin sensitivity, and lipid accumulation. J Lipid Res 46: 1369‐1379, 2005.
 57. Gabrielsson BG , Johansson JM , Lönn M , Jernås M , Olbers T , Peltonen M , Larsson I , Lönn L , Sjöström L , Carlsson B , Carlsson LMS . High expression of complement components in omental adipose tissue in obese men. Obes Res 11: 699‐708, 2003.
 58. Gauvreau D , Roy C , Tom F‐Q , Lu H , Miegueu P , Richard D , Song W‐C , Stover C , Cianflone K . A new effector of lipid metabolism: Complement factor properdin. Mol Immunol 51: 73‐81, 2012.
 59. Germinario R , Sniderman AD , Manuel S , Lefebvre SP , Baldo A , Cianflone K . Coordinate regulation of triacylglycerol synthesis and glucose transport by acylation‐stimulating protein. Metabolism 42: 574‐580, 1993.
 60. Gershov D , Kim S , Brot N , Elkon KB . C‐Reactive protein binds to apoptotic cells, protects the cells from assembly of the terminal complement components, and sustains an antiinflammatory innate immune response: Implications for systemic autoimmunity [Online]. J Exp Med 192: 1353‐1364, 2000. http://www.ncbi.nlm.nih.gov/pubmed/11067883
 61. Grant RW , Dixit VD . Adipose tissue as an immunological organ. Obesity 23: 512‐518, 2015.
 62. van Greevenbroek MMJ , Ghosh S , van der Kallen CJH , Brouwers MCGJ , Schalkwijk CG , Stehouwer CDA . Up‐regulation of the complement system in subcutaneous adipocytes from nonobese, hypertriglyceridemic subjects is associated with adipocyte insulin resistance. J Clin Endocrinol Metab 97: 4742‐4752, 2012.
 63. Gregor MF , Hotamisligil GS . Inflammatory mechanisms in obesity. Annu Rev Immunol 29: 415‐445, 2011.
 64. Gursoy Calan O , Calan M , Yesil Senses P , Unal Kocabas G , Ozden E , Sari KR , Kocar M , Imamoglu C , Senses YM , Bozkaya G , Bilgir O . Increased adipsin is associated with carotid intima media thickness and metabolic disturbances in polycystic ovary syndrome. Clin Endocrinol (Oxf) 85: 910‐917, 2016.
 65. Halaas JL , Gajiwala KS , Maffei M , Cohen SL , Chait BT , Rabinowitz D , Lallone RL , Burley SK , Friedman JM . Weight‐reducing effects of the plasma protein encoded by the obese gene [Online]. Science 269: 543‐546, 1995. http://www.ncbi.nlm.nih.gov/pubmed/7624777
 66. Hales CN , Luzio JP , Siddle K . Hormonal control of adipose‐tissue lipolysis. Biochem Soc Symp: 97–135, 1978.
 67. Hardy OT , Czech MP , Corvera S . What causes the insulin resistance underlying obesity? Curr Opin Endocrinol Diabetes Obes 19: 81‐87, 2012.
 68. Herwald H , Egesten A . On PAMPs and DAMPs. J Innate Immun 8: 427‐428, 2016.
 69. Hill JO , Wyatt HR , Peters JC . Energy balance and obesity. Circulation 126: 126‐132, 2012.
 70. Holm C . Molecular mechanisms regulating hormone‐sensitive lipase and lipolysis. Biochem Soc Trans 31: 1120‐1124, 2003.
 71. Homma H , Kurachi H , Nishio Y , Takeda T , Yamamoto T , Adachi K , Morishige K , Ohmichi M , Matsuzawa Y , Murata Y . Estrogen suppresses transcription of lipoprotein lipase gene. Existence of a unique estrogen response element on the lipoprotein lipase promoter. J Biol Chem 275: 11404‐11411, 2000.
 72. Hotamisligil GS , Shargill NS , Spiegelman BM . Adipose expression of tumor necrosis factor‐alpha: Direct role in obesity‐linked insulin resistance. Science 259: 87‐91, 1993.
 73. Huh JY , Park YJ , Ham M , Kim JB . Crosstalk between adipocytes and immune cells in adipose tissue inflammation and metabolic dysregulation in obesity. Mol Cells 37: 365‐371, 2014.
 74. Iwaki M , Matsuda M , Maeda N , Funahashi T , Matsuzawa Y , Shimomura I . Induction of adiponectin, a fat‐derived antidiabetic and antiatherogenic factor, by nuclear receptors. Diabetes 52: 1655‐1663, 2003.
 75. Jaganathan R , Ravindran R , Dhanasekaran S . Emerging role of adipocytokines in type 2 diabetes as mediators of insulin resistance and cardiovascular disease. Can J Diabetes 42: 446‐456.e1, 2018.
 76. James ER , Fresco VM , Robertson LL . Glucocorticoid‐induced changes in the global gene expression of lens epithelial cells. J Ocul Pharmacol Ther 21: 11‐27, 2005.
 77. Janeway CA Jr , Travers P , Walport M , Shlomchik MJ . The complement system and innate immunity. In: Immunobiology: The Immune System in Health and Disease (5th ed). New York: Garland Science, 2001.
 78. Joannic J‐L , Oppert J‐M , Lahlou N , Basdevant A , Auboiron S , Raison J , Bornet F , Guy‐Grand B. Plasma leptin and hunger ratings in healthy humans. Appetite 30: 129‐138, 1998.
 79. Johnston RB , Klemperer MR , Alper CA , Rosen FS . The enhancement of bacterial phagocytosis by serum. The role of complement components and two cofactors. J Exp Med 129: 1275‐1290, 1969.
 80. Johswich K , Martin M , Thalmann J , Rheinheimer C , Monk PN , Klos A . Ligand specificity of the anaphylatoxin C5L2 receptor and its regulation on myeloid and epithelial cell lines. J Biol Chem 281: 39088‐39095, 2006.
 81. Jones JR , Barrick C , Kim K‐A , Lindner J , Blondeau B , Fujimoto Y , Shiota M , Kesterson RA , Kahn BB , Magnuson MA . Deletion of PPAR in adipose tissues of mice protects against high fat diet‐induced obesity and insulin resistance. Proc Natl Acad Sci 102: 6207‐6212, 2005.
 82. Kalant D , MacLaren R , Cui W , Samanta R , Monk PN , Laporte SA , Cianflone K . C5L2 is a functional receptor for acylation‐stimulating protein. J Biol Chem 280: 23936‐23944, 2005.
 83. Kalkhoff RK . Metabolic effects of progesterone. Am J Obstet Gynecol 142: 735‐738, 1982.
 84. Karsten CM , Wiese AV , Mey F , Figge J , Woodruff TM , Reuter T , Scurtu O , Kordowski A , Almeida LN , Briukhovetska D , Quell KM , Sun J , Ender F , Schmudde I , Vollbrandt T , Laumonnier Y , Köhl J . Monitoring C5aR2 expression using a floxed tdTomato‐C5aR2 knock‐in mouse. J Immunol, 2017. DOI: 10.4049/jimmunol.1700710.
 85. Kelly KR , Kashyap SR , O'Leary VB , Major J , Schauer PR , Kirwan JP . Retinol‐binding protein 4 (RBP4) protein expression is increased in omental adipose tissue of severely obese patients. Obesity (Silver Spring) 18: 663‐666, 2010.
 86. Kershaw EE , Hamm JK , Verhagen LAW , Peroni O , Katic M , Flier JS . Adipose triglyceride lipase: Function, regulation by insulin, and comparison with adiponutrin [Online]. Diabetes 55: 148‐157, 2006. http://www.ncbi.nlm.nih.gov/pubmed/16380488
 87. Kildsgaard J , Zsigmond E , Chan L , Wetsel RA . A critical evaluation of the putative role of C3adesArg (ASP) in lipid metabolism and hyperapobetalipoproteinemia. Mol Immunol 36: 869‐876, 1999.
 88. Kim JY , Van De Wall E , Laplante M , Azzara A , Trujillo ME , Hofmann SM , Schraw T , Durand JL , Li H , Li G , Jelicks LA , Mehler MF , Hui DY , Deshaies Y , Shulman GI , Schwartz GJ , Scherer PE . Obesity‐associated improvements in metabolic profile through expansion of adipose tissue. J Clin Invest 117: 2621‐2637, 2007.
 89. Kishore U , Gaboriaud C , Waters P , Shrive AK , Greenhough TJ , Reid KBM , Sim RB , Arlaud GJ . C1q and tumor necrosis factor superfamily: Modularity and versatility. Trends Immunol 25: 551‐561, 2004.
 90. Klos A , Bank S, Gietz C , Bautsch W , Koehl J , Burg M , Kretzschmar T . C3a receptor on dibutyryl‐cAMP‐differentiated U937 cells and human neutrophils: The human C3a receptor characterized by functional responses and 125I‐C3a binding. Biochemistry 31: 11274‐11282, 1992.
 91. Koistinen HA , Vidal H , Karonen SL , Dusserre E , Vallier P , Koivisto VA , Ebeling P . Plasma acylation stimulating protein concentration and subcutaneous adipose tissue C3 mRNA expression in nondiabetic and type 2 diabetic men. Arterioscler Thromb Vasc Biol 21: 1034‐1039, 2001.
 92. Kolehmainen M , Vidal H , Ohisalo JJ , Pirinen E , Alhava E , Uusitupa MIJ . Hormone sensitive lipase expression and adipose tissue metabolism show gender difference in obese subjects after weight loss. Int J Obes Relat Metab Disord 26: 6‐16, 2002.
 93. Kolev M , Kemper C . Keeping it all going‐complement meets metabolism. Front Immunol 8: 1, 2017.
 94. Kovtun A , Bergdolt S , Hägele Y , Matthes R , Lambris JD , Huber‐Lang M , Ignatius A . Complement receptors C5aR1 and C5aR2 act differentially during the early immune response after bone fracture but are similarly involved in bone repair. Sci Rep 7, 2017.
 95. Kwok KHM , Lam KSL , Xu A . Heterogeneity of white adipose tissue: Molecular basis and clinical implications. Exp Mol Med 48: e215, 2016.
 96. Lacasa D , Le Liepvre X , Ferre P , Dugail I . Progesterone stimulates adipocyte determination and differentiation 1/sterol regulatory element‐binding protein 1c gene expression. potential mechanism for the lipogenic effect of progesterone in adipose tissue. J Biol Chem 276: 11512‐11516, 2001.
 97. Lam YY , Ravussin E . Analysis of energy metabolism in humans: A review of methodologies. Mol Metab 5: 1057‐1071, 2016.
 98. Lapidus L , Bengtsson C , Larsson B , Pennert K , Rybo E , Sjöström L . Distribution of adipose tissue and risk of cardiovascular disease and death: A 12 year follow up of participants in the population study of women in Gothenburg, Sweden. Br Med J (Clin Res Ed) 289: 1257‐1261, 1984.
 99. Larsen GL , McCarthy K , Webster RO , Henson J , Henson PM . A differential effect of C5a and C5a des Arg in the induction of pulmonary inflammation [Online]. Am J Pathol 100: 179‐192, 1980. http://www.ncbi.nlm.nih.gov/pubmed/7395964
 100. Larsson B , Svärdsudd K , Welin L , Wilhelmsen L , Björntorp P , Tibblin G . Abdominal adipose tissue distribution, obesity, and risk of cardiovascular disease and death: 13 year follow up of participants in the study of men born in 1913. Br Med J (Clin Res Ed) 288: 1401‐1404, 1984.
 101. Li F , Luo Z , Huang W , Lu Q , Wilcox CS , Jose PA , Chen S . Response gene to complement 32, a novel regulator for transforming growth factor‐beta‐induced smooth muscle differentiation of neural crest cells. J Biol Chem 282: 10133‐10137, 2007.
 102. Li Y , Wright GL , Peterson JM . C1q/TNF‐related protein 3 (CTRP3) function and regulation. Compr Physiol 7: 863‐878, 2017.
 103. de Lind van Wijngaarden RFA , Cianflone K , Gao Y , Leunissen RWJ , Hokken‐Koelega ACS . Cardiovascular and metabolic risk profile and acylation‐stimulating protein levels in children with Prader‐Willi syndrome and effects of growth hormone treatment. J Clin Endocrinol Metab 95: 1758‐1766, 2010.
 104. Liu Y , Wang Q , Pan Y , Gao Z , Liu Y , Chen S . Effects of over‐expressing resistin on glucose and lipid metabolism in mice. J Zhejiang Univ Sci B 9: 44‐50, 2008.
 105. Liu Z , Tang Q , Wen J , Tang Y , Huang D , Huang Y , Xie J , Luo Y , Liang M , Wu C , Lu Z , Tan A , Gao Y , Wang Q , Jiang Y , Yao Z , Lin X , Zhang H , Mo Z , Yang X . Elevated serum complement factors 3 and 4 are strong inflammatory markers of the metabolic syndrome development: A longitudinal cohort study. Sci Rep 6: 18713, 2016.
 106. Lo JC , Ljubicic S , Leibiger B , Kern M , Leibiger IB , Moede T , Kelly ME , Chatterjee Bhowmick D , Murano I , Cohen P , Banks AS , Khandekar MJ , Dietrich A , Flier JS , Cinti S , Blüher M , Danial NN , Berggren P‐O , Spiegelman BM . Adipsin is an adipokine that improves β cell function in diabetes. Cell 158: 41‐53, 2014.
 107. Lopes HF , Klein RL , Garvey WT , Goodfriend T , Egan BM . Influence of acute hyperlipidemia to adipocyte‐derived hormones in lean normotensive and subjects with metabolic syndrome. Diabetol Metab Syndr 6: 132, 2014.
 108. Lowell BB , Napolitano A , Usher P , Dulloo AG , Rosen BS , Spiegelman BM , Flier JS . Reduced adipsin expression in murine obesity: Effect of age and treatment with the sympathomimetic‐thermogenic drug mixture ephedrine and caffeine. Endocrinology 126: 1514‐1520, 1990.
 109. Makki K , Froguel P , Wolowczuk I . Adipose tissue in obesity‐related inflammation and insulin resistance: Cells, cytokines, and chemokines. ISRN Inflamm 2013: 1‐12, 2013.
 110. Mamane Y , Chung Chan C , Lavallee G , Morin N , Xu L‐J , Huang J , Gordon R , Thomas W , Lamb J , Schadt EE , Kennedy BP , Mancini JA . The C3a anaphylatoxin receptor is a key mediator of insulin resistance and functions by modulating adipose tissue macrophage infiltration and activation. Diabetes 58: 2006‐2017, 2009.
 111. Manna P , Jain SK . Obesity, oxidative stress, adipose tissue dysfunction, and the associated health risks: Causes and therapeutic strategies. Metab Syndr Relat Disord 13: 423‐444, 2015.
 112. Manthey HD , Woodruff TM , Taylor SM , Monk PN . Complement component 5a (C5a). Int J Biochem Cell Biol 41: 2114‐2117, 2009.
 113. Marcil M , Vu H , Cui W , Dastani Z , Engert JC , Gaudet D , Castro‐Cabezas M , Sniderman AD , Genest J , Cianflone K . Identification of a novel C5L2 variant (S323I) in a French Canadian family with familial combined hyperlipemia. Arterioscler Thromb Vasc Biol 26: 1619‐1625, 2006.
 114. Mårin P , Odén B , Björntorp P . Assimilation and mobilization of triglycerides in subcutaneous abdominal and femoral adipose tissue in vivo in men: Effects of androgens. J Clin Endocrinol Metab 80: 239‐243, 1995.
 115. Martin M , Blom AM . Complement in removal of the dead – balancing inflammation. Immunol Rev 274: 218‐232, 2016.
 116. Marycz K , Weiss C , Śmieszek A , Kornicka K . Evaluation of oxidative stress and mitophagy during adipogenic differentiation of adipose‐derived stem cells isolated from equine metabolic syndrome (EMS) horses. Stem Cells Int 2018: 1‐18, 2018.
 117. Maslowska MH , Sniderman AD , MacLean LD , Cianflone K . Regional differences in triacylglycerol synthesis in adipose tissue and in cultures preadipocytes [Online]. J Lipid Res 34: 228, 1993. https://www.researchgate.net/publication/14770567_Regional_differences_in_triacylglycerol_synthesis_in_adipose_tissue_and_in_cultured_preadipocytes?ev=auth_pub
 118. Maslowska M , Vu H , Phelis S , Sniderman AD , Rhode BM , Blank D , Cianflone K . Plasma acylation stimulating protein, adipsin and lipids in non‐obese and obese populations. Eur J Clin Invest 29: 679‐686, 1999.
 119. Maslowska M , Legakis H , Assadi F , Cianflone K . Targeting the signaling pathway of acylation stimulating protein. J Lipid Res 47: 643‐652, 2006.
 120. Melone M , Wilsie L , Palyha O , Strack A , Rashid S . Discovery of a new role of human resistin in hepatocyte low‐density lipoprotein receptor suppression mediated in part by proprotein convertase subtilisin/kexin type 9. J Am Coll Cardiol 59: 1697‐1705, 2012.
 121. Mlinar B , Marc J . New insights into adipose tissue dysfunction in insulin resistance. Clin Chem Lab Med 49: 1925‐1935, 2011.
 122. Monjo M , Rodríguez AM , Palou A , Roca P . Direct effects of testosterone, 17 beta‐estradiol, and progesterone on adrenergic regulation in cultured brown adipocytes: Potential mechanism for gender‐dependent thermogenesis. Endocrinology 144: 4923‐4930, 2003.
 123. Moore KJ , Sheedy FJ , Fisher EA . Macrophages in atherosclerosis: A dynamic balance. Nat Rev Immunol 13: 709‐721, 2013.
 124. Moreno‐Navarrete JM , Fernández‐Real JM . The complement system is dysfunctional in metabolic disease: Evidences in plasma and adipose tissue from obese and insulin resistant subjects. Semin Cell Dev Biol (October 26, 2017), 2017. DOI: 10.1016/j.semcdb.2017.10.025.
 125. Moreno‐Navarrete JM , Martínez‐Barricarte R , Catalán V , Sabater M , Gómez‐Ambrosi J , Ortega FJ , Ricart W , Blüher M , Frühbeck G , Rodríguez de Cordoba S , Fernández‐Real JM . Complement factor H is expressed in adipose tissue in association with insulin resistance. Diabetes 59: 200‐209, 2010.
 126. Morgan BP . Regulation of the complement membrane attack pathway. Crit Rev Immunol 19: 173‐198, 1999.
 127. Munkonda MN , Lapointe M , Miegueu P , Roy C , Gauvreau D , Richard D , Cianflone K . Recombinant acylation stimulating protein administration to C3‐/‐ mice increases insulin resistance via adipocyte inflammatory mechanisms. PLoS One 7: e46883, 2012.
 128. Munkonda MN , Martin J , Poirier P , Carrington A , Biron S , Lebel S , Cianflone K . Acylation stimulating protein reduction precedes insulin sensitization after BPD‐DS bariatric surgery in severely obese women. Nutr Diabetes 2: e41, 2012.
 129. Murray I , Köhl J , Cianflone K . Acylation‐stimulating protein (ASP): Structure‐function determinants of cell surface binding and triacylglycerol synthetic activity. Biochem J 342 (Pt 1): 41‐48, 1999.
 130. Murray I , Sniderman AD , Cianflone K . Enhanced triglyceride clearance with intraperitoneal human acylation stimulating protein in C57BL/6 mice. Am J Physiol 277: E474‐E480, 1999.
 131. Napolitano A , Lowell BB , Damm D , Leibel RL , Ravussin E , Jimerson DC , Lesem MD , Van Dyke DC , Daly PA , Chatis P . Concentrations of adipsin in blood and rates of adipsin secretion by adipose tissue in humans with normal, elevated and diminished adipose tissue mass. Int J Obes Relat Metab Disord 18: 213‐8, 1994.
 132. Nesargikar P , Spiller B , Chavez R . The complement system: History, pathways, cascade and inhibitors. Eur J Microbiol Immunol 2: 103‐111, 2012.
 133. Nigro E , Scudiero O , Monaco ML , Palmieri A , Mazzarella G , Costagliola C , Bianco A , Daniele A . New insight into adiponectin role in obesity and obesity‐related diseases. Biomed Res Int 2014: 658913, 2014.
 134. Nilsson B , Hamad OA , Ahlström H , Kullberg J , Johansson L , Lindhagen L , Haenni A , Ekdahl KN , Lind L . C3 and C4 are strongly related to adipose tissue variables and cardiovascular risk factors. Eur J Clin Invest 44: 587‐596, 2014.
 135. Nishimoto H , Yamamoto A , Furukawa S , Wakisaka S , Maeda T . C1q/TNF‐related protein 3 expression and effects on adipocyte differentiation of 3T3‐L1 cells. Cell Biol Int, 2016. DOI: 10.1002/cbin.10674.
 136. Noris M , Remuzzi G . Overview of complement activation and regulation. Semin Nephrol 33: 479‐492, 2013.
 137. O'Brien SN , Welter BH , Mantzke KA , Price TM . Identification of progesterone receptor in human subcutaneous adipose tissue. J Clin Endocrinol Metab 83: 509‐513, 1998.
 138. Onat A , Uzunlar B , Hergenç G , Yazici M , Sari I , Uyarel H , Can G , Sansoy V . Cross‐sectional study of complement C3 as a coronary risk factor among men and women. Clin Sci 108: 129‐135, 2005.
 139. Onat A , Can G , Rezvani R , Cianflone K . Complement C3 and cleavage products in cardiometabolic risk. Clin Chim Acta 412: 1171‐1179, 2011.
 140. Ouchi N , Parker JL , Lugus JJ , Walsh K . Adipokines in inflammation and metabolic disease. Nat Rev Immunol 11: 85‐97, 2011.
 141. Ozata M , Gungor D , Turan M , Ozisik G , Bingol N , Ozgurtas T , Ozdemir IC . Improved glycemic control increases fasting plasma acylation‐stimulating protein and decreases leptin concentrations in type II diabetic subjects. J Clin Endocrinol Metab 86: 3659‐3664, 2001.
 142. Paglialunga S , Fisette A , Yan Y , Deshaies Y , Brouillette J‐F , Pekna M , Cianflone K . Acylation‐stimulating protein deficiency and altered adipose tissue in alternative complement pathway knockout mice. Am J Physiol Endocrinol Metab 294: E521‐E529, 2008.
 143. Paglialunga S , Julien P , Tahiri Y , Cadelis F , Bergeron J , Gaudet D , Cianflone K . Lipoprotein lipase deficiency is associated with elevated acylation stimulating protein plasma levels. J Lipid Res 50: 1109‐1119, 2009.
 144. Paglialunga S , Fisette A , Munkonda M , Gao Y , Richard D , Cianflone K . The effects of acylation stimulating protein supplementation VS antibody neutralization on energy expenditure in wildtype mice. BMC Physiol 10: 4, 2010.
 145. Palin SL , McTernan PG , Anderson LA , Sturdee DW , Barnett AH , Kumar S . 17Beta‐estradiol and anti‐estrogen ICI: compound 182,780 regulate expression of lipoprotein lipase and hormone‐sensitive lipase in isolated subcutaneous abdominal adipocytes. Metabolism 52: 383‐388, 2003.
 146. Pattrick M , Luckett J , Yue L , Stover C . Dual role of complement in adipose tissue. Mol Immunol 46: 755‐760, 2009.
 147. Peake P , Shen Y . Factor H binds to the N‐terminus of adiponectin and modulates complement activation. Biochem Biophys Res Commun 397: 361‐366, 2010.
 148. Peake PW , Shen Y , Walther A , Charlesworth JA . Adiponectin binds C1q and activates the classical pathway of complement. Biochem Biophys Res Commun 367: 560‐565, 2008.
 149. Pedersen SB , Bruun JM , Hube F , Kristensen K , Hauner H , Richelsen B . Demonstration of estrogen receptor subtypes alpha and beta in human adipose tissue: Influences of adipose cell differentiation and fat depot localization. Mol Cell Endocrinol 182: 27‐37, 2001.
 150. Pedersen SB , Kristensen K , Richelsen B . Anti‐glucocorticoid effects of progesterone in vivo on rat adipose tissue metabolism. Steroids 68: 543‐550, 2003.
 151. Peterson JM . C1q/TNF‐related protein‐3 (CTRP1) enhances fatty acid oxidation via AMK activation and ACC inhibition. J Biol Chem 287: 1576‐1587, 2012.
 152. Peterson JM , Wei Z , Wong GW . C1q/TNF‐related protein‐3 (CTRP3), a novel adipokine that regulates hepatic glucose output. J Biol Chem 285: 39691‐39701, 2010.
 153. Peterson JM , Aja S , Wei Z , Wong GW . CTRP1 protein enhances fatty acid oxidation via AMP‐activated protein kinase (AMPK) activation and acetyl‐CoA carboxylase (ACC) inhibition. J Biol Chem 287: 1576‐1587, 2012.
 154. Peterson JM , Seldin MM , Tan SY , Wong GW . CTRP2 overexpression improves insulin and lipid tolerance in diet‐induced obese mice. PLoS One 9, 2014.
 155. Phieler J , Garcia‐Martin R , Lambris JD , Chavakis T . The role of the complement system in metabolic organs and metabolic diseases. Semin Immunol 25: 47‐53, 2013.
 156. Phillips CM , Kesse‐Guyot E , Ahluwalia N , McManus R , Hercberg S , Lairon D , Planells R , Roche HM . Dietary fat, abdominal obesity and smoking modulate the relationship between plasma complement component 3 concentrations and metabolic syndrome risk. Atherosclerosis 220: 513‐519, 2012.
 157. Pillemer L . The properdin system. Trans N Y Acad Sci 17: 526‐530, 1955.
 158. Pillemer L , Blum L , Lepow Ih , Ross Oa , Todd Ew , Wardlaw Ac . The properdin system and immunity. I. Demonstration and isolation of a new serum protein, properdin, and its role in immune phenomena. Science 120: 279‐285, 1954.
 159. Platt KA , Claffey KP , Wilkison WO , Spiegelman BM , Ross SR . Independent regulation of adipose tissue‐specificity and obesity response of the adipsin promoter in transgenic mice [Online]. J Biol Chem 269: 28558‐28562, 1994. http://www.ncbi.nlm.nih.gov/pubmed/7961801
 160. Pomeroy C , Mitchell J , Eckert E , Raymond N , Crosby R , Dalmasso AP . Effect of body weight and caloric restriction on serum complement proteins, including Factor D/adipsin: Studies in anorexia nervosa and obesity. Clin Exp Immunol 108: 507‐515, 1997.
 161. Poursharifi P , Lapointe M , Pétrin D , Devost D , Gauvreau D , Hébert TE , Cianflone K . C5L2 and C5aR interaction in adipocytes and macrophages: Insights into adipoimmunology. Cell Signal 25: 910‐918, 2013.
 162. Poursharifi P , Lapointe M , Fisette A , Lu H , Roy C , Munkonda MN , Fairlie DP , Cianflone K . C5aR and C5L2 act in concert to balance immunometabolism in adipose tissue. Mol Cell Endocrinol 382: 325‐333, 2014.
 163. Poursharifi P , Rezvani R , Gupta A , Lapointe M , Marceau P , Tchernof A , Cianflone K . Association of immune and metabolic receptors C5aR and C5L2 with adiposity in women. Mediators Inflamm 2014: 413921, 2014.
 164. Qaid MM , Abdelrahman MM , González‐Redondo P . Role of insulin and other related hormones in energy metabolism—A review. Cogent Food Agric 2, 2016.
 165. Qiao L , Kinney B , Schaack J , Shao J . Adiponectin inhibits lipolysis in mouse adipocytes. Diabetes 60: 1519‐1527, 2011.
 166. Ravussin E . Adiponectin enhances insulin action by decreasing ectopic fat deposition. Pharmacogenomics J 2: 4‐7, 2002.
 167. Rezvani R , Onat A , Can G , Cianflone K . Apparent sex‐specific divergence of acylation stimulating protein levels with respect to metabolic parameters of pathogenetic and clinical relevance. J Endocrinol Metab 2: 1‐10, 2012.
 168. Ricklin D , Hajishengallis G , Yang K , Lambris JD . Complement: A key system for immune surveillance and homeostasis. Nat Immunol 11: 785‐797, 2010.
 169. Rodriguez‐Cuenca S , Monjo M , Proenza AM , Roca P . Depot differences in steroid receptor expression in adipose tissue: Possible role of the local steroid milieu. Am J Physiol Metab 288: E200‐E207, 2005.
 170. Rosen BS , Cook KS , Yaglom J , Groves DL , Volanakis JE , Damm D , White T , Spiegelman BM . Adipsin and complement factor D activity: An immune‐related defect in obesity. Science 244: 1483‐1487, 1989. DOI: 10.1126/science.2734615.
 171. Roy C , Paglialunga S , Fisette A , Schrauwen P , Moonen‐Kornips E , St‐Onge J , Hesselink MK , Richard D , Joanisse DR , Cianflone K . Shift in metabolic fuel in acylation‐stimulating protein‐deficient mice following a high‐fat diet. Am J Physiol Endocrinol Metab 294: E1051‐E1059, 2008.
 172. Rubinow KB . Estrogens and body weight regulation in men. Adv Exp Med Biol 1043: 285‐313, 2017.
 173. Rytka JM , Wueest S , Schoenle EJ , Konrad D . The portal theory supported by venous drainage‐selective fat transplantation. Diabetes 60: 56‐63, 2011.
 174. Saleh J , Summers LK , Cianflone K , Fielding BA , Sniderman AD , Frayn KN . Coordinated release of acylation stimulating protein (ASP) and triacylglycerol clearance by human adipose tissue in vivo in the postprandial period. J Lipid Res 39: 884‐891, 1998.
 175. Saleh J , Christou N , Cianflone K . Regional specificity of ASP binding in human adipose tissue. Am J Physiol – Endocrinol Metab 276, 1999.
 176. Saleh J , Blevins JE , Havel PJ , Barrett JA , Gietzen DW , Cianflone K . Acylation stimulating protein (ASP) acute effects on postprandial lipemia and food intake in rodents. Int J Obes Relat Metab Disord 25: 705‐713, 2001.
 177. Saleh J , Cianflone K , Chaudhary T , Al‐Riyami H , Al‐Abri M , Bayoumi R . Increased plasma acylation‐stimulating protein correlates with hyperlipidemia at late gestation. Obesity 15: 646‐652, 2007.
 178. Saleh J , Al‐Riyami B , Chaudhary N , Cianflone K . Cord blood ASP is predicted by maternal lipids and correlates with fetal birth weight. Obesity 16: 1193‐1198, 2008.
 179. Saleh J , Al‐Khanbashi M , Al‐Maarof M , Al‐Lawati M , Rizvi SG , Cianflone K . Acylation‐stimulating protein increases and correlates with increased progesterone levels during the luteal phase of the menstrual cycle. Eur J Endocrinol 160: 301‐307, 2009.
 180. Saleh J , Al‐Wardy N , Farhan H , Al‐Khanbashi M , Cianflone K . Acylation stimulating protein: A female lipogenic factor? Obes Rev 12: 440‐448, 2011.
 181. Saleh J , Farhan H , Al‐Saqri I , Al‐Riyami B , Cianflone K . Plasma gamma‐glutamyltransferase is strongly determined by acylation stimulating protein levels independent of insulin resistance in patients with acute coronary syndrome. Dis Markers 35: 155‐161, 2013.
 182. 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: 342802, 2013.
 183. Sánchez‐Corral P , Pouw RB , López‐Trascasa M , Józsi M . Self‐damage caused by dysregulation of the complement alternative pathway: Relevance of the factor H protein family. Front Immunol 9: 1607, 2018.
 184. Schadt EE , Lamb J , Yang X , Zhu J , Edwards S , Thakurta DG , Sieberts SK , Monks S , Reitman M , Zhang C , Lum PY , Leonardson A , Thieringer R , Metzger JM , Yang L , Castle J , Zhu H , Kash SF , Drake TA , Sachs A , Lusis AJ . An integrative genomics approach to infer causal associations between gene expression and disease. Nat Genet, 2005. DOI: 10.1038/ng1589.
 185. Schäffler A , Buechler C . CTRP family: Linking immunity to metabolism. Trends Endocrinol Metab 23: 194‐204, 2012.
 186. Schäffler A , Schölmerich J . Innate immunity and adipose tissue biology. Trends Immunol 31: 228‐235, 2010.
 187. Scherer PE , Williams S , Fogliano M , Baldini G , Lodish HF . A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem 270: 26746‐26749, 1995.
 188. Schmidt CQ , Lambris JD , Ricklin D . Protection of host cells by complement regulators. Immunol Rev 274: 152‐171, 2016.
 189. Segers FM , Verdam FJ , de Jonge C , Boonen B , Driessen A , Shiri‐Sverdlov R , Bouvy ND , Greve JW , Buurman WA , Rensen SS . Complement alternative pathway activation in human nonalcoholic steatohepatitis. PLoS One 9: e110053, 2014.
 190. Seldin MM , Peterson JM , Byerly MS , Wei Z , Wong GW . Myonectin (CTRP15), a novel myokine that links skeletal muscle to systemic lipid homeostasis. J Biol Chem 287: 11968‐11980, 2012.
 191. Seldin MM , Tan SY , Wong GW . Metabolic function of the CTRP family of hormones. Rev Endocr Metab Disord 15: 111‐123, 2014.
 192. Shapiro L , Scherer PE . The crystal structure of a complement‐1q family protein suggests an evolutionary link to tumor necrosis factor. Curr Biol 8: 335‐340, 1998.
 193. Simpson KA , Singh MAF . Effects of exercise on adiponectin: A systematic review. Obesity 16: 241‐256, 2008.
 194. Sissons JG , West RJ , Fallows J , Williams DG , Boucher BJ , Amos N , Peters DK . The complement abnormalities of lipodystrophy. N Engl J Med 294: 461‐465, 1976.
 195. Sivakumar K , Bari MF , Adaikalakoteswari A , Guller S , Weickert MO , Randeva HS , Grammatopoulos DK , Bastie CC , Vatish M . Elevated fetal adipsin/acylation‐stimulating protein (ASP) in obese pregnancy: Novel placental secretion via Hofbauer cells. J Clin Endocrinol Metab 98: 4113‐4122, 2013.
 196. Sjögren J , Li M , Björntorp P . Androgen hormone binding to adipose tissue in rats. Biochim Biophys Acta 1244: 117‐120, 1995.
 197. Sniderman AD , Cianflone KM , Eckel RH . Levels of acylation stimulating protein in obese women before and after moderate weight loss. Int J Obes (Lond) 15: 333‐336, 1991.
 198. Song N‐J , Kim S , Jang B‐H , Chang S‐H , Yun UJ , Park K‐M , Waki H , Li DY , Tontonoz P , Park KW . Small molecule‐induced complement factor D (adipsin) promotes lipid accumulation and adipocyte differentiation. PLoS One 11: e0162228, 2016.
 199. Steiner T , Francescut L , Byrne S , Hughes T , Jayanthi A , Guschina I , Harwood J , Cianflone K , Stover C , Francis S . Protective role for properdin in progression of experimental murine atherosclerosis. PLoS One 9: e92404, 2014.
 200. Stengel A , Goebel M , Taché Y . Nesfatin‐1: A novel inhibitory regulator of food intake and body weight. Obes Rev 12: 261‐271, 2011.
 201. Steppan CM , Bailey ST , Bhat S , Brown EJ , Banerjee RR , Wright CM , Patel HR , Ahima RS , Lazar MA . The hormone resistin links obesity to diabetes. Nature 409: 307‐312, 2001.
 202. Stofkova A , Krskova K , Vaculin S , Jurcovicova J . Enhanced activity of hormone sensitive lipase (HSL) in mesenteric but not epididymal fat correlates with higher production of epinephrine in mesenteric adipocytes in rat model of cachectic rheumatoid arthritis. Autoimmunity 49: 268‐276, 2016.
 203. Stokes III J , Garrison RJ , Kannel WB . The independent contributions of various indices of obesity to the 22‐year incidence of coronary heart disease: The Framingham heart study. In: Metabolic Complications of Human Obesities. Amsterdam: Elsevier Science Publishers, 1985.
 204. Strålfors P , Björgell P , Belfrage P . Hormonal regulation of hormone‐sensitive lipase in intact adipocytes: identification of phosphorylated sites and effects on the phosphorylation by lipolytic hormones and insulin. Proc Natl Acad Sci U S A 81: 3317‐3321, 1984.
 205. Su HR . S‐protein/vitronectin interaction with the C5b and the C8 of the complement membrane attack complex. Int Arch Allergy Immunol 110: 314‐317, 1996.
 206. Tang JH , Wen Y , Wu F , Zhao XY , Zhang MX , Mi J , Cianflone K . Increased plasma acylation‐stimulating protein in pediatric proteinuric renal disease. Pediatr Nephrol 23: 959‐964, 2008.
 207. Tang D , Kang R , Coyne CB , Zeh HJ , Lotze MT . PAMPs and DAMPs: Signal 0s that spur autophagy and immunity. Immunol Rev 249: 158‐175, 2012.
 208. Tao Y , Cianflone K , Sniderman AD , Colby‐Germinario SP , Germinario RJ . Acylation‐stimulating protein (ASP) regulates glucose transport in the rat L6 muscle cell line. Biochim Biophys Acta – Lipids Lipid Metab 1344: 221‐229, 1997.
 209. Tilg H , Moschen AR . Adipocytokines: Mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol, 2006. DOI: 10.1038/nri1937.
 210. Unamuno X , Gómez‐Ambrosi J , Rodríguez A , Becerril S , Frühbeck G , Catalán V . Adipokine dysregulation and adipose tissue inflammation in human obesity. Eur J Clin Invest 48: e12997, 2018.
 211. Vague J . A determinant factor of the forms of obesity. Obes Res 4: 201‐203, 1996.
 212. Vlaicu SI , Cudrici C , Ito T , Fosbrink M , Tegla CA , Rus V , Mircea PA , Rus H . Role of response gene to complement 32 in diseases. Arch Immunol Ther Exp (Warsz) 56: 115‐122, 2008.
 213. Vlaicu SI , Tatomir A , Boodhoo D , Vesa S , Mircea PA , Rus H . The role of complement system in adipose tissue‐related inflammation. Immunol Res 64: 653‐664, 2016.
 214. Wajchenberg BL . Subcutaneous and visceral adipose tissue: Their relation to the metabolic syndrome. Endocr Rev 21: 697‐738, 2000.
 215. Wallis R , Mitchell DA , Schmid R , Schwaeble WJ , Keeble AH . Paths reunited: Initiation of the classical and lectin pathways of complement activation. Immunobiology 215: 1‐11, 2010.
 216. Wamba PCF , Mi J , Zhao X‐Y , Zhang M‐X , Wen Y , Cheng H , Hou D‐Q , Cianflone K . Acylation stimulating protein but not complement C3 associates with metabolic syndrome components in Chinese children and adolescents. Eur J Endocrinol 159: 781‐790, 2008.
 217. Wedellová Z , Dietrich J , Šiklová‐Vítková M , Kološtová K , Kováčiková M , Dušková M , Brož J , Vedral T , Štich V , Polák J . Adiponectin inhibits spontaneous and catecholamine‐induced lipolysis in human adipocytes of non‐obese subjects through AMPK‐dependent mechanisms. Physiol Res 60: 139‐148, 2011.
 218. Wei Z , Peterson JM , Wong GW . Metabolic regulation by C1q/TNF‐related Protein‐13 (CTRP13). J Biol Chem 286: 15652‐15665, 2011.
 219. Wei Z , Seldin MM , Natarajan N , Djemal DC , Peterson JM , Wong GW . C1q/tumor necrosis factor‐related protein 11 (CTRP11), a novel adipose stroma‐derived regulator of adipogenesis. J Biol Chem 288: 10214‐10229, 2013.
 220. Wei Z , Lei X , Petersen PS , Aja S , Wong GW . Targeted deletion of C1q/TNF‐related protein 9 increases food intake, decreases insulin sensitivity, and promotes hepatic steatosis in mice. AJP Endocrinol Metab 306: E779‐E790, 2014.
 221. Wen Y , Wang HW , MacLaren R , Wu J , Lu HL , Cianflone K . Palmitate and oleate induction of acylation stimulating protein resistance in 3T3‐L1 adipocytes and preadipocytes. J Cell Biochem 104: 391‐401, 2008.
 222. 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 7: 444‐452, 1999.
 223. White RT , Damm D , Hancock N , Rosen BS , Lowell BB , Usher P , Flier JS , Spiegelman BM . Human adipsin is identical to complement factor D and is expressed at high levels in adipose tissue [Online]. J Biol Chem 267: 9210‐9213, 1992. http://www.ncbi.nlm.nih.gov/pubmed/13743880
 224. Wong GW , Wang J , Hug C , Tsao T‐S , Lodish HF . A family of Acrp30/adiponectin structural and functional paralogs. Proc Natl Acad Sci U S A 101: 10302‐10307, 2004.
 225. Wong GW , Krawczyk SA , Kitidis‐Mitrokostas C , Ge G , Spooner E , Hug C , Gimeno R , Lodish HF . Identification and characterization of CTRP9, a novel secreted glycoprotein, from adipose tissue that reduces serum glucose in mice and forms heterotrimers with adiponectin. FASEB J 23: 241‐258, 2009.
 226. Wu Y , Zhang J , Wen Y , Wang H , Zhang M , Cianflone K . Increased acylation‐stimulating protein, C‐reactive protein, and lipid levels in young women with polycystic ovary syndrome. Fertil Steril 91: 213‐219, 2009.
 227. Xia Z , Sniderman AD , Cianflone K . Acylation‐stimulating protein (ASP) deficiency induces obesity resistance and increased energy expenditure in ob/ob mice. J Biol Chem 277: 45874‐45879, 2002.
 228. Xu H , Chen M . Targeting the complement system for the management of retinal inflammatory and degenerative diseases. Eur J Pharmacol 787: 94‐104, 2016.
 229. Yamauchi T , Kamon J , Waki H , Terauchi Y , Kubota N , Hara K , Mori Y , Ide T , Murakami K , Tsuboyama‐Kasaoka N , Ezaki O , Akanuma Y , Gavrilova O , Vinson C , Reitman ML , Kagechika H , Shudo K , Yoda M , Nakano Y , Tobe K , Nagai R , Kimura S , Tomita M , Froguel P , Kadowaki T . The fat‐derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7: 941‐946, 2001.
 230. Yang Y , Lu HL , Zhang J , Yu HY , Wang HW , Zhang MX , Cianflone K . Relationships among acylation stimulating protein, adiponectin and complement C3 in lean vs obese type 2 diabetes. Int J Obes (Lond) 30: 439‐446, 2006.
 231. Yang G , Pang W , Zhao C , Chen Y , Mo D , Zhao C , Wu W . Knockdown of CTRP6 inhibits adipogenesis via lipogenic marker genes and Erk1/2 signalling pathway. Cell Biol Int, 2015. DOI: 10.1002/cbin.10422.
 232. Yesilova Z , Ozata M , Oktenli C , Bagci S , Ozcan A , Sanisoglu SY , Uygun A , Yaman H , Karaeren N , Dagalp K . Increased acylation stimulating protein concentrations in nonalcoholic fatty liver disease are associated with insulin resistance. Am J Gastroenterol 100: 842‐849, 2005.
 233. Ylitalo K , Pajukanta P , Meri S , Cantor RM , Mero‐Matikainen N , Vakkilainen J , Nuotio I , Taskinen MR . Serum C3 but not plasma acylation‐stimulating protein is elevated in Finnish patients with familial combined hyperlipidemia. Arterioscler Thromb Vasc Biol 21: 838‐843, 2001.
 234. Zatolokin PA , Litvinova LS , Skuratovskaia DA , Vasilenko MA , Kirienkova EV , Mironyuk NI . The role of production of adipsin and leptin in the development of insulin resistance in patients with abdominal obesity. Dokl Biochem Biophys 475: 271‐276, 2017.
 235. 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 292: E1433‐E1440, 2007.
 236. Zhou Q , Ge Q , Ding Y , Qu H , Wei H , Wu R , Yao L , Wei Q , Feng Z , Long J , Deng H . Relationship between serum adipsin and the first phase of glucose‐stimulated insulin secretion in individuals with different glucose tolerance. J Diabetes Investig 9: 1128‐1134, 2018.
 237. Zipfel PF , Skerka C . Complement regulators and inhibitory proteins. Nat Rev Immunol 9: 729‐740, 2009.

 

Teaching Material

J. Saleh, M. Al-Maqbali, D. Abdel-Hadi. Role of Complement and Complement-related Adipokines in Regulation of Energy Metabolism and Fat Storage.Compr Physiol 9: 2019, 1411-1429.

Didactic Synopsis

Major Teaching Points:

  • The heightened inflammatory state associated with adiposity produces adipokines that not only enhance the immune response within adipose tissue, but may also contribute to energy regulation.
  • Complement activation may provide an important link that connects adiposity-related inflammation to metabolic dysfunction such as insulin resistance.
  • In addition to their proinflammatory role in obesity, many complement adipokines have “insulin-like” anabolic effects.
  • Complement factors are differentially expressed in subcutaneous and omental fat depots.
  • The coordinated autocrine/paracrine effects of complement and complement-related adipokines, through their target receptors, form a regulated network maintaining energy balance in the adipose tissue.

Didactic Legends

The following legends to the figures that appear throughout the article are written to be useful for teaching.

Figure 1 The classical pathway, the lectin pathway, and the alternative pathway are activated in response to cellular damage. C3 convertases cleave C3 to C3a and C3b. C3bBb initiates the formation of C5 convertases that cleave C5 to C5a and C5b. C5b subsequently binds to C6, C7, C8, and C9, resulting in the formation of the MAC complex to form pores in the membrane of pathogens and promote cell lysis. Activation of the complement alternative pathway produces C3a, which is cleaved by carboxypeptidase (CP) to generate the Acylation Stimulating Protein ASP/C3a desArg. Factor H is a key negative regulator which downregulates the action of C3/C5 convertases. The decay-accelerating factor (DAF) destabilizes C3/C5 convertases by accelerating the decay activity. Factor I and C4b-binding protein (C4BP) degrade C3b. C1 esterase inhibitor (C1-INH) inactivates C1r and C1s and compete with MASP variants for binding MBL. Properdin upregulates the alternative pathway by stabilizing the C3bBb complex.

Figure 2 ASP effectively enhances triacylglycerol (TG) synthesis, independent of the insulin effects. ASP binds to the CL25 receptor to activate the following pathways: (i) Glucose cellular uptake by translocation of glucose transporters (GLUT) to the cell surface to provide the glycerol backbone for the synthesis of the intracellular TG molecule. (ii) Enhances FA esterification by activation of diacylglycerol acyltransferase (DGAT), the key enzyme in TG synthesis. (iii) Inhibits hormone-sensitive lipase (HSL) and intracellular lipolysis.

Figure 3 CTRPs are inflammatory mediators that share structural homology with C1q and adiponectin. CTRPs, involved in the energy regulation of adipose tissue, are derived from adipose tissue, which mainly act as insulin-like, anabolic, and lipogenic factors. Exceptions are CTRP 3 & 11 and Factor H that have antiadipogenic effects, while CTRP 11 and adiponectin have anti-inflammatory roles. These counterregulatory roles are essential to prevent uncontrolled proinflammatory responses and maintain immune-metabolic homeostasis in adipose tissue.

Figure 4 Most complement adipokines exhibit insulin-like effects through activation of insulin, or by enhancing insulin sensitivity with anabolic effects in adipose tissue. Anti-inflammatory complement adipokines have protective roles in the expanding adipose tissue microenvironment. A hypothetical scheme that summarizes the integrated roles of complement adipokines in the regulation of energy metabolism in the adipocyte microenvironment. C3a enhances insulin production from the pancreas and adipose tissue sensitivity to insulin effects and acts as a precursor for the potent lipogenic factor ASP. Adipsin mediates the release of ASP from C3a, which activates PPAR? (a major adipocyte differentiation factor). PPAR? activates the release of adiponectin, which exerts lipogenic effects, and acts as a protective anti-inflammatory factor. Factor H and properdin play counterregulatory roles in the activation of the alternative pathway. Most CTRPs have insulin-like effects, except CTRP 3 and 11 that show antiadipogenic activity. CTRP 3 and 12 have anti-inflammatory effects that, together with adiponectin and Factor H, contribute to immune-metabolic homeostasis in adipose tissue.

 


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Article Title: Role of Complement and Complement‐Related Adipokines in Regulation of Energy Metabolism and Fat Storage
 

How to Cite

Jumana Saleh, Muna Al‐Maqbali, Dalia Abdel‐Hadi. Role of Complement and Complement‐Related Adipokines in Regulation of Energy Metabolism and Fat Storage. Compr Physiol 2019, 9: 1411-1429. doi: 10.1002/cphy.c170037