title: Deficiency of C5L2 increases macrophage infiltration and alters adipose tissue function in mice.
abstract: BACKGROUND
  Obesity is considered as a systemic chronic low grade inflammation characterized by increased serum pro-inflammatory proteins and accumulation of macrophages within white adipose tissue (WAT) of obese patients. C5L2, a 7-transmembrane receptor, serves a dual function, binding the lipogenic hormone acylation stimulating protein (ASP), and C5a, involved in innate immunity.
  
  
  OBJECTIVE
  We evaluated the impact of C5L2 on macrophage infiltration in WAT of wildtype (Ctl) and C5L2 knock-out (C5L2(-/-)) mice over 6, 12 and 24 weeks on a chow diet and moderate diet-induced obesity (DIO) conditions.
  
  
  RESULTS
  In Ctl mice, WAT C5L2 and C5a receptor mRNA increased (up to 10-fold) both over time and with DIO. By contrast, in C5L2(-/-), there was no change in C5aR in WAT. C5L2(-/-) mice displayed higher macrophage content in WAT, varying by time, fat depot and diet, associated with altered systemic and WAT cytokine patterns compared to Ctl mice. However, in all cases, the M1 (pro-) vs M2 (anti-inflammatory) macrophage proportion was unchanged but C5L2(-/-) adipose tissue secretome appeared to be more chemoattractant. Moreover, C5L2(-/-) mice have increased food intake, increased WAT, and altered WAT lipid gene expression, which is reflected systemically. Furthermore, C5L2(-/-) mice have altered glucose/insulin metabolism, adiponectin and insulin signalling gene expression in WAT, which could contribute to development of insulin resistance.
  
  
  CONCLUSIONS
  Disruption of C5L2 increases macrophage presence in WAT, contributing to obesity-associated pathologies, and further supports a dual role of complement in WAT. Understanding this effect of the complement system pathway could contribute to targeting treatment of obesity and its comorbidities.
authors: Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center (CRIUCPQ), Laval University, Quebec, Quebec, Canada.
authors: Danny
authors: D
authors: Gauvreau
authors: Abhishek
authors: A
authors: Gupta
authors: Alexandre
authors: A
authors: Fisette
authors: Fun-Qun
authors: FQ
authors: Tom
authors: Katherine
authors: K
authors: Cianflone
mesh_terms: D054392:Adipokines / Q000378:metabolism; D000818:Animals; D001835:Body Weight; D002478:Cells, Cultured; D002630:Chemotactic Factors / Q000378:metabolism; D003165:Complement System Proteins / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D002149:Energy Intake; D005260:Female; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism; D018836:Inflammation Mediators / Q000097:blood; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D050152:Intra-Abdominal Fat / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D050356:Lipid Metabolism / Q000235:genetics; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D009765:Obesity / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D044087:Receptor, Anaphylatoxin C5a; D019707:Receptors, Chemokine / Q000172:deficiency*; D044042:Receptors, Formyl Peptide / Q000378:metabolism
chemical_list: D054392:Adipokines; C000594938:C5ar2 protein, mouse; D002630:Chemotactic Factors; D016207:Cytokines; D018836:Inflammation Mediators; D007328:Insulin; D044087:Receptor, Anaphylatoxin C5a; D019707:Receptors, Chemokine; D044042:Receptors, Formyl Peptide; D003165:Complement System Proteins; D005947:Glucose
references: J Clin Endocrinol Metab. 2007 Mar;92(3):1023-33
references: 17164304
references: Eur J Immunol. 2011 Sep;41(9):2472-6
references: 21952799
references: J Biol Chem. 2003 Mar 28;278(13):11123-9
references: 12540846
references: J Endocrinol. 2007 Aug;194(2):293-304
references: 17641279
references: J Clin Invest. 2007 Jan;117(1):175-84
references: 17200717
references: Mol Immunol. 2000 Jun;37(8):407-12
references: 11090875
references: J Lipid Res. 2005 Nov;46(11):2347-55
references: 16150820
references: J Clin Invest. 2003 Dec;112(12):1821-30
references: 14679177
references: Biochemistry. 2003 Aug 12;42(31):9406-15
references: 12899627
references: Immunobiology. 2013 Jan;218(1):127-33
references: 22622332
references: Diabetes. 2007 Apr;56(4):901-11
references: 17395738
references: Biochem J. 2000 Jan 15;345 Pt 2:161-79
references: 10620491
references: Mol Immunol. 2009 Feb;46(5):755-60
references: 18954909
references: Nature. 2006 Dec 14;444(7121):860-7
references: 17167474
references: Curr Opin Endocrinol Diabetes Obes. 2007 Oct;14(5):359-64
references: 17940463
references: Am J Clin Nutr. 2011 Apr;93(4):875S-83
references: 21289219
references: J Lipid Res. 2008 Sep;49(9):1894-903
references: 18503031
references: Arterioscler Thromb Vasc Biol. 1997 Jul;17(7):1239-44
references: 9261252
references: Mol Immunol. 2009 Sep;46(14):2753-66
references: 19477527
references: Adv Exp Med Biol. 2008;632:35-46
references: 19025112
references: Prostaglandins Other Lipid Mediat. 2009 Dec;90(3-4):81-4
references: 19800413
references: Cell. 1999 Oct 29;99(3):239-42
references: 10555139
references: FASEB J. 2005 Jun;19(8):1003-5
references: 15784721
references: J Biol Chem. 2002 Mar 1;277(9):7165-9
references: 11773063
references: J Clin Invest. 2003 Dec;112(12):1785-8
references: 14679172
references: Nat Biotechnol. 2003 Jun;21(6):652-9
references: 12730667
references: Int J Obes Relat Metab Disord. 1997 Apr;21(4):261-6
references: 9130021
references: J Leukoc Biol. 2005 Jul;78(1):1-8
references: 15734795
references: Br J Pharmacol. 2007 Oct;152(4):429-48
references: 17603557
references: Mol Immunol. 2009 Oct;46(16):3207-17
references: 19767107
references: Diabetes. 2008 Dec;57(12):3239-46
references: 18829989
references: Mol Aspects Med. 2004 Oct-Dec;25(5-6):495-520
references: 15363638
references: J Biol Chem. 2005 Jun 24;280(25):23936-44
references: 15833747
references: J Clin Endocrinol Metab. 1997 Dec;82(12):4196-200
references: 9398739
references: Lipids. 1991 Jul;26(7):495-9
references: 1943492
references: Physiol Res. 2005;54(2):133-40
references: 15544426
references: Arterioscler Thromb Vasc Biol. 1999 Apr;19(4):972-8
references: 10195925
references: Diabetes. 2010 May;59(5):1171-81
references: 20185806
references: Trends Immunol. 2010 Jun;31(6):228-35
references: 20434953
references: Clin Chim Acta. 2011 Jun 11;412(13-14):1171-9
references: 21419112
references: Anticancer Res. 2011 Jul;31(7):2511-6
references: 21873168
references: J Clin Invest. 2006 Jun;116(6):1494-505
references: 16691291
references: Int J Obes (Lond). 2006 Mar;30(3):439-46
references: 16302015
references: Curr Opin Clin Nutr Metab Care. 2010 Jul;13(4):366-70
references: 20473150
references: Nature. 2007 Mar 8;446(7132):203-7
references: 17322907
references: Diabetes. 2009 Sep;58(9):2006-17
references: 19581423
references: Am J Physiol Endocrinol Metab. 2010 Dec;299(6):E1016-27
references: 20841504
references: Eur J Clin Invest. 1999 Aug;29(8):679-86
references: 10457151
references: J Clin Invest. 2003 Dec;112(12):1796-808
references: 14679176
references: J Biol Chem. 2009 Jul 31;284(31):20692-8
references: 19494115
references: J Clin Invest. 2011 Jun;121(6):2111-7
references: 21633179
references: Nat Med. 2008 May;14(5):551-7
references: 18454156