title: Critical illness induces nutrient-independent adipogenesis and accumulation of alternatively activated tissue macrophages.
abstract: BACKGROUND
  We previously reported that in artificially-fed critically ill patients, adipose tissue reveals an increase in small adipocytes and accumulation of M2-macrophages. We hypothesized that nutrient-independent factors of critical illness explain these findings, and that the M2-macrophage accumulation may not be limited to adipose tissue.
  
  
  METHODS
  In a long-term cecal ligation and puncture (CLP) mouse model of sepsis, we compared the effect of parenteral nutrition (CLP-fed, n = 13) with nutrient restriction (CLP-restricted, n = 11) on body composition, adipocyte size and macrophage accumulation in adipose tissue, liver and lungs. Fed healthy mice (n = 11) were studied as controls. In a human study, in vivo adipose tissue biopsies were studied from ICU patients (n = 40) enrolled in a randomized control trial which compared early initiation of parenteral nutrition (PN) versus tolerating nutrient restriction during the first week of ICU stay. Adipose tissue morphology was compared with healthy human controls (n = 13).
  
  
  RESULTS
  Irrespective of nutritional intake, critically ill mice lost weight, fat and fat-free mass. Adipocyte number, proliferation marker Proliferating Cell Nuclear Antigen (PCNA) and adipogenic markers PPARγ and CCAAT/enhancer binding protein-β (C/EBPβ) increased with illness, irrespective of nutritional intake. M2-macrophage accumulation was observed in adipose tissue, liver and lungs of critically ill mice. Macrophage M2-markers correlated with CCL2 expression. In adipose tissue biopsies of critically ill patients, increased adipogenic markers and M2 macrophage accumulation were present irrespective of nutritional intake.
  
  
  CONCLUSIONS
  Adipogenesis and accumulation of tissue M2-macrophages are hallmarks of prolonged critical illness, irrespective of nutritional management. During critical illness, M2-macrophages accumulate not only in adipose tissue, but also in the liver and lungs.
authors.forename: Mirna
authors.initials: M
authors.lastname: Marques
authors.forename: Sarah
authors.initials: S
authors.lastname: Perre
authors.forename: Annelies
authors.initials: A
authors.lastname: Aertgeerts
authors.forename: Sarah
authors.initials: S
authors.lastname: Derde
authors.forename: Fabian
authors.initials: F
authors.lastname: Güiza
authors.forename: Michael P
authors.initials: MP
authors.lastname: Casaer
authors.forename: Greet
authors.initials: G
authors.lastname: Hermans
authors.forename: Greet
authors.initials: G
authors.lastname: Van den Berghe
authors.forename: Lies
authors.initials: L
authors.lastname: Langouche
mesh_terms: D050156:Adipogenesis / Q000502:physiology*; D000273:Adipose Tissue / Q000378:metabolism* / Q000473:pathology; D000368:Aged; D000818:Animals; D016638:Critical Illness; D005260:Female; D006801:Humans; D008262:Macrophage Activation / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009752:Nutritional Status / Q000502:physiology*
references.citation: Science. 1989 Sep 8;245(4922):1118-21
references.pmid: 2570461
references.citation: J Clin Invest. 2005 Aug;115(8):2277-86
references.pmid: 16075063
references.citation: Cell Metab. 2006 Jul;4(1):13-24
references.pmid: 16814729
references.citation: Drug Alcohol Depend. 2010 Jun 1;109(1-3):126-9
references.pmid: 20061095
references.citation: Obesity (Silver Spring). 2010 Jul;18(7):1283-8
references.pmid: 19927138
references.citation: Diabetes. 2011 Mar;60(3):797-809
references.pmid: 21266330
references.citation: Curr Opin Pharmacol. 2004 Dec;4(6):621-8
references.pmid: 15525554
references.citation: N Engl J Med. 2011 Aug 11;365(6):506-17
references.pmid: 21714640
references.citation: Nat Protoc. 2009;4(1):31-6
references.pmid: 19131954
references.citation: J Trauma. 1987 Mar;27(3):262-6
references.pmid: 3104621
references.citation: Diabetes. 2007 Apr;56(4):901-11
references.pmid: 17395738
references.citation: Cell Metab. 2007 Aug;6(2):137-43
references.pmid: 17681149
references.citation: FASEB J. 2006 Jul;20(9):1540-2
references.pmid: 16754744
references.citation: J Infect Dis. 2000 Jun;181 Suppl 3:S462-72
references.pmid: 10839741
references.citation: Crit Care Med. 1990 May;18(5):467-73
references.pmid: 2109673
references.citation: Annu Rev Biochem. 2012;81:715-36
references.pmid: 22463691
references.citation: Physiol Rev. 2012 Apr;92(2):739-89
references.pmid: 22535896
references.citation: Immunobiology. 2008;213(9-10):733-49
references.pmid: 18926289
references.citation: Eur Surg Res. 2003 Nov-Dec;35(6):486-91
references.pmid: 14593232
references.citation: Nat Rev Endocrinol. 2012 Feb 07;8(6):374-8
references.pmid: 22310851
references.citation: Mol Endocrinol. 2004 Sep;18(9):2123-31
references.pmid: 15243132
references.citation: Endocrinology. 2012 Feb;153(2):973-84
references.pmid: 22166982
references.citation: Diabetologia. 2009 May;52(5):882-90
references.pmid: 19252892
references.citation: Intensive Care Med. 2011 Nov;37(11):1793-9
references.pmid: 21818652
references.citation: Nat Methods. 2010 Jun;7(6):447-9
references.pmid: 20453868
references.citation: J Clin Endocrinol Metab. 2011 Apr;96(4):E633-45
references.pmid: 21270330
references.citation: Immunity. 2010 May 28;32(5):593-604
references.pmid: 20510870
references.citation: Trends Immunol. 2002 Nov;23(11):549-55
references.pmid: 12401408
references.citation: Am J Respir Crit Care Med. 2001 Sep 1;164(5):891-5
references.pmid: 11549551
references.citation: Chest. 2005 Jun;127(6):2125-31
references.pmid: 15947330
references.citation: Trials. 2011 Jan 24;12:21
references.pmid: 21261975
references.citation: ScientificWorldJournal. 2011;11:2509-29
references.pmid: 22235182
references.citation: Am J Respir Crit Care Med. 2010 Aug 15;182(4):507-16
references.pmid: 20442437
references.citation: Metabolism. 1974 Nov;23(11):1091-102
references.pmid: 4607783
references.citation: Nature. 2007 Jun 28;447(7148):1116-20
references.pmid: 17515919
references.citation: FEBS Lett. 2011 Jul 21;585(14):2279-84
references.pmid: 21689652
references.citation: Cell Mol Neurobiol. 2012 Jul;32(5):801-13
references.pmid: 22402834
references.citation: Crit Care Med. 2006 Dec;34(12):2929-39
references.pmid: 17075374
references.citation: Crit Care. 2011;15(5):R245
references.pmid: 22018099
references.citation: Diabetes. 2004 May;53(5):1285-92
references.pmid: 15111498
references.citation: Nat Cell Biol. 2012 Jan 15;14(2):209-19
references.pmid: 22246346
references.citation: Nat Rev Immunol. 2005 Dec;5(12):953-64
references.pmid: 16322748
references.citation: J Lipid Res. 1997 Apr;38(4):795-804
references.pmid: 9144094
references.citation: Am J Physiol Endocrinol Metab. 2008 Jan;294(1):E1-9
references.pmid: 17957035
references.citation: Curr Opin Lipidol. 2011 Oct;22(5):365-72
references.pmid: 21825981
references.citation: Ann Surg. 2002 Jan;235(1):152-61
references.pmid: 11753055
references.citation: Biochim Biophys Acta. 2010 Mar;1801(3):207-8
references.pmid: 20045080
references.citation: Surgery. 1983 Aug;94(2):331-5
references.pmid: 6879447