Adipose Tissue and Endocrine Function in Critical Care

  • Mirna Marques
  • Lies Langouche
Reference work entry


In addition to energy storage and insulation, the white adipose tissue is a complex endocrine organ responsible for the secretion of a high number of adipocyte-originated signaling molecules. These so-called adipokines are involved in the control of metabolism, linking the nutrient status to the tissues involved in energy intake and expenditure and affecting insulin sensitivity. Additionally, resident and recruited macrophages constitute an important part of the adipose tissue, responsible for the secretion of inflammatory and anti-inflammatory cytokines. Up until now, more than 40 different adipokines have been described. From these, leptin and adiponectin are the most studied during critical illness.

Although knowledge is still limited, current available literature suggests that the endocrine functions of adipose tissue might play an adaptive role during critical illness. In the acute phase of illness, the anti-inflammatory and insulin-sensitizing adiponectin is reduced, while pro-inflammatory cytokine expression in adipose tissue is upregulated. In the prolonged phase of critical illness, both adiponectin and anti-inflammatory cytokine production are increasing. Reports on the pro-inflammatory leptin during critical illness are controversial in both humans and animal investigations, possibly due to confounders such as gender, body mass index, and nutritional strategy.

Observational studies report lower mortality in obese than in lean critically ill patients, an association referred to as the “obesity paradox.” Potentially, the altered adipokine secretion profile observed in obesity plays a protective role during critical illness.


Adipose Tissue Critical Illness White Adipose Tissue Adiponectin Level Visceral Adipose Tissue 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

List of Abbreviations


Adiponectin receptor


Acute respiratory distress syndrome


C-X-C motif chemokine 10


EGF-like module-containing mucin-like hormone receptor


High molecular weight






Low molecular weight




Monocyte chemoattractant protein-1


Medium molecular weight


Plasminogen activator inhibitor-1


Peroxisome proliferator-activated receptor γ


Retinol-binding protein 4


Reactive oxygen species


Tumor necrosis factor-alpha


  1. Abhyankar S, Leishear K, Callaghan FM, Demner-Fushman D, McDonald CJ. Lower short- and long-term mortality associated with overweight and obesity in a large cohort study of adult intensive care unit patients. Crit Care. 2012;16:R235.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Ahfeldt T, Schinzel RT, Lee YK, Hendrickson D, Kaplan A, Lum DH, Camahort R, Xia F, Shay J, Rhee EP, Clish CB, Deo RC, Shen T, Lau FH, Cowley A, Mowrer G, Al-Siddiqi H, Nahrendorf M, Musunuru K, Gerszten RE, Rinn JL, Cowan CA. Programming human pluripotent stem cells into white and brown adipocytes. Nat Cell Biol. 2012;14:209–19.CrossRefPubMedPubMedCentralGoogle Scholar
  3. Ahima RS, Lazar MA. Adipokines and the peripheral and neural control of energy balance. Mol Endocrinol. 2008;22:1023–31.CrossRefPubMedPubMedCentralGoogle Scholar
  4. Akinnusi ME, Pineda LA, El Solh AA. Effect of obesity on intensive care morbidity and mortality: a meta-analysis. Crit Care Med. 2008;36:151–8.CrossRefPubMedGoogle Scholar
  5. Arnalich F, Lopez J, Codoceo R, Jim NM, Madero R, Montiel C. Relationship of plasma leptin to plasma cytokines and human survival in sepsis and septic shock. J Infect Dis. 1999;180:908–11.CrossRefPubMedGoogle Scholar
  6. Behnes M, Brueckmann M, Lang S, Putensen C, Saur J, Borggrefe M, Hoffmann U. Alterations of leptin in the course of inflammation and severe sepsis. BMC Infect Dis. 2012;12:217.CrossRefPubMedPubMedCentralGoogle Scholar
  7. Boden G, Chen X, Mozzoli M, Ryan I. Effect of fasting on serum leptin in normal human subjects. J Clin Endocrinol Metab. 1996;81:3419–23.PubMedGoogle Scholar
  8. Bornstein SR, Licinio J, Tauchnitz R, Engelmann L, Negrao AB, Gold P, Chrousos GP. Plasma leptin levels are increased in survivors of acute sepsis: associated loss of diurnal rhythm, in cortisol and leptin secretion. J Clin Endocrinol Metab. 1998;83:280–3.CrossRefPubMedGoogle Scholar
  9. Cowley MA, Smart JL, Rubinstein M, Cerdan MG, Diano S, Horvath TL, Cone RD, Low MJ. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature. 2001;411:480–4.CrossRefPubMedGoogle Scholar
  10. de Oliveira C, de Mattos AB, Biz C, Oyama LM, Ribeiro EB, do Nascimento CM. High-fat diet and glucocorticoid treatment cause hyperglycemia associated with adiponectin receptor alterations. Lipids Health Dis. 2011;10:11.CrossRefPubMedPubMedCentralGoogle Scholar
  11. Faggioni R, Fantuzzi G, Fuller J, Dinarello CA, Feingold KR, Grunfeld C. IL-1 beta mediates leptin induction during inflammation. Am J Physiol. 1998;274:R204–8.PubMedGoogle Scholar
  12. Fantuzzi G. Adiponectin and inflammation: consensus and controversy. J Allergy Clin Immunol. 2008;121:326–30.CrossRefPubMedGoogle Scholar
  13. Gavrila A, Chan JL, Yiannakouris N, Kontogianni M, Miller LC, Orlova C, Mantzoros CS. Serum adiponectin levels are inversely associated with overall and central fat distribution but are not directly regulated by acute fasting or leptin administration in humans: cross-sectional and interventional studies. J Clin Endocrinol Metab. 2003;88:4823–31.CrossRefPubMedGoogle Scholar
  14. Gordon S, Martinez FO. Alternative activation of macrophages: mechanism and functions. Immunity. 2010;32:593–604.CrossRefPubMedGoogle Scholar
  15. Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol. 2005;5:953–64.CrossRefPubMedGoogle Scholar
  16. Graham TE, Yang Q, Bluher M, Hammarstedt A, Ciaraldi TP, Henry RR, Wason CJ, Oberbach A, Jansson PA, Smith U, Kahn BB. Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects. N Engl J Med. 2006;354:2552–63.CrossRefPubMedGoogle Scholar
  17. Grunfeld C, Feingold KR. Tumor necrosis factor, cytokines, and the hyperlipidemia of infection. Trends Endocrinol Metab. 1991;2:213–9.CrossRefPubMedGoogle Scholar
  18. Grunfeld C, Zhao C, Fuller J, Pollack A, Moser A, Friedman J, Feingold KR. Endotoxin and cytokines induce expression of leptin, the ob gene product, in hamsters. J Clin Invest. 1996;97:2152–7.CrossRefPubMedPubMedCentralGoogle Scholar
  19. Heuer JG, Bailey DL, Sharma GR, Zhang T, Ding C, Ford A, Stephens EJ, Holmes KC, Grubbs RL, Fynboe KA, Chen YF, Jakubowski JA. Cecal ligation and puncture with total parenteral nutrition: a clinically relevant model of the metabolic, hormonal, and inflammatory dysfunction associated with critical illness. J Surg Res. 2004;121:178–86.CrossRefPubMedGoogle Scholar
  20. Hillenbrand A, Weiss M, Knippschild U, Stromeyer HG, Henne-Bruns D, Huber-Lang M, Wolf AM. Association of adiponectin levels and insulin demand in critically ill patients. Diabetes Metab Syndr Obes. 2011;4:45–51.CrossRefPubMedPubMedCentralGoogle Scholar
  21. Hogue Jr CW, Stearns JD, Colantuoni E, Robinson KA, Stierer T, Mitter N, Pronovost PJ, Needham DM. The impact of obesity on outcomes after critical illness: a meta-analysis. Intensive Care Med. 2009;35:1152–70.CrossRefPubMedGoogle Scholar
  22. Jain M, Budinger GR, Lo A, Urich D, Rivera SE, Ghosh AK, Gonzalez A, Chiarella SE, Marks K, Donnelly HK, Soberanes S, Varga J, Radigan KA, Chandel NS, Mutlu GM. Leptin promotes fibroproliferative acute respiratory distress syndrome by inhibiting peroxisome proliferator-activated receptor-gamma. Am J Respir Crit Care Med. 2011;183:1490–8.CrossRefPubMedPubMedCentralGoogle Scholar
  23. Janke J, Engeli S, Boschmann M, Adams F, Bohnke J, Luft FC, Sharma AM, Jordan J. Retinol-binding protein 4 in human obesity. Diabetes. 2006;55:2805–10.CrossRefPubMedGoogle Scholar
  24. Jeevanandam M, Begay CK, Petersen SR. Plasma leptin levels in trauma patients: effect of adjuvant recombinant human growth hormone in intravenously fed multiple trauma patients. JPEN J Parenter Enteral Nutr. 1998;22:340–6.CrossRefPubMedGoogle Scholar
  25. Jernas M, Olsson B, Sjoholm K, Sjogren A, Rudemo M, Nellgard B, Carlsson LM, Sjostrom CD. Changes in adipose tissue gene expression and plasma levels of adipokines and acute-phase proteins in patients with critical illness. Metabolism. 2009;58:102–8.CrossRefPubMedGoogle Scholar
  26. Koch A, Weiskirchen R, Sanson E, Zimmermann HW, Voigt S, Duckers H, Trautwein C, Tacke F. Circulating retinol binding protein 4 in critically ill patients before specific treatment: prognostic impact and correlation with organ function, metabolism and inflammation. Crit Care. 2010;14:R179.CrossRefPubMedPubMedCentralGoogle Scholar
  27. Kolaczynski JW, Nyce MR, Considine RV, Boden G, Nolan JJ, Henry R, Mudaliar SR, Olefsky J, Caro JF. Acute and chronic effects of insulin on leptin production in humans: Studies in vivo and in vitro. Diabetes. 1996;45:699–701.CrossRefPubMedGoogle Scholar
  28. Konner AC, Bruning JC. Selective insulin and leptin resistance in metabolic disorders. Cell Metab. 2012;16:144–52.CrossRefPubMedGoogle Scholar
  29. Kotnik P, Fischer-Posovszky P, Wabitsch M. RBP4: a controversial adipokine. Eur J Endocrinol. 2011;165:703–11.CrossRefPubMedGoogle Scholar
  30. Kremen J, Dolinkova M, Krajickova J, Blaha J, Anderlova K, Lacinova Z, Haluzikova D, Bosanska L, Vokurka M, Svacina S, Haluzik M. Increased subcutaneous and epicardial adipose tissue production of proinflammatory cytokines in cardiac surgery patients: possible role in postoperative insulin resistance. J Clin Endocrinol Metab. 2006;91:4620–7.CrossRefPubMedGoogle Scholar
  31. La Cava A, Matarese G. The weight of leptin in immunity. Nat Rev Immunol. 2004;4:371–9.CrossRefPubMedGoogle Scholar
  32. Langouche L, Vander Perre S, Wouters PJ, D’Hoore A, Hansen TK, Van den Berghe G. Effect of intensive insulin therapy on insulin sensitivity in the critically ill. J Clin Endocrinol Metab. 2007;92:3890–7.CrossRefPubMedGoogle Scholar
  33. Langouche L, Vander Perre S, Frystyk J, Flyvbjerg A, Hansen TK, Van den Berghe G. Adiponectin, retinol binding protein 4 and leptin in protracted critical illness of pulmonary origin. Crit Care. 2009;13:R112.CrossRefPubMedPubMedCentralGoogle Scholar
  34. Langouche L, Vander Perre S, Thiessen S, Gunst J, Hermans G, D’Hoore A, Kola B, Korbonits M, Van den Berghe G. Alterations in adipose tissue during critical illness: an adaptive and protective response? Am J Respir Crit Care Med. 2010;182:507–16.CrossRefPubMedGoogle Scholar
  35. Langouche L, Marques MB, Ingels C, Gunst J, Derde S, Vander Perre S, D’Hoore A, Van den Berghe G. Critical illness induces alternative activation of M2 macrophages in adipose tissue. Crit Care. 2011;15:R245.CrossRefPubMedPubMedCentralGoogle Scholar
  36. Langouche L, Vander PS, Marques M, Boelen A, Wouters PJ, Casaer MP, Van den BG. Impact of early nutrient restriction during critical illness on the nonthyroidal illness syndrome and its relation with outcome: a randomized, controlled clinical study. J Clin Endocrinol Metab. 2013;98:1006–13.CrossRefPubMedGoogle Scholar
  37. LeGall-Salmon E, Stevens WD, Levy JR. Total parenteral nutrition increases serum leptin concentration in hospitalized, undernourished patients. JPEN J Parenter Enteral Nutr. 1999;23:38–42.CrossRefPubMedGoogle Scholar
  38. Leuwer M, Welters I, Marx G, Rushton A, Bao H, Hunter L, Trayhurn P. Endotoxaemia leads to major increases in inflammatory adipokine gene expression in white adipose tissue of mice. Pflugers Arch. 2009;457:731–41.CrossRefPubMedGoogle Scholar
  39. Mancuso P, Gottschalk A, Phare SM, Peters-Golden M, Lukacs NW, Huffnagle GB. Leptin-deficient mice exhibit impaired host defense in Gram-negative pneumonia. J Immunol. 2002;168:4018–24.CrossRefPubMedGoogle Scholar
  40. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23:549–55.CrossRefPubMedGoogle Scholar
  41. Marik PE, Varon J. Sepsis: state of the art. Dis Mon. 2001;47:465–532.CrossRefPubMedGoogle Scholar
  42. Marques MB, Langouche L. Endocrine, metabolic, and morphologic alterations of adipose tissue during critical illness. Crit Care Med. 2013;41:317–25.CrossRefPubMedGoogle Scholar
  43. Martino JL, Stapleton RD, Wang M, Day AG, Cahill NE, Dixon AE, Suratt BT, Heyland DK. Extreme obesity and outcomes in critically ill patients. Chest. 2011;140:1198–206.CrossRefPubMedPubMedCentralGoogle Scholar
  44. Maruna P, Lindner J, Kubzova KM. Leptin and soluble leptin receptor changes after pulmonary endarterectomy: relations to cortisol and cytokine network. Physiol Res. 2009;58:569–76.PubMedGoogle Scholar
  45. McCowen KC, Ling PR, Friel C, Sternberg J, Forse RA, Burke PA, Bistrian BR. Patterns of plasma leptin and insulin concentrations in hospitalized patients after the initiation of total parenteral nutrition. Am J Clin Nutr. 2002;75:931–5.PubMedGoogle Scholar
  46. Mehta NN, McGillicuddy FC, Anderson PD, Hinkle CC, Shah R, Pruscino L, Tabita-Martinez J, Sellers KF, Rickels MR, Reilly MP. Experimental endotoxemia induces adipose inflammation and insulin resistance in humans. Diabetes. 2010;59:172–81.CrossRefPubMedGoogle Scholar
  47. Meyer C, Robson D, Rackovsky N, Nadkarni V, Gerich J. Role of the kidney in human leptin metabolism. Am J Physiol. 1997;273:E903–7.PubMedGoogle Scholar
  48. Minokoshi Y, Alquier T, Furukawa N, Kim YB, Lee A, Xue B, Mu J, Foufelle F, Ferre P, Birnbaum MJ, Stuck BJ, Kahn BB. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature. 2004;428:569–74.CrossRefPubMedGoogle Scholar
  49. Moody BJ. Changes in the serum concentrations of thyroxine-binding prealbumin and retinol-binding protein following burn injury. Clin Chim Acta. 1982;118:87–92.CrossRefPubMedGoogle Scholar
  50. Moshyedi AK, Josephs MD, Abdalla EK, Mackay SL, Edwards III CK, Copeland III EM, Moldawer LL. Increased leptin expression in mice with bacterial peritonitis is partially regulated by tumor necrosis factor alpha. Infect Immun. 1998;66:1800–2.PubMedPubMedCentralGoogle Scholar
  51. Odegaard JI, Chawla A. Mechanisms of macrophage activation in obesity-induced insulin resistance. Nat Clin Pract Endocrinol Metab. 2008;4:619–26.CrossRefPubMedPubMedCentralGoogle Scholar
  52. Okamoto Y, Kihara S, Funahashi T, Matsuzawa Y, Libby P. Adiponectin: a key adipocytokine in metabolic syndrome. Clin Sci (Lond). 2006;110:267–78.CrossRefGoogle Scholar
  53. Oliveros H, Villamor E. Obesity and mortality in critically ill adults: a systematic review and meta-analysis. Obesity (Silver Spring). 2008;16:515–21.CrossRefGoogle Scholar
  54. Orbak Z, Ertekin V, Akcay F, Ozkan B, Ors R. Serum leptin levels in neonatal bacterial septicemia. J Pediatr Endocrinol Metab. 2003;16:727–31.CrossRefPubMedGoogle Scholar
  55. Ouedraogo R, Gong Y, Berzins B, Wu X, Mahadev K, Hough K, Chan L, Goldstein BJ, Scalia R. Adiponectin deficiency increases leukocyte-endothelium interactions via upregulation of endothelial cell adhesion molecules in vivo. J Clin Invest. 2007;117:1718–26.CrossRefPubMedPubMedCentralGoogle Scholar
  56. Papaspyrou-Rao S, Schneider SH, Petersen RN, Fried SK. Dexamethasone increases leptin expression in humans in vivo. J Clin Endocrinol Metab. 1997;82:1635–7.CrossRefPubMedGoogle Scholar
  57. Papathanassoglou ED, Moynihan JA, Ackerman MH, Mantzoros CS. Serum leptin levels are higher but are not independently associated with severity or mortality in the multiple organ dysfunction/systemic inflammatory response syndrome: a matched case control and a longitudinal study. Clin Endocrinol (Oxf). 2001;54:225–33.CrossRefGoogle Scholar
  58. Quasim T, McMillan DC, Wallace AM, Kinsella J. The relationship between leptin concentrations, the systemic inflammatory response and illness severity in surgical patients admitted to ITU. Clin Nutr. 2004;23:233–8.CrossRefPubMedGoogle Scholar
  59. Roberts R, Hodson L, Dennis AL, Neville MJ, Humphreys SM, Harnden KE, Micklem KJ, Frayn KN. Markers of de novo lipogenesis in adipose tissue: associations with small adipocytes and insulin sensitivity in humans. Diabetologia. 2009;52:882–90.CrossRefPubMedGoogle Scholar
  60. Robinson K, Kruger P, Prins J, Venkatesh B. The metabolic syndrome in critically ill patients. Best Pract Res Clin Endocrinol Metab. 2011;25:835–45.CrossRefPubMedGoogle Scholar
  61. Shapiro NI, Khankin EV, Van MM, Shih SC, Lu S, Yano M, Castro PR, Maratos-Flier E, Parikh SM, Karumanchi SA, Yano K. Leptin exacerbates sepsis-mediated morbidity and mortality. J Immunol. 2010;185:517–24.CrossRefPubMedPubMedCentralGoogle Scholar
  62. Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest. 2012;122:787–95.CrossRefPubMedPubMedCentralGoogle Scholar
  63. Starr ME, Evers BM, Saito H. Age-associated increase in cytokine production during systemic inflammation: adipose tissue as a major source of IL-6. J Gerontol A Biol Sci Med Sci. 2009;64:723–30.CrossRefPubMedGoogle Scholar
  64. Sweeney G. Cardiovascular effects of leptin. Nat Rev Cardiol. 2010;7:22–9.CrossRefPubMedGoogle Scholar
  65. Teoh H, Quan A, Bang KW, Wang G, Lovren F, Vu V, Haitsma JJ, Szmitko PE, Al-Omran M, Wang CH, Gupta M, Peterson MD, Zhang H, Chan L, Freedman J, Sweeney G, Verma S. Adiponectin deficiency promotes endothelial activation and profoundly exacerbates sepsis-related mortality. Am J Physiol Endocrinol Metab. 2008;295:E658–64.CrossRefPubMedPubMedCentralGoogle Scholar
  66. Tschop J, Nogueiras R, Haas-Lockie S, Kasten KR, Castaneda TR, Huber N, Guanciale K, Perez-Tilve D, Habegger K, Ottaway N, Woods SC, Oldfield B, Clarke I, Chua Jr S, Farooqi IS, O’Rahilly S, Caldwell CC, Tschop MH. CNS leptin action modulates immune response and survival in sepsis. J Neurosci. 2010;30:6036–47.CrossRefPubMedPubMedCentralGoogle Scholar
  67. Tzanela M, Orfanos SE, Tsirantonaki M, Kotanidou A, Sotiropoulou C, Christophoraki M, Vassiliadi D, Thalassinos NC, Roussos C. Leptin alterations in the course of sepsis in humans. In Vivo. 2006;20:565–70.PubMedGoogle Scholar
  68. Van den Berghe G, Wouters P, Carlsson L, Baxter RC, Bouillon R, Bowers CY. Leptin levels in protracted critical illness: effects of growth hormone-secretagogues and thyrotropin-releasing hormone. J Clin Endocrinol Metab. 1998;83:3062–70.PubMedGoogle Scholar
  69. Vassiliadi DA, Tzanela M, Kotanidou A, Orfanos SE, Nikitas N, Armaganidis A, Koutsilieris M, Roussos C, Tsagarakis S, Dimopoulou I. Serial changes in adiponectin and resistin in critically ill patients with sepsis: associations with sepsis phase, severity, and circulating cytokine levels. J Crit Care. 2012;27:400–9.CrossRefPubMedGoogle Scholar
  70. Venkatesh B, Hickman I, Nisbet J, Cohen J, Prins J. Changes in serum adiponectin concentrations in critical illness: a preliminary investigation. Crit Care. 2009;13:R105.CrossRefPubMedPubMedCentralGoogle Scholar
  71. Walkey AJ, Rice TW, Konter J, Ouchi N, Shibata R, Walsh K, deBoisblanc BP, Summer R. Plasma adiponectin and mortality in critically ill subjects with acute respiratory failure. Crit Care Med. 2010;38:2329–34.CrossRefPubMedPubMedCentralGoogle Scholar
  72. Wang Y, Lam KS, Yau MH, Xu A. Post-translational modifications of adiponectin: mechanisms and functional implications. Biochem J. 2008;409:623–33.CrossRefPubMedGoogle Scholar
  73. Weisberg SP, Hunter D, Huber R, Lemieux J, Slaymaker S, Vaddi K, Charo I, Leibel RL, Ferrante Jr AW. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest. 2006;116:115–24.CrossRefPubMedGoogle Scholar
  74. Wu J, Bostrom P, Sparks LM, Ye L, Choi JH, Giang AH, Khandekar M, Virtanen KA, Nuutila P, Schaart G, Huang K, Tu H, van Marken Lichtenbelt WD, Hoeks J, Enerback S, Schrauwen P, Spiegelman BM. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell. 2012;150:366–76.CrossRefPubMedPubMedCentralGoogle Scholar
  75. Yang Q, Graham TE, Mody N, Preitner F, Peroni OD, Zabolotny JM, Kotani K, Quadro L, Kahn BB. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature. 2005;436:356–62.CrossRefPubMedGoogle Scholar
  76. Yousef AA, Amr YM, Suliman GA. The diagnostic value of serum leptin monitoring and its correlation with tumor necrosis factor-alpha in critically ill patients: a prospective observational study. Crit Care. 2010;14:R33.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of Cellular and Molecular MedicineUniversity of Leuven (KU Leuven), Laboratory of Intensive Care MedicineLeuvenBelgium

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