Critical illness induces nutrient-independent adipogenesis and accumulation of alternatively activated tissue macrophages

Greet Van den Berghe,Fabian Güiza,Mirna Marques,Michael P Casaer,Sarah Derde,Sarah Perre,Lies Langouche,Annelies Aertgeerts,Greet Hermans

doi:10.1186/cc12887

Abstract

IntroductionWe 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.MethodsIn 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).ResultsIrrespective 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.ConclusionsAdipogenesis 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.

Highlights

We previously reported that in artificially-fed critically ill patients, adipose tissue reveals an increase in small adipocytes and accumulation of M2-macrophages
We studied adipogenesis and macrophage accumulation in subcutaneous adipose tissue (AT) biopsies harvested in vivo after one week of critical illness from human patients enrolled in a randomized, controlled trial (RCT) in which early initiation of parenteral nutrition (PN) was compared with tolerating nutrient restriction in the first seven days of intensive care unit (ICU) stay [12]
The loss of fat mass in cecal ligation and puncture (CLP)-fed mice corresponded to a 26% reduction in total body fat mass

Summary

Introduction

We previously reported that in artificially-fed critically ill patients, adipose tissue reveals an increase in small adipocytes and accumulation of M2-macrophages. We previously documented increased formation of small adipocytes during critical illness with increased glucose and lipid storage properties [5,6]. These changes might be beneficial during critical illness as newlyformed, small adipocytes with augmented insulin. These previous observations were based on biopsies from prolonged severely ill patients who had received parenteral nutrition (PN) throughout the ICU stay. The observed changes in adipose tissue (AT) might be related to the administration of PN or to nutrition-independent factors.

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Conclusion