Critical illness induces nutrient-independent adipogenesis and accumulation of alternatively activated tissue macrophages
© Marques et al.; licensee BioMed Central Ltd. 2013
Received: 28 February 2013
Accepted: 28 June 2013
Published: 10 September 2013
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.
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).
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.
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.
Several observational studies have shown lower mortality in overweight and obese versus lean critically ill patients, an association known as the 'obesity paradox' [1–4]. 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 newly-formed, small adipocytes with augmented insulin sensitivity and lipid-storage capacity might prevent excess circulating lipids and glucose . In addition, we demonstrated a remarkable macrophage accumulation in adipose tissue of critically ill patients with a predominant M2-phenotype . Increased insulin sensitivity and β-oxidation of free fatty acids (FFA), but also phagocytosis of infectious microorganisms, production of anti-inflammatory and tissue-healing factors are potential beneficial features of M2-macrophages during critical illness (CI) .
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 thus be related to the administration of PN or to nutrition-independent factors. In health, excessive caloric intake promotes hypertrophy and hyperplasia of adipocytes, and accumulation of M1-macrophages [4, 9]. Macrophage accumulation could also be evoked by catecholamines and hypoxia, factors accepted to play a role in the pathophysiology of sepsis [10, 11]. It is thus plausible that other tissues involved in innate immunity could also display macrophage accumulation during CI.
We hypothesized that nutrition-independent factors evoke the morphological changes in AT during CI. We, therefore, studied the impact of PN administration, as compared with nutrient restriction, on body composition, adipogenesis and macrophage accumulation in AT, liver and lungs in an antibiotic-treated fluid-resuscitated mouse model of sepsis. In addition, we studied adipogenesis and macrophage accumulation in subcutaneous 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 PN was compared with tolerating nutrient restriction in the first seven days of ICU stay .
Materials and methods
Set-up of the experimental animal model
Baseline and outcome variables of studied critically ill patients and healthy volunteers
Early PN patients N= 20
Late PN patients N= 20
P-value Early vs. Late
Healthy Controls N= 13
P-value Ill vs. Healthy
Male sex - no. (%)
Age - yr (mean ± SE)
60 ± 2
63 ± 3
60 ± 3
BMI - Kg/m2 (mean ± SE)
23.1 ± 0.9
23.2 ± 1.2
23.9 ± 1.3
Malignancy no. (%)
Diabetes no. (%)
NRS score - median [IQR]
4 [3 to 7]
4 [3 to 6]
APACHE II SCORE - median [IQR]
30 [21 to 47]
33 [23 to 42]
Reason for admission - no. (%)
New infection - no (%)
Duration of ICU stay - median [IQR]
15 [10 to 33]
18 [10 to 40]
ICU non-survivors - no (%)
Triglyceride content in liver and skeletal muscle
Triglyceride content of tissue was determined with a colorimetric commercial assay (triglyceride quantification kit, Abcam, Cambridge, UK).
Paraformaldehyde-fixed paraffin sections were stained with F4/80Ab (general anti-macrophage antibody (Ab) for mice (Abcam)), CD163Ab (Santa Cruz Biotechnology, Santa Cruz, CA, USA), and Peroxisome Proliferator-Activated Receptor Gamma (PPARγ)-Ab (Abcam). For human samples, the general macrophage marker CD68 was used (Dako, Glostrup, Denmark). Macrophage accumulation in AT sections was evaluated in a blinded fashion by two observers on a Leica DM3000 Microscope (Wetzlar, Germany). Macrophage staining in liver and lungs, PPARγ staining in AT and adipocyte size were quantified on digital microscopical images with in-house designed algorithms developed in Matlab 7.4.0 and Image Processing Toolbox (Matworks, Natick, MA, USA) as described earlier . The estimated proportion of adipocytes was calculated by dividing total end weight of body fat (second DEXA quantification) by mean adipocyte size. This calculation was then plotted proportionally to the mean estimated number of adipocytes of the healthy mice .
Messenger RNA was isolated and cDNA quantified in real time as previously described . Data are expressed normalized to GAPDH or HPRT as fold-change of the mean of the control group. For the quantification of Proliferating Cell Nuclear Antigen (PCNA), CCAAT/enhancer binding protein-β (C/EBPβ), hormone sensitive lipase (HSL), tumor necrosis factor-α (TNFα), inducible nitric oxide synthase (iNOS), Arginase-1, interleukin 10 (IL-10), chemokine (C-C motif) ligand 2 (CCL2), and CD-163 messenger RNA, commercial gene expression assays (TaqMan, Life Technologies, Gent, Belgium) were used.
The following predefined statistical plan was used: (1) to assess the impact of illness, the fed healthy controls were compared with the CLP-fed; (2) to assess the impact of feeding during illness, the CLP-fed were compared with the CLP-restricted. Unpaired t-test was used for normally distributed data; the non-parametric Mann-Whitney u test for non-normally distributed data. Exponential gene expression data were log transformed. For comparison of proportions, the X-square test was used. The significance of correlations was assessed by calculation of the Pearson (r) correlation coefficient. Statistical significance was considered when P-values ≤ 0.05.
Mouse study - impact of PN during CI on body composition, adipogenesis and lipolysis
Part of the fat was lost from ectopic sites, evidenced by lowered triglyceride content in liver and skeletal muscle in CLP-fed compared to healthy mice. Reduction of triglyceride content from liver and skeletal muscle was further accentuated in CLP-restricted compared to CLP-fed animals (Figure 2D). Total body fat mass correlated with triglyceride content in liver and muscle (R = 0.625, P = 0.01).
To assess adipogenesis, the number of adipocytes was estimated by dividing total body fat mass by adipocyte size: CLP-fed mice displayed 50% higher number of adipocytes compared to healthy mice (Figure 3B). CLP-fed and CLP-restricted mice showed a comparable increased number of adipocytes. Gene expression of the proliferation marker PCNA was up-regulated in CLP-fed mice compared to healthy controls in subcutaneous and renal AT (not in epidydimal AT). CLP-fed and CLP-restricted mice showed a comparable PCNA gene expression (Figure 3C). Immunostaining of the adipogenic transcription factor PPARγ was significantly higher in CLP-fed compared to healthy mice in all AT depots. CLP-fed and CLP-restricted mice showed comparable PPARγ immunostaining (Figure 3D). C/EBPβ expression was higher in CLP-fed than in healthy animals in all AT depots. In subcutaneous AT, CLP-restricted mice showed a further increase in C/EBPβ gene expression when compared to CLP-fed mice (Figure 3E). In visceral AT, CLP-fed and CLP-restricted mice showed comparable increase in C/EBPβ gene expression.
Mouse study: impact of PN during CI on tissue macrophages
Macrophage accumulation in adipose tissue of septic mice
Healthy (n = 8)
CLP-fed (n = 6)
Ill vs Healthy: P = 0.0009
CLP-restricted (n = 6)
Fed vs Restricted: P = 0.6
Healthy (n = 6)
CLP-fed (n = 6)
Ill vs Healthy: P = 0.01
CLP-restricted (n = 7)
Fed vs Restricted: P = 0.8
Healthy (n = 11)
CLP-fed (n = 11)
Ill vs Healthy: P = 0.005
CLP-restricted (n = 5)
Fed vs Restricted: P = 0.6
Expression of M1 and M2 markers was comparable in CLP-fed and CLP-restricted mice in all AT depots (Figure 4). Only in subcutaneous and epididymal AT, iNOS was reduced and in renal AT, arginase expression was further increased in CLP-restricted compared to CLP-fed mice. Subcutaneous and visceral AT sections were immunostained for CD163. Positive M2 macrophage staining was present in all AT depots of CLP-fed and CLP-restricted mice.
As a possible trigger for the macrophage accumulation, we quantified gene expression of the chemo-attractant factor CCL2. The gene expression of CCL2 was higher in all AT depots, lungs and liver of CLP-fed when compared to healthy mice (Figures 4F and 5). The gene expression of CCL2 in CLP-fed and CLP-restricted mice was comparable in all AT depots, lungs and liver. CCL2 expression correlated positively with arginase expression (R = 0.566, P = 0.007 in inguinal AT, R = 0.912, P < 0.0001 in epidydimal AT, R = 0.598, P = 0.009 in renal AT). CCL2 gene expression correlated positively with CD163 gene expression in the liver (R = 0.424, P = 0.01) and lungs (R = 0.730, P < 0.0001).
Human study: impact of PN during CI on adipose tissue morphology and gene expression
Adipocyte size decreased in early PN 'fed' critically-ill patients compared to healthy controls (Figure 6B). Medium adipocyte size was equally reduced in early PN 'fed' patients and late PN 'restricted' patients. Immuno-staining revealed accumulation of macrophages in all biopsies of critically-ill patients (Figure 6C). Gene expression of TNFα was unaffected by illness, while arginase-1 gene expression was higher in early PN 'fed' critically-ill patients than in controls (Figure 6D, E). Gene expression of TNFα was equally up-regulated in early PN 'fed' and late PN 'restricted' patients.
It is known from the literature that glucocorticoids can both stimulate adipogenesis  and promote M2 polarization . Nineteen of the 40 patients received corticosteroids during the study period. However, arginase expression (P = 0.25), TNFα expression (P = 0.47) and adipocyte size (P = 0.6) were not different between patients receiving or not receiving steroids. In contrast, patients receiving steroids during the study period, had a higher percentage of CD68 staining then patients not receiving steroids (P = 0.03).
Sepsis-induced critical illness in mice evoked nutrition-resistant loss of body weight, fat-free mass and fat mass, the latter partially explained by ectopic triglyceride loss. Concomitantly, critical illness increased adipogenesis resulting in an increased number of smaller adipocytes, irrespective of nutrition. Macrophages of a predominant M2-phenotype, accumulated in subcutaneous and visceral AT as well as in the liver and lungs of both fed and fasted septic mice. In the liver and lungs, fasting appeared to further enhance M2 over M1 polarization. In all tested tissues of the septic mouse model, increased expression of the chemotatic factor CCL2 correlated positively with macrophage accumulation. In the human study, we could confirm that increased adipogenesis and M2-macrophage accumulation in the adipose tissue was present in critically-ill patients, independent from parenteral nutrition administration.
Critical illness uniformly induces hypercatabolism, characterized by profound loss of lean tissue . In humans, aggressive artificial nutrition was shown unable to prevent lean tissue wasting, whereas fat mass was preserved or even increased [26–28]. In our septic mouse model, we observed loss of both fat and fat-free mass after five days of critical illness in both CLP-fed and CLP-restricted mice. The 26% reduction in total body fat mass in mice may seem to contradict the available human data [26, 28]. This discrepancy might be due to the length of our experimental animal set-up, as five days can be considered quite an extended time for mice. On the other hand, the methodology used in our experiment allowed the quantification of the total amount of fat in the body, including ectopic lipid depositions. Indeed, we demonstrated a reduction of triglyceride content in non-adipose tissues, such as liver and skeletal muscle, a reduction which was even more pronounced with nutrient restriction. Our observation of triglyceride reduction in liver does not contradict the known occurrence of fatty liver in critically ill patients, because our mouse model was well controlled for hyperglycemia, which is a major trigger for hepatic steatosis during critical illness [29, 30].
Although some of the body fat mass was probably lost in the AT depots, the 26% reduction in total body fat mass contrasted sharply with the more than 40% reduction in median adipocyte size, indicating other factors involved in the decreased adipocyte size. Indeed, the observed reduction in adipocyte size could not be explained by lipolysis, as HSL expression was strongly reduced by illness and further reduced by fasting during illness. Instead, our data indicate that the increased number of small adipocytes resulted from increased adipogenesis. Indeed, the proliferation marker PCNA and nuclear transcription factors C/EBPβ and PPARγ were up-regulated, factors that are essential and sufficient to induce white adipocyte differentiation from stem cells . The increase of the adipogenic markers was unaffected by nutrition, suggesting an illness-related trigger. A possible role of increased adipogenesis during critical illness would be to better deal with toxic metabolites, such as circulating triglycerides and glucose [32, 33], preventing their accumulation in the liver and muscle. Newly-formed small adipocytes indeed have an increased capacity of storing triglycerides and glucose from the circulation [6, 7, 34]. Unexpectedly, fasting during CI further reduced lipolysis in visceral AT. This may suggest that during critical illness, fasting either does not signal the adipose tissue to release stored triglycerides or that increased adipogenesis evoked by illness overwhelms any lipolytic response.
The second important alteration we observed in AT during CI, again unaffected by nutrition, was the accumulation of macrophages. Similarly to the AT, the lungs and liver of critically ill mice showed a clear accumulation of macrophages, unaffected by nutrition. In all studied tissues, the markers for macrophage accumulation correlated strongly with CCL2, suggesting an orchestrated response to illness in innate immune-related organs. Cellular hypoxia and catecholamines, known to stimulate production and secretion of chemoattractant factors, may play a role in this process [10, 35–37]. Additionally, recruited macrophages and adipocytes could further evoke catecholamine release inducing a vicious circle [38, 39].
Depending on the trigger, tissue macrophages can polarize to the pro-inflammatory M1-state or to the anti-inflammatory M2-state . The activation of M1 macrophages is a classical feature of cellular immune response to infection while the alternative activation of M2 macrophages plays a role in healing and repair. In this study, we observed a marked increase in M2 macrophages in AT, lungs and liver of critically ill mice and in AT of critically ill humans. In AT, M2 accumulation predominated compared to M1 markers, but in both liver and lungs of critically ill fed mice, M1 and M2 expression were increased concurrently. In the entire organism, macrophages are able to rapidly 'switch' from one phenotype to the other depending on the micro-environment . Thus, a certain degree of overlap of phenotypes or even an 'in-between' phenotype can be expected [40, 41]. From a metabolic point of view, the M1 to M2 'switch' during critical illness seems highly beneficial as M2 macrophages are able to efficiently engulf and β-oxidize FFA, and boost insulin sensitivity [41, 42]. In this case, fasting might add some extra benefit as it is associated with a further M1 to M2 'switch' in the liver and lungs, thereby possibly protecting against ectopic lipid accumulation [43, 44]. So, quite different from what is observed in obesity, during CI, M2 macrophages predominate. Altogether with the newly-formed adipocytes, M2 macrophages could prevent or reduce ectopic lipotoxicity [5, 45]. We previously documented an increased expression of PPARγ as a possible trigger for the M2-phenotyping switch, and not the classically expected cytokines Il-4 or Il-13 . In this study, we confirmed an increase in PPARγ, the master regulator of both adipogenesis and M1 to M2 switching [46–48]. Possible activators for PPARγ are circulating fatty acids and locally produced prostaglandins .
To assess the clinical relevance of the findings in the septic mouse model of CI, we studied human subcutaneous AT biopsies harvested from adult ICU patients, who participated in a RCT in which 'early initiation of parenteral nutrition' was compared with 'tolerating nutrient restriction' during the first week in ICU . In these biopsies, taken in vivo after one week of illness in the ICU, we observed comparable alterations as in the mice. In critically ill humans, we could indeed demonstrate increased adipogenic markers and M2 macrophage accumulation, irrespective of nutrition.
The following limitations of the study should be highlighted: First, a sham group with surgical instrumentation required for the CLP model was not added. This was done as the key question was the impact of critical illness versus health and the role of nutrition versus nutrient restriction during critical illness. The surgical instrumentation and the treatment aspects of the model were considered to be part of the critically ill condition and its treatment. Second, we a priori postulated a difference between CLP-fed and healthy-fed mice, with no difference between CLP-fed and CLP-restricted mice. For the second negative hypothesis, the study may not have been specifically powered.
Adipogenesis and M2 macrophage accumulation in AT appears to be a hallmark of critical illness, independent of nutritional intake. Accumulation of M2 macrophages is present not only in AT, but also in the liver and lungs suggesting an important global role during illness. Further investigation of the metabolic meaning and underlying triggers of these alterations may shed light on the function of adipose tissue during critical illness and its potential role in the "obesity paradox".
Adipogenesis and accumulation of tissue M2-macrophages are hallmarks of prolonged critical illness, irrespective of nutritional management.
M2-macrophages accumulate not only in AT, but also in the liver and lungs.
body mass index
CCAAT/enhancer binding protein-β
chemokine (C-C motif) ligand 2
cecal ligation and puncture
free fatty acids
hormone sensitive lipase
intensive care unit
inducible nitric oxide synthase
proliferating cell nuclear antigen
peroxisome proliferator-activated receptor γ
tumor necrosis factor-α
total parenteral nutrition.
This work was supported by long-term structural Flemish funding Methusalem (GVdB), Belgian government. For the development of our mouse model, we are very grateful for the expert technical assistance from Professor Dr. Peter Radermacher and Professor Dr. Enrico Calzia, Dr. Katja Baumgart, and Sandra Weber, from Ulm University, Germany; Professor Dr. Christopher P. O'Donnell and Lia C. Romano from Pittsburgh University, USA; and Professor Dr. Daniel Teitelbaum from the University of Michigan, USA. We thank the control volunteers, patients and family members for participating in the study. We acknowledge Alexander Wilmer MD PhD and Yves Debaveye MD PhD for their contribution to the harvesting of biopsies from critically ill patients. We would like to thank Professor Dr. Frank Van der Aa (Urology UZ Leuven) and Professor Dr. Marc Miserez (Abdominal Surgery UZ Leuven) for allowing us to harvest adipose tissue biopsies from their patients.
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