Systemic inflammation in childhood obesity: circulating inflammatory mediators and activated CD14++ monocytes.
OBJECTIVE
In adults, circulating inflammatory mediators and activated CD14(++) monocytes link obesity to its metabolic and cardiovascular complications. However, it is largely unknown whether these inflammatory changes already occur in childhood obesity. To survey inflammatory changes during the early stages of obesity, we performed a comprehensive analysis of circulating inflammatory mediators, monocyte populations and their function in childhood obesity.


METHODS
In lean and obese children aged 6 to 16 years (n = 96), 35 circulating inflammatory mediators including adipokines were measured. Hierarchical cluster analysis of the inflammatory mediator profiles was performed to investigate associations between inflammatory mediator clusters and clinical variables. Whole-blood monocyte phenotyping and functional testing with the toll-like receptor 4 ligand, lipopolysaccharide, were also executed.


RESULTS
First, next to leptin, the circulating mediators chemerin, tissue inhibitor of metalloproteinase 1, EGF and TNF receptor 2 were identified as novel inflammatory mediators that are increased in childhood obesity. Second, cluster analysis of the circulating mediators distinguished two obesity clusters, two leanness clusters and one mixed cluster. All clusters showed distinct inflammatory mediator profiles, together with differences in insulin sensitivity and other clinical variables. Third, childhood obesity was associated with increased CD14(++) monocyte numbers and an activated phenotype of the CD14(++) monocyte subsets.


CONCLUSIONS
Inflammatory mediator clusters were associated with insulin resistance in obese and lean children. The activation of CD14(++) monocyte subsets, which is associated with increased development of atherosclerosis in obese adults, was also readily detected in obese children. Our results indicate that inflammatory mechanisms linking obesity to its metabolic and cardiovascular complications are already activated in childhood obesity.
Department of Metabolic Diseases, University Medical Center Utrecht, Room STR3.217, Universiteitsweg 100, 3584 CG, Utrecht, the Netherlands.|Department of Pediatric Immunology and Center for Molecular and Cellular Intervention, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands.
H S
HS
Schipper
Department of Pediatrics, Meander Medical Center, Amersfoort, the Netherlands.
R
R
Nuboer
Department of Metabolic Diseases, University Medical Center Utrecht, Room STR3.217, Universiteitsweg 100, 3584 CG, Utrecht, the Netherlands.
S
S
Prop
Department of Virology, Erasmus Medical Center, Rotterdam, the Netherlands.
H J
HJ
van den Ham
Department of Theoretical Biology and Bioinformatics, Utrecht University, Utrecht, the Netherlands.
F K
FK
de Boer
Department of Theoretical Biology and Bioinformatics, Utrecht University, Utrecht, the Netherlands.
Ç
Ç
Kesmir
Department of Pediatric Immunology and Center for Molecular and Cellular Intervention, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands.
I M H
IMH
Mombers
Department of Pediatric Immunology and Center for Molecular and Cellular Intervention, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands.
K A
KA
van Bekkum
Department of Metabolic Diseases, University Medical Center Utrecht, Room STR3.217, Universiteitsweg 100, 3584 CG, Utrecht, the Netherlands.
J
J
Woudstra
Department of Pediatric Immunology and Center for Molecular and Cellular Intervention, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands.
J H
JH
Kieft
Laboratory for Experimental Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands.
I E
IE
Hoefer
Department of Pediatric Immunology and Center for Molecular and Cellular Intervention, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands.
W
W
de Jager
Department of Pediatric Immunology and Center for Molecular and Cellular Intervention, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands.
B
B
Prakken
Department of Pediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands.
M
M
van Summeren
Department of Metabolic Diseases, University Medical Center Utrecht, Room STR3.217, Universiteitsweg 100, 3584 CG, Utrecht, the Netherlands. E.Kalkhoven@umcutrecht.nl.
E
E
Kalkhoven
D000293:Adolescent; D016022:Case-Control Studies; D002452:Cell Count; D018925:Chemokines / Q000097:blood; D002648:Child; D016000:Cluster Analysis; D015897:Comorbidity; D004815:Epidermal Growth Factor / Q000097:blood; D005260:Female; D006801:Humans; D007249:Inflammation / Q000097:blood* / Q000453:epidemiology / Q000473:pathology*; D018836:Inflammation Mediators / Q000097:blood*; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin / Q000097:blood; D018950:Lipopolysaccharide Receptors / Q000378:metabolism*; D008297:Male; D009000:Monocytes / Q000276:immunology / Q000473:pathology*; D009765:Obesity / Q000097:blood* / Q000453:epidemiology / Q000473:pathology*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000097:blood; D012044:Regression Analysis; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
D018925:Chemokines; D018836:Inflammation Mediators; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin; D018950:Lipopolysaccharide Receptors; C478630:RARRES2 protein, human; D047889:Receptors, Tumor Necrosis Factor, Type II; D019715:Tissue Inhibitor of Metalloproteinase-1; D042461:Vascular Endothelial Growth Factor A; D004815:Epidermal Growth Factor