Pediatric obesity has become an epidemic health issue in industrialized regions. Data from the NHANES (National Health and Nutrition Examination Survey) survey (2007–2008) indicate that approximately 9.5% of infants and toddlers were at or above the 95th
percentile of the weight-for-recumbent-length growth charts, 11.9% of children and adolescents aged 2 to 19 years were severely obese (at or above the 97th percentile of the BMI-for-age growth charts), 16.9% were obese and 31.7% were overweight (1
); the European Association for the Study of Obesity (EASO) has recently shown that overweight prevalence in European pediatric population (age 7-17 years) was 16-22%, while 4-6% of children and adolescents were already obese (2
). The proportion of overweight and obese children and adolescents near doubled in 2010 compared to that reported in 1990-2003. It is estimated that in European Union almost 1.3 million children become overweight annually and that obesity incidence in the pediatric population is 300 000 new cases/year (3
Obesity is associated to a metabolic risk which evolves to a cardiovascular risk. Obesity complications, as type 2 diabetes, dyslipidemia, arterial hypertension - formerly recognized in adult obese population - have recently been described in obese children and adolescents, with continuous growing prevalence, paralleling those of overweight prevalence (4
Insulin resistance has a defined role in metabolic complications of obesity. There are several molecular mechanisms concurring to its appearance – recent years papers have demonstrated that various adipokines and cytokine derived from adipocytes per se or from others cellular elements of stromal or vascular origins in adipose tissue are responsible for insulin resistance and metabolic alterations in obese persons.
Adiponectin is the main adipokine secreted by adipocytes and the only adipokine down regulated in obesity. It has insulin-sensitizing effects through multiple mechanisms (inhibits hepatic gluconeogenesis (8
), increases glucose uptake in adipocytes (9
) and muscle cells (10
) and protective cardiovascular effects (diminishes adhesion molecules expression, smooth muscle cells proliferation, suppress macrophage transformation in foam cells, has direct antithrombotic effects (11
), stimulates nitric oxide production in small vessels (15
Plasmatic levels of adiponectin were negatively correlated with BMI, adipose tissue proportion and fasting insulinemia in different adult populations (17
) and also in pediatric populations: Pima Indians children (25
), Japanese children (26
), Taiwanese children (27
The molecular mechanism of its lower secretion in obese people is not fully understood: its down-regulation may be induced by insulin resistance or its secretion may be suppressed by high plasmatic levels of TNFα and IL-6 (18
In adults, a strong correlation of adiponectin to insulin-resistance biomarkers has been demonstrated and hypoadiponectinemia was associated to progression to type 2 diabetes (17
). A negative correlation between plasmatic levels of adiponectin and insulin-resistance was also demonstrated in pediatric populations: Taiwanese children (27
), Hispanic children (32
), Latino children and adolescents (33
Leptin, primarily adipose tissue-derived protein product of the obesity (OB) gene, originally identified as an important regulator of energy metabolism, is a multifunctional polypeptide which may be associated with the occurrence of insulin resistance and diabetes in humans.
Plasma levels of leptin showed positive correlations with BMI, WC and adipose tissue proportion in various adult populations (34
). In children, these correlations are demonstrated in a limited number of studies and for smaller groups (25
). Plasmatic levels of leptin seem to be a better predictor of future weight gain in prospective studies (38
Although in vitro
and animal models studies have demonstrated the insulin-sensitizing effects of leptin (41
) hyperleptinemia associated to obesity is associated in clinical studies with insulin-resistance in both obese adults and children (34
); this apparent discordance can be explained by a state of leptin resistance described in obese persons (46
Resistin is a protein secreted in human adipose tissue by preadipocytes (47
) and mainly by monocytes from the stromal component (48
). Resistin acquired initial attention as a potential link between obesity and glucose regulation. In rodents, resistin can induce insulin resistance, while its implication in the control of insulin sensitivity is still a matter of debate in humans. Several clinical studies have demonstrated that plasmatic levels of resistin are positively correlated to BMI (49
) while others failed to identify its correlation to adiposity (47
There are also controversies regarding resistin's correlation to insulin sensitivity in humans: several clinical studies on variable groups (obese or diabetic persons) have demonstrated that resistin is positively correlated to insulin-resistance (53
), while other population studies disproved these remarks – resistin was not correlated to insulin-resistance in Pima Indiens (52
) or healthy normal-weight individuals (55
TNFα, a protein synthesized especially by macrophages, is a cytokine implied in systemic inflammation. It is also expressed in adipocytes and is associated with obesity (58
), adipocytes cell volume (59
), and inhibition of glucose uptake in adipocytes from lean individuals (58
). TNFα is overproduced in adipose tissue of several rodent models of obesity and has a key role in the pathogenesis of insulin resistance in these species. However, its actual involvement in glucose metabolism disorders in humans remains controversial.
IL-6 production by human adipose tissue increases during obesity. It may induce hepatic C reactive protein synthesis and may promote the onset of cardiovascular complications.
Both TNF-a and IL-6 can alter insulin sensitivity by triggering different key steps in the insulin signaling pathway.
studies have shown that TNFα and IL-6 have pivotal roles in insulin resistance, acting directly at the insulin receptor (60
). Both TNFα and IL-6 are positively related to adiposity, particularly visceral fat, and correlate with insulin resistance and other CVD risk factors in adults (60
In children, data regarding IL-6 and TNFα plasmatic levels are sparse. Levels of these inflammatory markers seem to decrease with increasing age (65
) and this can become a confounding factor in interpreting results in obese pediatric population.
Although in vitro
and animal models studies have indicated a direct relationship between plasmatic TNFα and the degree of adiposity, in vivo
studies have shown that mRNA expression for TNFα in adipose tissue is not directly dependent to BMI (66
); leptin and other adipokines overexpressed in obese persons seem to stimulate TNFα production in the monocyte-macrophage system. This may be an explanation for the paucity of clinical data regarding its role in metabolic complications associated to obesity.
The adipocytokines' plasmatic levels and their correlations to classical metabolic and cardiovascular risk factors are far to be defined in adults and even less in children. ❑