Childhood obesity: evidences of an early metabolic process leading to atherosclerosis
Atherosclerosis has its beginnings in early childhood
Atherosclerotic cardiovascular disease is the most common cause of death and disability in the industrialized world. Atherosclerosis has a long preclinical phase characterized by the progressive development of artery wall damage already in childhood and young adulthood well before the clinical manifestations of disease later in adulthood. Autopsy studies as well as intravascular ultrasound studies or coronary arteriography clearly demonstrated atherosclerotic changes in the coronary arteries of adolescents and young adults(1). Moreover, increased carotid intima-media thickness as well as arterial reduced distensibility is suggestive of early atherosclerotic process also in children(2).
Obesity accelerates the risk of atherosclerosis through the Metabolic Syndrome
Some metabolic disturbances such as insulin resistance, hypertension and dyslipidemia have been clearly identified as cardiovascular risk factors and promoters of the atherosclerotic process(3). Cardiovascular risk factors have a tendency to occur in clusters especially in obese individuals characterizing the so-called Metabolic Syndrome(4). Obesity plays a central role in the development of the Metabolic Syndrome: excess of fat accumulation often precedes the development of insulin resistance, hypertension and dyslipidemia. Moreover, each of the components of the Metabolic Syndrome worsens with increasing adiposity. Consistent evidence exists on the association between childhood obesity and the Metabolic Syndrome in adulthood, as well as between early onset obesity and mortality in adulthood, independently of body size at adult age(5). Childhood obesity predicts the risk of developing a constellation of metabolic, hemodynamic and inflammatory disorders associated with cardiovascular disease. Moreover, a significant number of obese children are already affected by the Metabolic Syndrome(6).
Adipose tissue of obese children is involved in the inflammatory process
Obese children (as adults) often have low grade inflammation, as suggested by CRP, TNFalpha, IL-6 circulating levels, higher in obese than in non-obese individuals(7). The causes of inflammation in obesity are not known although an early elementary lesion in the adipose tissue of obese children has been recently demonstrated, in which macrophage infiltration is the main feature(8). Both macrophages and adipocytes secrete cytokines and inflammatory mediators which are potentially involved in the lipotoxic perturbations of liver, pancreas, and skeletal muscle as well as in endothelial cell dysfunction(9). For instance leptin, one of the most extensively studied adipokines, is directly involved in increasing angiogenic activity and oxidative stress as well as promoting vascular calcification and smooth muscle cell proliferation(10).
Interestingly, the evidence that insulin resistance may explain most of the features of the Metabolic Syndrome – but not those of inflammation – justifies the hypothesis that insulin resistance may develop independently from inflammation though it is affected by inflammatory mediators secreted in the adipose tissue and therefore may share common antecedents of atherosclerosis.
Under- or over- nutrition in early life is an independent risk factor for obesity in adulthood
Intrauterine and early postnatal life are sensitive periods for the development of the metabolic self-regulation mechanism of the organism. Consistent evidence exists on the effect of early environmental factors on the long-term phenotype, so that individuals exposed to under- or over-nutrition in early life develop a thrifty phenotype that predisposes them to obesity and its consequences later in life(11). Infants born large or small for gestational age are at higher risk of obesity and its associated disorders than infants born appropriate for gestational age(12). Moreover, a rapid weight gain in the first months of life, independently from risk co-factors, has been associated with a higher risk of obesity in young adulthood(13). The mother’s nutrition as well as infant feeding play an active role in all these processes.
Summary and conclusion
Cardiovascular disease is the most common cause of death in industrialized countries. Prevention of cardiovascular disease is done through prevention of atherosclerosis which is promoted by obesity and other disorders frequently associated with obesity, like diabetes, hypertension and dyslipidemia. Both obesity and atherosclerosis are associated with inflammation. An early elementary inflammatory lesion has been recently demonstrated in the adipose tissue of obese children, suggesting that the adipose tissue plays a central role in the development of the inflammatory process promoting atherosclerosis. Moreover, other factors such as fetal and early postnatal growth have been identified as independent risk factors for both obesity and metabolic disorders.
On the basis of this evidence, obesity prevention has to be started as soon as possible in life. Food intake in pregnancy as well as breast feeding and weaning procedures are potential sensitive targets to prevent obesity and metabolic disorders.
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