Childhood obesity: a health problem gone global

Childhood obesity has been of medical interest for more than 150 years1, 2. Until the middle of the 20th century the prevalence of obesity in the general population of the United States was relatively moderate3. However, in the last two decades the prevalence has risen to epidemic proportions4, 5, 6. In fact, 34.4 percent of the population of the United States are now considered overweight (and not obese) and 33.9 percent are considered to be obese7, affecting more than 200 million people. Similarly, the number of children diagnosed with obesity and/or obesity-related diabetes has been continuously increasing over the past 20 years in countries around the world8, 9, 10. In 2010 in the United States, 17 percent of children and adolescents were obese – including those with severe obesity11, with the prevalence of obesity having tripled since 19803. Particularly worrisome is the 10.4% prevalence of obesity among the 2 to 5 year olds in the US12, with other parts of the world catching up13, 14. The World Health Organization (WHO) defines obesity (in adults: BMI >30 kg/m2) as a disease for which excessive calorie intake, in conjunction with lack of physical exercise, have been identified as major predisposing and aggravating factors15, 16. Obesity also serves as soil for the development of other diseases15, particularly insulin resistance (pre-diabetes), type 2 diabetes mellitus, arterial hypertension, dyslipidemia/hypertriglyceridemia, and fatty liver disease/non-alcoholic steatohepatitis (NASH)15, 17, 18. At the same time, obesity also worsens these conditions once they have developed15. In addition, mutations in certain genes such as the leptin receptor are associated with early-onset childhood obesity and excessive body mass indices19, 20, 21. High birth weights or diabetes of the mother (pregnancy-associated diabetes) have been proposed as potential factors affecting postnatal health, and lack of breastfeeding has been suggested to contribute to a higher risk for obesity during adolescence22. A number of other factors have been associated with a higher risk to develop obesity, which include the disease susceptibility of certain ethnic groups, poverty and/or low socioeconomic status, which are often associated with a low health concerns/self-concern3, 7. By contrast, some Asian countries such as Japan which have a very low overall prevalence of obesity23. This may be in part due to composition of Asian diets, while excess access to inexpensive, high calorie food has been identified as a major factor contributing to the rising number of obese children in countries such as the USA and in European countries24. Not surprisingly, childhood obesity has also been steadily growing in China where over the past decades people have in part adopted Western dietary patterns24. Increased health risk is not limited to obesity, but already apparent with overweight. Indeed, long-term studies following the health of overweight children for more than 40 years found significantly increased risks for a number of diseases25 (Figure 1).

Figure 1
figure 1

Aggravating effect of childhood obesity on the life-time risk for other disease conditions, including a greater risk for adult obesity, which itself continues to worsen disease development.

Atherosclerosis begins in childhood

Obese children are at a higher risk for accelerated development of vascular disease26, which is aggravated by the worsening of risk factors secondary to obesity. Atherosclerosis, a systemic chronic inflammatory disease of the large arteries, is the main cause of cardiovascular and cerebrovascular events27. The disease accounts for the majority of deaths due to myocardial infarction and stroke in Western as well as in Eastern and developing countries27. First vascular abnormalities, inflammatory changes and plaque development can be observed in children already in the first year of life28; consistent with these observations, the disease process begins in utero, during which the precursor of the atherosclerotic plaque — the “fatty streak” — is already present29, 30. The development of fatty streaks, which represent inflammatory accumulations of macrophages in the subintimal space — is aggravated by maternal hypercholesterolemia and thus sets the basis for vascular disease later in life30. The cause of cardiovascular and cerebrovascular events most often is due to rupture of “soft” atherosclerotic plaques filled with a lipid core underlying a thinned fibrous cap27, pathological findings some of which are already present in young adults26, 31. Plaque development is accelerated in the presence of risk factors such as arterial hypertension, dyslipidemia, diabetes, male sex, and obesity, which are equally important for children and adults26, 31. Interestingly, girls and young women appear to be largely protected from the aggravating effect of obesity on plaque progression26. Among all cardiovascular risk factors, obesity is of particular importance since it aggravates several other risk factors such as arterial hypertension, insulin resistance/diabetes, or dyslipidemia.

Childhood obesity causes changes consistent with “Premature” vascular aging

Inflammation also plays a role for insulin resistance and metabolic changes associated with obesity32 and abnormal inflammatory activation has been reported to occur in obese children33. In both children and adults, obesity causes generalized injury to the vasculature. This process also involves inflammatory activation, both locally in the vascular wall32 as well as in adipose tissue34. Inflammation also underlies insulin resistance (pre-diabetes) and type 2 diabetes34, conditions originally believed to be restricted to elderly individuals, but now increasingly found in obese juveniles35, 36. Similarly, an important aspect of obesity-associated vascular injury obtained from preclinical and clinical studies, is that many of the vascular changes found in obesity are highly similar to those seen with aging37, which not only represents a physiological process but in itself represents a strong and independent risk factor for future cardiovascular events37. As with aging37, experimental or human obesity shows an attenuation of endothelium-dependent vasodilation38, 39, a decrease in NO bioactivity38, 39 in conjunction with NO synthase uncoupling37, an increase in prostanoid-mediated endothelium-dependent contractions40, 41, 42, telomere shortening43, 44, 45, 46, increased vascular stiffness47, and increased arterial intima-media thickness26, 48. Obesity also increases tissue levels of endothelin-138, 49, 50, a strong vasoconstrictor peptide and atherogenic growth factor and proinflammatory stimulus51. Picard and Guarente recently reported interactions between life-span regulating genes and adipose tissue functions52. Thus, obesity can be considered a process which is compatible with accelerated aging which may — at least in part — explain the accelerated atherosclerosis development in children and young adults with obesity26.

Potential role for post-natal dietary vascular programming

A few years ago results from two clinical studies were reported that childhood obesity is associated with a several fold increased risk for cardiovascular events in adult life, even if body weight had meanwhile normalized9, 53, 54. These very intriguing observations, which are in part supported by an earlier study55, not only emphasize the importance of childhood obesity prevention but also suggest that still unknown mechanisms exist that must be set-off by the “childhood obesity environment” and, once activated, remain irreversibly active until later in life irrespective of changes in body weight. Thus, possible local “post-natal dietary programming” mechanisms may contribute to the underlying disease-promoting process in the arterial wall. Alternatively, acceletated progression of atherosclerosis in youth due to obesity may simply lead to established, irreversible atherosclerotic lesions that no longer can be affected by weight normalization. Indeed, advanced coronary artery disease present in their late teenage years and death from myocardial infarction has been described in young men exposed to extremely high stress conditions56, 57.

Continued need for disease prevention

Aside from highly complex disease processes, simple factors such as overnutrition and lack of knowledge about obesity prevention, respectively, are likely to be at least equally important. This can be exemplified by a case report from Germany where parents fed their infant almost exclusively with sugared water58. This infant developed severe obesity and at 2 years of age, was diagnosed with early cerebrovascular disease58 similar to increased vascular stiffening found in obese juveniles59, conditions normally found only at much later stages in life. Not surprisingly, reducing body weight in obese juveniles is associated with markedly improved cognitive function60, and recent data suggest that even cerebral and cerebellar development is negatively affected by childhood obesity61. Thus, awareness and education of parents12, educators, and pediatric medical staff should remain one of the key goals in order to achieve prevention of childhood obesity which, subsequently, should also result in a reduction of diseases associated with it. One of the questions is how we can monitor vascular health. The function of the vasculature, particularly endothelium-dependent vasomotion, reflects quite well the overall health status of the arterial system62. Human obesity, characterized by accumulation of ectopic (particularly visceral) fat63, is associated with abnormal endothelium-dependent vasomotion and enhanced contractility to endothelin-164, 65. Accordingly, a reduction in energy intake66 or reduction in body weight67 improves vascular function in obese patients. In human resistance arteries obesity is associated with vascular hypertrophy as indicated by an increased media-to-lumen ratio68, and a recent important study demonstrated that functional vascular abnormalities observed in obese individuals can be largely normalized by lowering body weight by reducing intra-abdominal fat mass in adults67. Thus, any reduction of obesity — in children as well as adults — is likely to translate into improved overall health and survival4, 15, 69. Indeed, preserved endothelium-dependent vasoreactivity is associated with greater survival in patients with cardiovascular disease62. Possibly, reducing subcutaneous fat may also have some beneficial effect on the pro-inflammatory risk profile70, 71.

Physical activity as therapeutic

The question remains of how to achieve a sustained reduction of childhood obesity, both at the individual level as well as for overall prevalence72. One of the central components of obesity prevention and therapy or – if absent a promotor of obesity — is physical exercise4, 73, 74, 75. Physical inactivity is a key cause contributing to and worsening childhood obesity76, and has now even become a concern in developing countries77. Exercise not only has a number of beneficial effects on several risk factors associated with obesity (reduction of sympathetic activation and blood pressure, improved lipid profile, improved insulin sensitivity4, 73, 74, 75), but also improves consumption of excess energy stores of fat and thus helps to reduce adipose tissue mass78. There is recent evidence that regular exercise may even infer with cellular processes associated with vascular aging79. A most recent study indicates that vascular elasticity as a function of age is also increased in obese children compared with their lean counterparts80, indicative of accelerated vascular growth and maturation and thus compatible with early aging. It is important, both for therapy and prevention of childhood obesity, that sufficient and regular exercise becomes and remains a part of children's everyday life in conjunction with normal calorie intake. It has been recently shown that weight loss in children reduces inflammatory activation81, one of the key factors for vascular disease progression82. Caloric restriction prolongs life in a number of species, including rodents and primates83, 84. It can only be speculated that in humans “global caloric restriction” in those countries with excess access to food would have similar effects on life expectancy and overall well-being5. Indeed some countries have taken political measures such as issuing special taxes on fat as the dietary componant with highest energy value85, 86. The prevention of childhood obesity is a chance that must be taken early in life by parents, health professionals, educators, and politicians69. Fortunately, health agencies have already begun to implement this need into their information policies provided to parents12 with whom children spend the most time. If we succeed with this task of promoting, achieving, and maintaining health among children — including a regular “regimen” of physical exercise16, 87, 88 —, this will ultimately reduce the number of tomorrow's patients and enable healthy aging at a low cardiovascular risk89.