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Journal of Pediatric Endocrinology and Metabolism

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Volume 27, Issue 7-8 (Jul 2014)

Issues

Common approach to childhood obesity in Japan

Toshihide Kubo
  • Corresponding author
  • Department of Pediatrics, National Hospital Organization, Okayama Medical Center, 1711-1 Tamasu, Naka-Ku, Okayama 701-1192, Japan
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Published Online: 2014-05-08 | DOI: https://doi.org/10.1515/jpem-2014-0047

Abstract

Although the prevalence of childhood obesity is plateauing, it remains a social concern. The Japan Society for the Study of Obesity devised criteria for obesity disease as a morbid state that requires medical treatment in 2002. Moreover, the Japanese Ministry of Health, Labour and Welfare announced diagnostic criteria for childhood metabolic syndrome in 2010 because of the increasing number of children with lifestyle-related diseases. The treatment of obesity needs to be prioritized, and three principles, other than behavioral therapy, have been introduced in this study for the general medical treatment of obesity without underlying diseases: (1) diet therapy, (2) exercise, and (3) no pharmacotherapy. However, preventing obesity is more important than its treatment. A previous study reported the tracking of an overweight status from infancy; therefore, it is important to prevent infants from becoming overweight. The concept of the developmental origins of health and disease has been attracting more attention in recent years; however, preventative measures prior to birth should also be considered to reduce the incidence of obesity. Although the methods used to approach the treatment of childhood obesity change with differences in race or lifestyle, those who are engaged in the medical treatment of childhood obesity worldwide can contribute to its treatment and prevention by a mutual exchange of information.

Keywords: children; developmental origins of health and disease; lifestyle related disease; obesity; overweight

Lifestyle-related diseases and obesity

Lifestyle-related diseases, a social concern in adults, are now being reported in children. A lifestyle-related disease in adults has been defined as a clinical condition in which lifestyle, such as eating habits, exercise routine, rest, smoking, and drinking, contribute to the development of symptoms and disease progression. In contrast, a childhood lifestyle-related disease has been defined as a disease that develops and progresses due to the influence of a caregiver’s lifestyle on a child’s feeding behavior and living activities from childhood. Childhood lifestyle-related diseases include hypertension, obesity, diabetes mellitus, and hyperlipidemia, which have also been reported in adults. Health checks need to be enforced in medical institutions in order to diagnose hypertension, diabetes mellitus, and hyperlipidemia in children. Periodical body measurements are currently being conducted at least once every term (every 3 to 4 months) at schools in Japan, which has led to the early detection of obesity in Japanese children. Obesity has been closely associated with hypertension, diabetes mellitus, and hyperlipidemia. Therefore, a focus needs to be placed on obesity and its early detection, early treatment, and prevention to reduce the incidence of lifestyle-related diseases in children.

What is obesity?

Being overweight refers to a state in which body fat is increased. Obesity has been attributed to the complex interplay between genetically determined body characteristics, appetite, nutritional intake, physical activity, energy expenditure, and environmental factors. On the other hand, complex syndromes are also associated with obesity such as Prader-Willi syndrome, hormonal disorders that result in weight gain such as Cushing’s syndrome, and gaining weight due to the adverse effects of medication such as corticosteroids. However, these underlying diseases can be ruled out in 90% of cases of childhood obesity in Japan.

How does fat accumulate?

Body fat accumulates in two ways. (1) Adipose cell multiplication: an increase in the number of adipose cells, which store fat. An increase has been reported in the number of adipose cells, especially in the infant and adolescent stages. (2) Adipose cell hypertrophy: adipose cells increase in size in order to store fat, and this has been implicated in adult obesity.

Trend in childhood obesity

The incidence of childhood obesity has been increasing worldwide in both developed and developing countries, as shown in Table 1 (1). However, Olds and his colleagues recently collected data from Australia, China, England, France, the Netherlands, New Zealand, Sweden, Switzerland, and the United States, and demonstrated that the prevalence of being overweight and obese appeared to stabilize at different levels in different countries (2). Differences in the prevalence of overweight schoolboys in Japan between 1977 and 2005, which was determined by the percentage of overweight (POW, described below), are shown in Figure 1A. Although the prevalence of overweight children increased until 2008, it appears to have decreased recently. Girls in higher-grade classes generally want to be thin, which may have led to a slight decrease in the number of overweight children (Figure 1B).

Table 1

Prevalence of overweight children in developed and developing countries.

(A) Changes in the prevalence of overweight children: a comparison between 1977 and 2005. (B) Changes in the prevalence of obesity in 2012: a comparison between boys and girls. yr, year.
Figure 1

(A) Changes in the prevalence of overweight children: a comparison between 1977 and 2005. (B) Changes in the prevalence of obesity in 2012: a comparison between boys and girls.

yr, year.

A clear positive association was observed between overweight children and income and educational levels, with urban-rural differences also been noted in China (Table 2) (3). In contrast, the prevalence of obesity, as judged by POW, was slightly higher in a public elementary school than that in an elite school affiliated with a university (Figure 2). Furthermore, an inverse correlation was observed between the prevalence of overweight adult women and income in Japan.

Table 2

Prevalence of being overweight and obesity among children aged 7–12 years old in rural and urban populations and various income and education levels defined by parental status, China 2002.

Comparison of the prevalence of obesity between two elementary schools.
Figure 2

Comparison of the prevalence of obesity between two elementary schools.

Indices to measure being overweight and obesity

The POW and body mass index (BMI) are generally used as indices to evaluate weight in Japan. POW is an appraisal method that is unique to Japan and has been used to periodically measure the weight of most children (4). POW is calculated as 100×(the measured weight – normal weight)/normal weight (%). Normal weight data based on age- and sex-specific standard body weights for height were obtained from the Ministry of Education, Culture, Sports, Science and Technology. POW ≥15% is considered to be mildly overweight, ≥20% moderately overweight, and ≥30% severely overweight in children <6 years old, and ≥20% mildly, ≥30% moderately, and ≥50% severely overweight in children 6 years or older. Theoretically, POW is not influenced by height; therefore, it is a convenient, highly useful index for comparing time-dependent changes. However, comparisons with other countries are difficult because POW is an index that is solely used in Japan.

Based on a recent investigation by the International Obesity Task Force, BMI is assumed to be an index of fat accumulation in children. Although it is not necessarily ideal, international cutoff points for being overweight and obese have been reported by Cole et al. (5). BMI is considered to be a very simple measurement because it is calculated as body weight (kg)/height2 (m2). However, due to age-dependent variations in the BMI, as shown in Figure 3 (6) it is difficult to examine time-dependent changes based on absolute values. BMI percentiles and standard deviations specific to Japanese people have recently been determined (7, 8).

BMI in relation to age from infancy to early adulthood in Japanese girls (mean±SE). y, year.
Figure 3

BMI in relation to age from infancy to early adulthood in Japanese girls (mean±SE).

y, year.

Although percentage body fat (%BF) is theoretically an ideal index that can be used to determine whether an individual is overweight, %BF measurements are not commonly recorded because a measuring device is required. Although %BF measurements by dual energy X-ray absorptiometry (DXA) were previously shown to be accurate, a bioelectrical impedance analysis (BIA) method was developed to take accurate measurements in children. Although the accuracy of BIA was reported to be slightly less than that of DXA, it has the important practical advantages of being simple and cheap to use. Figure 4 shows the %BF measured using BIA in relation to age in a primary school (9). Although diagnostic criteria have been established for obesity on the basis of %BF in Japan (Table 3), establishing a normal value for %BF has been difficult because a measuring device is not commonly used and these diagnostic criteria have not yet been widely applied. Therefore, the Japan Pediatric Society presently recommends POW as the 1st index of obesity. However, the combined use of BMI and POW will henceforth be needed in Japan because POW is not used in Europe or the United States, thereby making comparisons with various data in Western countries difficult.

Total percentage body fat (%BF) in relation to age. y, year.
Figure 4

Total percentage body fat (%BF) in relation to age.

y, year.

Table 3

Evaluation of obesity based on the percentage of body fat (%BF).

Deviations have been reported in POW, BMI, and %BF in adults, for example, due to sports people. An ideal example is the former yokozuna (champion sumo wrestler) Chiyonofuji, who was 183 cm and 127 kg, with POW 72.3% and BMI 37.9 kg/m2, but %BF of only 13%. However, this is not applicable to children because strong correlations have been reported between %BF and POW or BMI in children, as shown in Figure 5 (9). On another front, this figure shows a stronger correlation between %BF and BMI than that between %BF and POW. Therefore, BMI may be more useful than POW for examining fat distribution.

Correlation between BMI, POW, and %BF in primary school children.
Figure 5

Correlation between BMI, POW, and %BF in primary school children.

The cause of childhood obesity

Genetic factors have been implicated in childhood obesity. The BMI of monozygotic twins correlated well irrespective of whether they were reared together or separately. On the other hand, the correlation of BMI in dizygotic twins was shown to be similar to that of their siblings (10). The children of obese parents are more likely to become overweight than those of normal weight parents. We conducted a study on young women in Japan (6) and showed that the prevalence of overweight subjects with either one or two overweight parents was high. In addition, children with two overweight parents were slightly more overweight than those with only one overweight parent. Since early humans were exposed to periods of starvation, “thrifty genes” responsible for storing fat and reducing energy consumption have been conserved in the human genome (11). However, because this genotype efficiently prepares individuals for periods of famine, it appears to be obsolete in first world societies in which there is a constant abundance of food; therefore, this mismatch between the environment in which the brain evolved and the environment of today has led to widespread chronic obesity. Furthermore, Prader-Willi syndrome, Bardet-Biedl syndrome, and Alstrom syndrome have been associated with hereditary obesity.

Lifestyle choices, such as overeating and a lack of exercise, have also been implicated in childhood obesity. Formula-feeding and mixed nutrition have been shown to lead to a higher prevalence of overweight infants that that of breast-feeding. Moreover, the early start of baby food and excess seasoning has also led to an increase in the number of overweight infants. The unwholesome lifestyle and eating habits associated with later childhood and adolescence have also been implicated in the development of obesity, such as the preference for fast food, omitting breakfast, midnight snacking, playing video games, attending cram schools, refusing to go to school, and buying and eating food with pocket money. The link between “screen time” and obesity, cardiovascular risk factors, negative health indicators, and physical inactivity has been well documented (12, 13).

Many other problems including an altered appetite center, psychogenic factors, and adipose cell hypertrophy have also been linked to the development of obesity.

Consequences of childhood obesity

Table 4 shows examples of the consequences of childhood obesity.

Table 4

Consequences of obesity.

Hypertension

Essential hypertension has been reported in 0.1%–1.0% of children in Japan and being overweight as well as family histories are important risk factors. Nishina et al. suggested that visceral accumulation caused hyperinsulinemia and resultant hypertension in obese children, and concluded that systolic blood pressure was associated with hyperinsulinemia, hyperleptinemia, and the visceral accumulation of fat regardless of a family history of hypertension in obese children (14). The incidence of hypertension and higher blood pressure within normal limits was shown to be higher in obese children than in normal weight children (15). Therefore, improving lifestyles by changing to healthy eating habits and exercise is first needed to resolve obesity in order to treat the hypertension associated with this disease.

Hyperlipidemia

Hyperlipidemia includes primary hyperlipidemia as a hereditary disease, and secondary hyperlipidemia due to being overweight, and renal disease. The frequency of primary hyperlipidemia was previously shown to be higher in children than in adults. On the other hand, the prevalence of childhood obesity increased when Japanese eating habits became Westernized following the Second World War, and consequently consisted of a high energy and high fat diet. The severity of hypertriglyceridemia and hypercholesterolemia increases with weight. Hyperlipidemia in childhood and adolescence is a major factor that leads to the development of arteriosclerosis. Almost all cases of hyperlipidemia accompanying childhood obesity can be resolved with weight loss. However, because the prevalence of primary hyperlipidemia unrelated to body weight is high in children, differential diagnoses are needed when hyperlipidemia is reported.

Diabetes mellitus

Non-insulin-dependent diabetes mellitus (NIDDM) has been reported in 3–5 per 100,000 Japanese school children. Being overweight is an important risk factor for diabetes as well as the family history, and insulin resistance as a result of being overweight has been shown to trigger the onset of NIDDM. In contrast, 75%–85% of children with NIDDM are overweight. Good glycemic control is difficult in children with NIDDM unless weight control is practiced.

Other metabolic problems

Hyperuricemia

Most childhood cases of hyperuricemia are asymptomatic primary hyperuricemia. Although the prevalence of gout is increasing in young people in Japan, it is rare in children. A previous study showed that approximately 20% of overweight children had hyperuricemia and this correlated with POW (16).

Fatty liver

Hepatic dysfunction has been reported in 20%–25% of overweight children, with the main cause being fatty liver. Some cases have presented histology similar to that of alcoholic liver injury and have subsequently been diagnosed with nonalcoholic fatty liver disease (NAFLD). The prognosis of these patients is not good because some cases of NAFLD progress to nonalcoholic hepatitis (nonalcoholic steatohepatitis: NASH), which is a serious illness type from childhood.

Other physical abnormalities

Acanthosis nigricans occurs at the neck, axilla, elbow, and knee. It is an index of insulin resistance and also a useful physical symptom that indicates a risk of abnormal glucose tolerance or NIDDM. Striae cutis, thigh sores, joint obstacles, amenorrhea, and precocious puberty have also been reported. Moreover, the prevalence of gastroesophageal regurgitation was shown to be higher in obese children than in nonobese children (17).

Mental problems

While obesity is not classified as a psychiatric disorder, it can manifest several psychological symptoms (18). Mental anxiety arises as a result of being overweight and causes a vicious cycle in which stress increases weight gain. School refusal, psychogenic cough, pollakiuria, trichologia, irritable colon, and psychogenic vomiting have also been reported. Furthermore, depression, low self-esteem, disordered eating, signs of depression, worsening school performance, social isolation, and problems with bullying or being bullied have been identified as associate comorbidities (19).

Britz et al. reported that 42% of obese children met the Diagnostic and Statistical Manual IV criteria for a mood disorder and 40% for an anxiety disorder (20). Heskethe et al. showed a direct correlation between baseline BMI and low self-esteem (21).

Metabolic syndrome

Metabolic syndrome is the disease concept of merging dyslipidemia, hypertension, and carbohydrate metabolic disorder in the same individual based on visceral fat obesity. Diagnostic criteria have recently been established for metabolic syndrome in children by the Ministry of Health, Labour and Welfare in Japan (Table 5). The waist circumference (WC) standard, which is original in Japan, was established in these criteria. WC was correlated with the visceral fat area using computed tomography scans, and more accurately reflects the risk of complications than POW or %BF. Iwashima et al. also demonstrated that an increase in WC was related to cardiovascular risks in Japanese adolescents and concluded that WC was the most sensitive marker in the detection of arterial elasticity, even in school age children (22). Metabolic syndrome has been reported in 0.2%–2% of all children in Japan and in 10%–35% of overweight children. However, the validity of this finding needs to be confirmed in future studies.

Table 5

Diagnostic criteria for metabolic syndrome in Japanese children (6–15 years).

Obesity disease

Obesity has been attributed to health disturbances (medical abnormalities) due to or related to excessive weight gain, refers to a morbid state that requires medical treatment to reduce body weight, and is dealt with as a disease unit. The Japan Society for the Study of Obesity defined obesity in children as POW not <20%, and %BF agrees with the criteria shown in Table 3, while the items shown in Table 6 have been adopted in the diagnostic criteria for obesity disease (23).

Table 6

Diagnostic criteria of obesity disease.

Tracking

Tracking of an overweight status is well-known. In Japan, 80% of overweight infants became overweight schoolchildren, approximately half of overweight children became overweight adolescents, and 80% of overweight adolescents became overweight adults. In our vertical section investigation of 244 Japanese women, a positive relationship was found between the physical characteristics of children aged over 5 years old and that of adults (Table 7) (6), and tracking of one fourth of 3-year-old overweight children to overweight adults was observed (Table 8) (6).

Table 7

Pearson’s correlation coefficients showing associations between adult BMI (ABMI), BMI, and POW at each age.

Table 8

Percentage of subjects remaining in the same category at subsequent ages and at adulthood.

Prophylaxis

It is important to achieve weight control from infancy because tracking of an overweight status, as described above, has been reported from infancy. The final goal in reducing the prevalence of overweight children is to prevent visceral fat obesity, which is associated with health disturbances. As a primary prevention strategy, we attempted to prevent infants from becoming overweight. After later childhood, children are educated on body awareness as a secondary prevention strategy, which helps them to recognize increases in body weight and take the appropriate steps. The treatment of obesity, as a health disturbance due to excess weight after later childhood, is the third prevention strategy.

We previously reported that 30% or less of women who were overweight at 3 and 6 years old continued to be overweight in adulthood (Table 8), and also showed that adiposity rebound (AR) generally occurred at the age of 7 in Japanese women (6). Moreover, an increase in BMI between 7 and 8 years of age showed a positive correlation with adult BMI. On the other hand, an early AR has been associated with an increased risk of being overweight (24). Taylor et al. reported a significantly greater increase in fat mass velocity from 5 years of age in children with early AR (25). These findings indicated that the AR appears to be a useful indicator to predict adiposity for pediatricians, and early intervention before school age at the latest is necessary to prevent childhood obesity.

In line with the concept for the developmental origins of health and disease (DOHaD) (26) which has been generalized in recent years, the delivery of optimal-birth-weight neonates as an advanced, preventive approach is advocated.

In 1990, Barker and his colleagues promoted the concept of the fetal origin of adult disease (FOAD) (27, 28). They reported that newborn infants with low birthweights died of ischemic heart disease, or were more likely to develop acquired cardiac disease, essential hypertension, and NIDDM in adulthood. In Japan, the number of low-birth-weight infants with a birth weight of <2500 g is increasing. The incidence of low-birth-weight infants accounted for 5% of all births in the 1980s; however, this increased to 9.6% in 2009. Although these figures reflect the high level of neonatal care in Japan, it has also been attributed to the strong desire of young women in Japan to be thin, and babies born to these women are more likely to have low birth weights than those born from normal weight mothers. Therefore, measures taken from before birth are also important for the prevention of obesity.

Gluckman and Hanson also advocated the concept of DOHaD in 2004 (29), as described above. Environmental factors during developmental plasticity have been suggested to interact with genotypic variations, thereby changing the capacity of the organism to cope with its environment in later life. If developmental plasticity matches the environment at the time in which growth is completed, humans can be healthy; however, it is also the source of various diseases in adulthood if it does not match. Therefore, not only the intrauterine environment, but also that after birth (especially the nutrient state in the newborn and infant stage) is related to the risk of the onset of adulthood chronic disease in later life. Therefore, a rapid increase in the weight of a low-birth-weight infant does not necessarily contribute to the infant’s health. Therefore, breast-feeding is considered to be ideal nutrition for the prevention of future lifestyle-related diseases. Although breast-feeding may have slightly reduced the prevalence of overweight adults in our study (data not shown), we cannot confirm the benefits of breast milk due to many confounding factors and the lack of concrete evidence. Yamakawa et al. recently reported that breast-feeding was associated with a decrease in the risk of being overweight and obesity at 7 and 8 years of age, respectively, in schoolchildren in Japan (30).

In contrast, Curhan and his colleagues reported a clear relationship between high birth weights and the development of obesity in adulthood (31). Overall, it has been suggested that pregnant woman should give birth to babies at the proper weight. Namely, the prevention of obesity from infancy alone is inadequate, and it is important to tackle prevention from before birth and early after birth.

Instructions and treatment

Three principles have been introduced for the general medical treatment of obesity without underlying diseases as follows: (1) diet therapy, (2) exercise, and (3) no pharmacotherapy. Although behavioral therapy is also performed, it will be discussed in detail in other sections.

Lifestyle interventions

Lifestyle interventions are recommended as the primary treatment for childhood obesity and generally comprise diet and exercise interventions that involve the use of behavioral therapy techniques. As described in detail in the review by Reinehr, successful lifestyle interventions are frequently based on behavioral therapies (32), which stress the development of new eating and exercise habits and provide specific strategies for changing the individual’s environment. Behavioral therapies include impulse control techniques, self-instruction, cognitive restructuring, development of problem-solving strategies, behavioral contracts, booster systems, self-reflection curves, and model learning via parents. Although lifestyle interventions are more likely to fail if there is no cooperation by the family and are generally not very effective for severely obese children, it should be offered primarily to children with a real chance of success.

Diet therapy

A child and his caregiver should receive information from a dietitian on how to improve their eating habits and the types of food consumed. Caloric restriction is then conducted if needed to confirm the level of comprehension by the child himself and his caregiver. Meal instructions are given based on the records provided by the caregiver, indicating the meals eaten in the past 3 days, including snacks. The child may be hospitalized if necessary. The most important consideration of diet therapy is that the child is growing; therefore, an increase in bone and muscle mass, and decrease in fat mass, not simply a reduction in body weight, is desired. Since body height can be extended, an improvement in body weight may be obtained by just maintaining the same weight. It is important that the treatment does not become a serious obstacle when the patient takes part in group activities. For example, if meals are being served to children at a school canteen, the child can eat the meal. Moreover, cooperation at home is crucial, and the caregiver must not force excessive dietary restrictions upon the child. The cause of childhood obesity has mainly been attributed to the bad lifestyle choices of the adults responsible, as previously described in the definition of lifestyle-related diseases in children. As an extreme example, it is unreasonable to deprive a child of a midnight snack by saying, “Do not eat it, or you will grow fat” when the caregiver or the child’s siblings are eating the food. The caregiver also must stop eating midnight snacks to improve his health. One more important point is that instructions for children must not be too strict. Even when dietary restrictions are enforced, the child must also receive praise and a reward.

Exercise therapy

A child may be unable to reduce his weight by exercise alone. Furthermore, many overweight children do not enjoy exercise. Previous studies have shown that forcing an overweight child to exercise suddenly can lead to injuries, resulting in further increases in body weight. Therefore, it is more beneficial to make an overweight child continue to perform a fixed amount of exercise every day rather than making him participate in group exercise a few days a week. Exercise resulting in the consumption of 100–200 kcal each day is appropriate, and aerobics is considered an ideal exercise for fat metabolism. Walking or cycling to school is also a good form of exercise. When the above activities cannot be performed, helping with household chores may also be used to increase the level of physical activity by an overweight child, including cleaning the bathroom, watering the flowerbeds, and rearranging tableware after a meal.

Pharmacotherapy

Pharmacotherapy is generally not used to treat childhood obesity. Oristat, a gastrointestinal tract lipase inhibitor that decreases intestinal fat absorption, and Sibutramine, an antiobesity agent that acts as a nonselective inhibitor of serotonin and noradrenalin reuptake at the presynaptic cleft, thereby stimulating the satiety center, are widely prescribed in many countries (33). However, these two medicines cannot be prescribed for children in Japan. Although appetite depressants, such as Mazindol, may have to be used, an adaptation standard has been set in Japan of not <70% of POW or a BMI of 35 or higher. Mazindol is sometimes used in Japan in the case of extreme obesity in adolescence or Prader-Willi syndrome. Moreover, the efficacy of Bofu-tsusho-san, a Chinese medicine tablet, which reduces body weight by activating brown adipose cells, has been reported. We prescribe Bofu-tsusho-san to mild obesity children and have observed consistent effects. A previous study also demonstrated that Metformin hydrochloride, an insulin sensitizer indicated for the treatment of insulin resistance in type 2 diabetes that may reduce appetite by increasing glucagon-like-peptide levels, was effective in reducing body weight (34).

Others

Daily weight measurements are effective, especially before supper. Early elementary school children have been asked to write their weights in a calendar, and upper-grade elementary school children have created graphs. If children can develop an understanding of the numbers they are writing down, the psychological effect of this activity may have a positive impact on their weights.

Group guidance

School-based obesity-prevention interventions are important. As described above, the prevalence of obesity was shown to be higher in a public school than in an elite school (Figure 2). However, the overall %BF with age-related changes was slightly higher in the elite school, as shown in Figure 6. Therefore, when a school nurse notes weight gain trends in the entire school, it is necessary to determine whether she should put weight on group or individual guidance.

Comparison of %BF between two elementary schools. y, years.
Figure 6

Comparison of %BF between two elementary schools. y, years.

Surgery

Three main surgical procedures are used in the treatment of obesity: gastric restriction, a malabsorptive procedure, and extended roux-Y gastric bypass. In Japan, a BMI ≥40 or BMI ≥35 associated with severe disease is indicated for surgery; however, this is contraindicated for children in principle. Surgery may be indicated for severe cases of Prader-Willi syndrome.

Conclusions

This article introduced a unique approach to childhood obesity in Japan. Although the prevalence of childhood obesity is plateauing, the social concern associated with childhood obesity remains. The methods used to approach childhood obesity change with differences in race or lifestyle; therefore, those who are involved in childhood obesity worldwide can contribute to the treatment and prevention of this disease by a mutual exchange of information.

Conflict of interest statement

Author conflict of interest disclosure: There is no conflict of interest to declare.

Ethical approval: This review was approved by the NHO Okayama Medical Center Ethics Committee.

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About the article

Corresponding author: Toshihide Kubo, MD, PhD, Department of Pediatrics, National Hospital Organization, Okayama Medical Center, 1711-1 Tamasu, Naka-Ku, Okayama 701-1192, Japan, Phone: +81-86-294-9911, Fax: +81-86-294-9255, E-mail:


Received: 2014-01-29

Accepted: 2014-03-28

Published Online: 2014-05-08

Published in Print: 2014-07-01


Citation Information: Journal of Pediatric Endocrinology and Metabolism, ISSN (Online) 2191-0251, ISSN (Print) 0334-018X, DOI: https://doi.org/10.1515/jpem-2014-0047.

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