In 1994, the “Ina-machi Lifestyle-related Diseases Screening Program for School Children” was started to promote health among the school children residing in Ina-machi, Saitama Prefecture, Japan. Ina-machi is a town with a population of some 35,000 inhabitants, and is located approximately 30 km north of Tokyo, the capital of Japan. Traditionally, Ina-machi used to be prosperous in agriculture, such as fruit growing; however, it has developed in recent years into a bedroom suburb for commuters to the Tokyo area.
The activities that are currently being implemented to promote health in this town constitute an in-depth health program that consists of height, body weight, and waist circumference measurements, blood tests, and intervention in terms of lifestyle modification in those in whom such intervention is deemed necessary based on screening results. These activities are being implemented as an add-on program to the annual health checkup program which is in place as a lawfully mandatory measure in Japan.
In this study, we investigated which of the adipocytokines examined (leptin, adiponectin and resistin) might predict the future development of atherosclerotic disease among all the elementary school 4th graders in this town by examining these adipocytokines for correlation with the cardiovascular risk factors, i.e., AI, which is a minimally invasive and convenient test, waist circumference, W/H ratio, and BMI.
Furthermore, we investigated whether any association between the adipocytokines and cardiovascular risk factors examined might be altered in the subjects with obesity, a risk factor for atherosclerosis, and if so, which adipocytokine might be closely associated with the cardiovascular risk factors.
As shown in a study of adult obese patients with type 2 diabetes by Satoh et al (15) that the L/A ratio is better correlated with Pulse Wave Velocity (PWV) as an index for atherosclerosis, than leptin or adiponectin, not only leptin and adiponectin but L/A ratio were used in this study. Again, as resistin, adiponectin and R/A ratio have been reported to be differently associated with cardiovascular risk factors, resistin, adiponectin, and R/A ratio were also examined in the subjects for association with cardiovascular risk factors. Furthermore, as the W/H ratio has been reported in a study of Japanese school children by Hara et al (16) to be the best predictive factor among the cardiovascular risk factors including BMI, percent body fat, waist-to-hip ratio, and waist circumference, the W/H ratio was included among the cardiovascular risk factors to be examined, in addition to BMI and AI.
Clinical characteristics of the school children
There was a significant gender difference in BMI, leptin and the L/A ratio between the pre-pubertal boys and girls aged 9 to 10 years, with the leptin level particularly shown to be higher in the girls at 3.55 ng/mL than in the boys at 2.80 ng/mL (Table 1).
While leptin is generally known to vary greatly in serum concentration depending on the presence or absence of obesity, leptin is also reported to be positively correlated with subcutaneous fat mass (17,18). However, as shown in Table 1, BMI as an index for obesity was shown to be greater in the boys than in the girls, and waist circumference as an index for subcutaneous fat mass was not significantly different between the boys and girls, which made it difficult to account for the significantly higher leptin level in the girls compared to the boys. However, when the subjects were grouped by gender into obese and non-obese individuals (Table 2), the leptin level was shown to be significantly higher and the adiponectin level was shown to be significantly lower in the obese individuals, suggesting that these adipocytokines are significantly different between those with obesity and those without.
The leptin level was shown to be significantly different between the genders, regardless of the presence of obesity or of the subcutaneous fat mass present (Table 1), suggesting that the gender difference accounted for the difference in the leptin level between the genders, rather than obesity or subcutaneous fat mass. While sex hormones were thought less likely to affect the leptin values in these subjects, given their age of 9 to 10 years which suggested that the majority was pre-pubertal, they may not have an influence on the leptin level in the subjects. While there are several interesting findings reported on the association between leptin or adiponectin and testosterone (19–22), unfortunately, this study was performed as part of the health checkup programs implemented in accordance with the Japanese School Health Law, which included no sex hormone measures, and did not allow us to validate these findings in the literature. In the years to come, if estradiol and testosterone are to be included among the hematological examinations in school children, insight will be gained into the influence of these hormones on adipocytokines, as well as the association between adipocytokines, cardiovascular risk factors, and these sex hormones, to make it possible to screen those children at high cardiovascular risk with greater precision.
Association between the adipocytokines and cardiovascular risk factors
1) Analysis of association by gender
There was no significant difference by gender in the association between the adipocytokines and cardiovascular risk factors. In the entire study population, there was a positive correlation between leptin and the cardiovascular risk factors as well as a negative correlation between adiponectin and the cardiovascular risk factors, regardless of gender. Of the adipocytokines examined, only resistin showed no association with any of the cardiovascular risk factors studied, and analyses using the R/A ratio demonstrated no association with the cardiovascular risk factors.
2) Analysis of association by the presence or absence of obesity
There was a marked difference between the boys and girls in the association between the adipocytokines and cardiovascular risk factors when they were divided into obese and non-obese groups.
As the association between the adipocytokines and cardiovascular risk factors in the obese boys showed a similar pattern to that in the entire boy population, the obese boys may have consisted of individuals with high- and low-risk cardiovascular risk. However, given the greater correlation coefficients found for association between leptin or adiponectin and the cardiovascular risk factors among the obese boys, it was likely that those at higher cardiovascular risk concentrated in the obese boys. Therefore, of the obese boys examined, those showing high leptin and/or low adiponectin values are likely to be at higher cardiovascular risk. Furthermore, there was a strong correlation between the R/A ratio and the cardiovascular risk factors in the obese boys, suggesting that resistin is elevated and adiponectin is decreased in obese boys who are placed at higher cardiovascular risk.
In contrast, results were different for the obese girls than for the obese boys. The obese girls differed from their non-obese counterparts in terms of association between the adipocytokines and cardiovascular risk factors, and this association was found to be significant only between the L/A and W/H ratios, with nearly all significant associations found in the entire girl population disappearing in these girls. However, the association between the adipocytokines and cardiovascular risk factors in the non-obese girls was found to be similar to that in the entire girl population. These findings suggested that these obese girls constituted a homogeneous group in terms of cardiovascular risk, while the reason that the R/A ratio was significantly correlated with all the cardiovascular risk factors among the non-obese girls, because the non-obese girls consisted of individuals with both high and low cardiovascular risk. Therefore, it was not possible to identify any predictive factor from among the adipocytokines examined that might assist in detecting obese girls at even higher risk from among all the obese girl population, a population reported to be already at high risk in the literature.
These study findings suggest that the use of the international BMI-based criteria for obesity could not only lead to obese boys at low cardiovascular risk being included in the obese population which is associated with high risk, but also to non-obese girls with high cardiovascular risk being included in the non-obese population which is associated with low cardiovascular risk. While Japanese children appear to be not as different in physique from their Western counterparts as Japanese adults are from their Western counterparts, our findings suggest that it may not necessarily be appropriate to use the international criteria for obesity in Japanese children without reservation. And the difference among individuals of sex hormones in pre-pubertal may have an influence on adipocytokine levels.
In this study, we investigated whether or not adipocytokines might be used to predict the future development of atherosclerosis, as well as cardiovascular disease which is further downstream. Our study findings demonstrate that school children with high leptin and/or low adiponectin levels are placed at higher cardiovascular risk, regardless of gender. Furthermore, it was suggested that among even those with obesity as a cardiovascular risk factor, cardiovascular risk was found to be higher in individuals with high leptin and/or low adiponectin levels, regardless of gender, while this risk was found to be significant only in the obese boys. In addition, our study findings suggested that the definition of obesity might call for revision in regard to its BMI cut-off values and other factors. Further follow-up of the study subjects is required to confirm the usefulness of these adipocytokines in children as risk factors for the future progression of atherosclerosis as well as for the future development of cardiovascular disease.