We found that for children at high risk for adult obesity, high BMI and fat mass were associated with greater gain in body mass, but high baseline serum leptin concentration, independent of baseline BMI/fat mass, also predicted greater BMI and fat mass over time. We hypothesize that children who had high leptin at baseline were at increased risk for gain in fat mass due to inherent leptin resistance above that expected to be generated by their body fat mass. Although unlikely to be due to function-altering defects of the leptin receptor itself (3
), this inherent leptin resistance could conceivably reflect deleterious alterations downstream of the leptin receptor that could promote excessive weight gain.
This study confirms and extends previous observations of obese children (n = 68) (19
), obese Pima Indian children (n = 132) (18
), and African-American and Caucasian children of typical weight distribution (n = 85) (17
) that have found higher leptin to predict increased weight over time and contrasts with other smaller investigations (n < 40) that found the reverse relationship (15
). In addition to its larger sample size, the present investigation was strengthened compared with previous studies by separate modeling according to gender and race, a statistical analysis that incorporated multiple potentially confounding variables, and fat mass measured by DEXA as an outcome variable. Particularly during childhood and adolescence when muscle, organ, and bone mass may be changing at varying rates, body fat mass is a more accurate measure of adiposity than BMI (36
). The only other pediatric leptin study that measured fat mass by DEXA (17
) also found a positive relationship between leptin and adiposity growth over time.
In contrast to two other pediatric studies (15
) that found leptin to predict weight gain only in females, we found that high serum leptin predicted increased weight in both males and females. These previous studies used total sample sizes that may have been too small (n = 40 and n = 68) to permit reliable subdivision by sex, although somewhat smaller effects of high leptin in males (+5.2 kg additional fat mass) than in females (+11.8 kg additional fat mass) were estimated by the model in the current study. It also appeared that there was a diminished impact of baseline serum leptin to predict adiposity growth during puberty particularly among the non-Caucasian boys in the study (). However, additional research is necessary to confirm this relationship, as the interaction term for leptin by race by follow-up age did not reach significance in the model (). Our models also suggest a decreased velocity of growth in fat mass in late puberty, particularly in boys (), which is consistent with increased deposition of muscle mass during this time period and is in concordance with the existing literature (38
). As has also been found previously (39
), this postpubertal decline in fat mass growth appears to be less pronounced in Caucasian girls. However, from these models, which were formulated to test the role of leptin on weight change, firm conclusions cannot be drawn about the influence of sex and ethnicity on overall fat mass trajectory.
Skeletal age, physical activity, and SES did not independently predict increases in BMI or fat mass in these models. The physical activity measures obtained via questionnaire relied on subjects’ responses, which may not have accurately represented their physical activity (40
) and might thus have affected the questionnaire’s ability to predict growth of BMI or fat mass. However, several other previous studies have likewise found physical activity, assessed either by questionnaire (41
) or estimated using stable isotope methods (30
), not to predict weight change during adolescence. Measures of fitness, rather than of actual physical activity may ultimately be seen as superior for the purpose of assessing how activity impacts weight change (44
). Larger sample sizes or approaches that can reliably estimate activity over very long periods of time may be needed before activity measurements can be shown to contribute to weight change in children. Similarly, a considerably larger sample size may be needed to separate the effects of age from those of skeletal age. In addition to the need for a larger sample size and better methods to estimate physical activity to answer some research questions, there are other limitations of the study. These include the recruitment only of subjects living near Washington, D.C., and the fact that, in some instances, more than one child in a single family was enrolled in the study and that virtually all children had at least one overweight parent. Finally, because of limitations related to sample size, analyses of the associations between leptin and weight gain could not be performed separately for the non-overweight and overweight children in the study.
The ability of serum leptin to predict increases in body fat mass in children at high risk for adult obesity contrasts with studies in adults in which leptin was not a good predictor of future weight change (10
). In children, inherent leptin resistance may be a more salient indicator of risk for greater adipose growth than it is in adults, who have had a larger period of exposure to environmental conditions that predispose to weight gain and have had an opportunity to manifest the effects of genes affecting body weight that may have a later onset of action. This study thus also demonstrates that caution must be exercised when extrapolating data from adults to children or from normal-weight children to children at high risk for obesity, highlighting the potential differences in the control mechanisms for energy intake and expenditure that may be present in those with early-onset overweight.
There is a need for additional prospective, longitudinal studies to explore the role of leptin to predict weight gain in children who are not already identified as at risk for overweight by their own or their parents’ weight status. If leptin concentration in these non-overweight children is associated with the development of overweight, it could be used as a biomarker to identify at-risk children. Furthermore, additional studies are warranted to evaluate the predictive role of leptin compared with other known predictors of weight gain such as birth weight, maternal smoking during pregnancy, history of breastfeeding, time spent watching television, parental obesity (45
), and insulin concentration (47
). Indeed, there is an established relationship between hyperleptinemia and hyperinsulinemia (51
). A few (53
), but not all (58
), longitudinal studies in adults have actually suggested that high insulin sensitivity and low fasting plasma insulin are associated with increased weight gain, whereas insulin resistance may protect against weight gain. Conflicting data also exist for children, with both positive (47
) and negative (48
) associations reported between insulin and changes in fat mass. Thus, there is a clear need for future studies to elucidate the relationship between insulin and leptin as predictors of changes in weight over time. Future studies should also examine the role of insulin and how it relates to leptin as a predictor of increases in weight and body fat mass in both overweight and non-overweight children.
The present study may be of particular clinical interest because it is specifically applicable to elementary school-aged children believed to be at risk for adult obesity. As children pass through adolescence to adulthood and height stabilizes, weight status becomes even more tightly correlated to the comorbidities associated with obesity. Where previous research has been limited and contradictory, this study more definitively documents the importance of serum leptin as a marker that predicts future weight in children already identified as at risk for adult obesity and may assist in selecting the subset of those who are most in need of weight monitoring and early, intensive intervention.