Obesity is a serious health problem in adults and children alike. The number of children with obesity has been increasing, such that 25% of all children in the United States are now considered to be significantly overweight. Since weight loss by be associated with a decrease in linear growth rate, it is essential to better understand the relationship between nutrition and the hormone axes that control growth. The purpose of this research is to examine the physiological relationships between nutrition and growth by testing the hypothesis that obesity in childhood increases plasma leptin concentration which in turn increases the bioactivity of secreted growth hormone (GH) to produce excessive growth and bone maturation. Despite their rapid growth, obese children have low circulating GH concentrations physiologically and after provocative stimulation. Since GH circulates as a family of isoforms which have varying biological activity and varying detection rates in standard immunoassays, it is possible that rapid growth in children is the consequence of secretion of a highly biopotent form of GH with limited imunoactivity. In this research, a novel bioassay for GH relevant for use in human serum will be used to determine whether GH bioactivity is greater in obese children than in lean subjects and whether this biopotency can be reduced with weight loss. Insulin-like growth factor-I (IGF-I) medicates GH action and may decrease GH secretion through a negative feedback loop. IGF-I concentrations have variably been reported to be normal or increased in children with obesity. IGF-I concentrations have variably been reported to be normal or increased in children with obesity. IGF-I bioavailability can be controlled by a series of IGF-binding proteins whose concentrations may change with nutritional state. We will determine the relationship between GH bioactivity and IGF-I activity in obese and lean children as a function of nutrition by assessing bound and free IGF-I and its binding proteins. The fat cell product, leptin, may serve as an indicator of overall adiposity in children. Leptin is also thought to regulate appetite and may be permissive for pubertal maturation. The presence of leptin receptors in hypothalamus and ovary suggests that leptin may increase gonadotropin or estradiol production which may then facilitate growth. A new leptin assay for human serum will be used to determine correlations between adiposity, GH bioactivity, IGF-I availability, and growth. Finally, the effects of dieting on growth rate have been studied incompletely. As part of this study, the effects of judicious calorie restriction on growth rate in obese children will be determined. In all studies, obese girls will have hormone determinations in the fed state, after a short-term marked reduction in calories, and after a 6 month period of caloric restriction for weight maintenance. Lean children will serve as controls (studied in the fed state only). If our hypothesis is correct, changes in leptin should be positively correlated with changes in GH bioactivity.
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