Differential Impact of Simple Childhood Obesity on the Components of the Growth Hormone-Insulin-like Growth Factor (IGF)-IGF Binding Proteins Axis

Abstract

Simple childhood obesity is characterized by normal or even accelerated growth in spite of reduced growth hormone (GH) secretion. There are conflicting reports on the effects of obesity upon components of the GH-insulin-like growth factor-I (IGF-I)-IGF binding proteins (IGFBPs) system. In the present study we aimed to determine GH, IGF-I, IGFBP-3 and IGFBP-2 as well as some of the less explored components of this axis (IGFBP-3 proteolytic activity, IGFBP-3 plasma fragments, and total acid labile subunit [ALS]) in 22 obese and 17 age-matched control children. We also evaluated not only total GH binding protein (GHBP) serum levels but also GHBP bound to GH (complexed) in both groups. Obese and control groups strongly differed in BMI (obese: 4.7 +/- 0.36 vs control: 0.37 +/- 0.25 SDS, p <0.0001). In the obese group, we found lower GH serum levels, but normal serum levels of GH-GHBP complex, IGF-I, IGFBP-3, IGF-I/IGFBP-3 molar ratio, IGFBP-3 proteolytic activity, IGFBP-3 plasma fragments and total ALS. Obese children presented higher total circulating GHBP (6.0 +/- 0.44 vs 2.9 +/- 0.29 nmol/l, p <0.001) and insulin levels (10.5 +/- 1.5 vs 5.1 +/- 0.8 mU/l, p <0.001), while IGFBP-2 (4.6 +/- 0.5 vs 6.6 +/- 0.7%, p <0.05) and the ratio IGFBP-2/IGF-I (0.032 +/- 0.019 vs 0.095 +/- 0.01, p = 0.013) were lower than in controls. BMI and insulin were directly, and IGFBP-2 serum levels inversely, correlated to total GHBP serum levels when multiple regression analysis was performed (r = 0.74, p <0.001). By stepwise regression analysis, insulin (r = -0.37, p <0.05) and BMI (r = -0.52, p <0.01) inversely determined IGFBP-2. In summary, obese children present normal growth in spite of reduced GH secretion, probably because the combination of increased total GHBP and normal GH-GHBP complex serum levels (suggesting increased GH receptor [GHR] number and a normal serum GH reservoir, respectively) allow for the achievement of normal levels of IGF-I, IGFBP-3, IGFBP-3 proteolytic activity, IGFBP-3 plasma fragments and total ALS. Reduced IGFBP-2 serum levels and a lower ratio of IGFBP-2/IGF-I in obese children may suggest an increase of tissue IGF-I bioavailability, thus promoting its action. Normal IGF-I and GH availability may be contributing to maintain normal growth in obese children.

Antioxidation improves in puberty in normal weight and obese boys, in positive association with exercise-stimulated growth hormone secretion

“…When all subjects were taken as one group, among all baseline variables employed, waist circumference was the best negative predictor for postexercise GPX activity, as well as for ΔGSH, and the best positive predictor for postexercise, prooxidation TBARS and ΔTBARS. In this study, GH concentrations were lower in obese than that in normal-weight early pubertal subjects in accordance with previous reports regarding basal and stimulated GH secretion (23). In obesity, GH secretion may be inhibited at the level of pituitary and hypothalamus by increased insulin, free IGF1, and free fatty acid concentrations (24).…”

Pubertal height gain is inversely related to peak BMI in childhood

“…This was because the high growth associated with the Q-function in OwOb-children was compensated for by low growth associated with the P-function. Despite the fact that OwOb-children are taller during childhood than NwUw-children, it is known that obese children secrete low amounts of GH (33). This is believed to be due to the operation of negative feed-back mechanisms that arise owing to elevated IGF1 levels (33).…”

“…Despite the fact that OwOb-children are taller during childhood than NwUw-children, it is known that obese children secrete low amounts of GH (33). This is believed to be due to the operation of negative feed-back mechanisms that arise owing to elevated IGF1 levels (33). High insulin levels downregulates sex hormone-binding globulin production, which increases bioavailable estrogen, and activate gonadotropin secretion (34).…”

IGFBP-2 - taking the lead in growth, metabolism and cancer

“…In childhood obesity, the reduction in IGFBP-2 serum levels coupled with a lower ratio of IGFBP-2/IGF-I, suggest an increase of tissue IGF-I bioavailability which in turn might be contributing to the observed accelerated growth seen in the pre-pubertal years (Ballerini et al 2004).…”