Mechanisms of Linear Growth Acceleration in Childhood Obesity

Abstract

The obesity epidemic is alarming. Nearly one‐third of children in the Unites States are overweight or obese by the time they reach their pre‐teen years. Tall stature and accelerated bone elongation are distinctive clinical features of childhood obesity, which tend to co‐occur with painful conditions such as limb bowing, slipped epiphyses, fractures, and early onset osteoarthritis. Although linear growth rate is markedly increased, obese children paradoxically have normal circulating levels of IGF‐I, the major growth‐stimulating hormone. The causes of obesity‐induced growth acceleration remain elusive. Our lab has used a well‐established mouse model of excess dietary fat in order to examine bone elongation changes that occur with the development of juvenile obesity in young growing mice. We found, surprisingly, that brief exposure to a high‐fat diet accelerates bone elongation rate without increasing body mass or circulating IGF‐I levels. Interestingly, when we used in vivo multiphoton microscopy to measure how much systemic IGF‐I localized to growth plates in real time, we found significantly more (nearly twice as much) IGF‐I in the vasculature surrounding the growth plates of mice on a high‐fat diet relative to controls. Post‐mortem immunostaining confirmed that a high‐fat diet increased the number of activated IGF‐I receptors in the growth plate, but not total receptor number. Together, these results suggest that a high‐fat diet increases local bioavailability of IGF‐I in growth plate cartilage without altering systemic IGF‐I levels, and before changes in body mass become evident. This unique method of imaging growth factor transport in cartilage is an important advancement for addressing why linear growth is accelerated in obese children who have normal levels of systemic growth‐promoting hormones. While diets high in fat are well‐recognized for cardiovascular and metabolic complications, the role of dietary fat in bone lengthening is a novel and timely area of research. These studies may provide essential data for testing whether impeding IGF‐I actions in growth plates could be a beneficial approach for mitigating some of the deleterious skeletal consequences of childhood obesity.Support or Funding InformationSupported by the National Institute of General Medical Sciences (1P20GM121299‐01) and National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (1R15AR067451‐01).