Enhanced IGF‐I Delivery to the Growth Plate and Accelerated Bone Elongation in a Mouse Model of Juvenile Obesity
Authors: Serrat Maria A , Machnicki Allison L , Meadows Chad A , McCloud Darby , Thomas Dominic , Hurley John D , Ion Gabriela 
Published: June 2021

Childhood obesity can be devastating to the skeleton because its effects are often silent and undiagnosed until a child presents with disabling pain. Obese children have accelerated linear growth and skeletal maturation with diminished bone quality, leading to painful conditions such as limb bowing, joint instability, fractures, and early onset osteoarthritis. The major treatment obstacle is lack of knowledge of the underlying cause of obesity‐induced growth acceleration. Paradoxically, obese children have normal circulating levels of IGF‐I, the major growth‐stimulating hormone. Our goal was to characterize bone elongation rate and local IGF‐I delivery using a high‐fat diet to model the development of juvenile obesity in mice. We tested the hypothesis that a high‐fat diet would increase IGF‐I delivery to growth plates and bone elongation rate before the overt onset of obesity. To test this, we used in vivo multiphoton microscopy to quantify IGF‐I transport and measured bone elongation rate in weanling mice given a high‐fat diet.MethodsFemale 3‐week old C57BL/6 mice (N=26 total) were fed semi‐purified control (10% kcal fat) or high‐fat (60% kcal fat) diets for 14 days. Body mass, tail length and food intake were recorded (N=8/group). Bone elongation rate was measured from live x‐rays and fluorochrome labeled (oxytetracycline, 7.5 mg/kg IP) tibial slab sections. Femoral length was measured from digitized bone images at the 5‐week endpoint. For in vivo imaging (N=5/group), fluorescently‐labeled IGF‐I (~6 μg/g body wt) was quantified in warmed (34–36C) proximal tibial growth plates and vasculature by multiphoton microscopy at standardized depths and times as we have previously detailed. Statistical analyses were performed in SPSS using t‐tests. Significance was accepted at α = 0.05 (one‐tailed).ResultsMice on a high‐fat diet ate less than controls (2.7 vs 3.3 g/day; t = 6.3, p < 0.001), but their caloric intake was greater (13.9 vs 12.6 kcal/day; t = 2.8, p < 0.01). There were no significant differences in body mass at the start or end of the experiments; however, mice on a high‐fat diet were slightly larger and we qualitatively noted that they had more body fat. Femora (t = 4.6, p < 0.001) and tails (t = 2.9, p < 0.01) were 3% and 14% longer, respectively, in the high‐fat diet group and tibial elongation rate was over 16% greater (t = 4.1, p = 0.001). Multiphoton imaging revealed over twice as much IGF‐I in the vasculature surrounding the proximal tibial growth plates of mice on a high‐fat diet relative to chow‐fed controls (13% kcal fat), which were previously collected (t = 4.1, p < 0.01).DiscussionThese results support the hypothesis that a high‐fat diet increases bone elongation rate and IGF‐I delivery to the growth plate before the overt onset of obesity. This model is important for understanding the role of local IGF‐I transport in obesity‐induced linear growth acceleration, particularly because we show that bone length is increased without a significant change in body mass.Support or Funding InformationSupported by NIH National Institute of General Medical Sciences (1P20GM121299‐01) and National Institute of Arthritis and Musculoskeletal and Skin Diseases (1R15AR067451‐01).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.