The TALLYHO Mouse as a Model of Obesity‐Induced Linear Growth Acceleration

Obesity affects over 30% of adults in the United States and contributes to development of painful conditions such limb bowing, joint instability, increased risk of fractures, and early onset osteoarthritis. Nearly one third of American children are now classified as overweight or obese and are at risk of developing musculoskeletal complications because of stress from excess weight on their growing skeleton. Obese children have higher rates of linear growth and accelerated skeletal maturation when compared to their non‐obese peers. They tend to reach maturity earlier and thus typically attain normal adult height, but with diminished bone quality. It is unclear why obese children exhibit increased growth velocity. Among the animal models used in obesity research, the TALLYHO/Jng (TH) mouse is an inbred polygenic model that exhibits moderate obesity by 4‐weeks age and many of the traits consistent with human type 2 diabetes. While the physiology and genomics of the TH strain are well documented, little is known about its skeletal phenotype. OBJECTIVE The goal of this project was to characterize skeletal growth rate of the TH mouse as a model of obesity‐induced linear growth acceleration. We tested the HYPOTHESIS that TH mice have increased bone lengths when compared to non‐obese controls on both high‐fat and standard chow diets. METHODS We measured body mass and bone elongation rate in juvenile female TH obese and C57BL/6 (B6) non‐obese mice on standard chow during the active growth period between 3‐and 5‐weeks after birth (N=5 per group). Body mass was recorded daily and tibial elongation rate was measured using fluorochrome labeling. Femoral and humeral lengths were measured from digitized images at the study endpoint. To assess the impact of diet, we examined adult bone lengths in 20‐week‐old TH and B6 mice that were fed high‐fat (58% kcal from fat) or standard chow (13% kcal from fat) diets beginning at 4‐weeks age (N=8–10 per group). RESULTS At 3‐weeks, TH mice on chow were over 25% larger than B6 mice and grew at an accelerated rate. By 5‐weeks, TH mice were over 31% larger and tibial elongation rates were nearly 9% greater. Tail and femoral lengths were increased by 8% and 3%, respectively, in TH mice at the 5‐week endpoint (p<0.05 by independent samples t‐test). Humeral length was 2% greater, but the difference at 5‐weeks was not significant. After 16 weeks on a high‐fat diet, TH mice were twice as large in body mass than TH standard chow controls, while B6 mice on a high‐fat diet were over 20% larger than their respective controls. Femoral and humeral lengths were approximately 2% longer in the high‐fat diet groups than the chow controls within each genotype (p<0.05 by one‐way ANOVA), but femoral length did not differ between genotypes at 20‐weeks age. CONCLUSION These data demonstrate that the TH mouse is a good model of obesity‐induced linear growth acceleration. Results from the adult study are consistent with the early maturation and attainment of normal adult height typical of obese children. Future studies utilizing the TH mouse will be important for determining mechanisms underlying obesity‐enhanced bone elongation and for potentially preventing devastating skeletal consequences of obesity. Support or Funding Information Supported by pilot funding from the Appalachian Clinical and Translational Science Institute at the Marshall University Joan C. Edwards School of Medicine