Adolescent obesity incurs adult skeletal deficits in murine induced obesity model.

Adolescent obesity has risen dramatically in the last few decades. While adult obesity may be osteoprotective, the effects of obesity during adolescence, which is a period of massive bone accrual, are not clear. We used a murine model of induced adolescent obesity to examine the structural, mechanical, and compositional differences between obese and healthy weight bone in 16-week-old female C57Bl6 mice. We also examined the effects of a return to normal weight after skeletal maturity (24 weeks old). We found obese adolescent bone exhibited decreased trabecular bone volume, increased cortical diameter, increased ultimate stress, and increased brittleness (decreased plastic energy to fracture), similar to an aging phenotype. The trabecular bone deficits remained after return to normal weight after skeletal maturity. However, after returning to normal diet, there was no difference in ultimate stress nor plastic energy to fracture between groups as the normal diet group increased ultimate stress and brittleness. Interestingly, compositional changes appeared in the former high-fat diet mice after skeletal maturity with a lower mineral to matrix ratio compared to normal diet mice. In addition there was a trend toward increased fluorescent advanced glycation endproducts in the former high-fat diet mice compared to normal diet mice but this did not reach significance (p < 0.05) due to the large variability. The skeletal consequences of adolescent obesity may have lasting implications for the adult skeleton even after return to normal weight. Given the rates of adolescent obesity, skeletal health should be a concern.

Manipulating load-induced fluid flow in vivo to promote bone adaptation.

Mechanical stimulation is critical to maintaining bone mass and strength. Strain has been commonly thought of as the mechanical stimulus driving bone adaptation. However, numerous studies have hypothesized that fluid flow in the lacunar-canalicular system plays a role in mechanoadaptation. The role of fluid flow compared to strain magnitude on bone remodeling has yet to be characterized. This study aimed to determine the contribution of fluid flow velocity compared to strain on bone adaptation. We used finite element modeling to design in vivo experiments, manipulating strain and fluid flow contributions. Using a uniaxial compression tibia model in mice, we demonstrated that high fluid flow velocity results in significant bone adaptation even under low strain magnitude. In contrast, high strain magnitude paired with low fluid velocity does not trigger a bone response. These findings support previous hypotheses stating that fluid flow is the principal mechanical stimulus driving bone adaptation. Moreover, they give new insights regarding bone adaptative response and provide new pathways toward treatment against age-related mechanosensitivity loss in bone.

Mechanoadaptation of the bones of mice with high fat diet induced obesity in response to cyclical loading.

An upward trend in childhood obesity implies a great need to determine its effects, both immediate and long-term. Obesity is osteoprotective in adults, but we know very little about the effects of obesity on the growing skeleton, particularly its ability to adapt to load. The objective of this research is to assess bone mechanoadaptation in adolescent obese mice. Ten mice were fed a high-fat diet (HFD) from 4 to 16 weeks of age, while a control group of the same size received a normal diet (ND). At 14 weeks of age, right tibiae were cyclically loaded with a 12 N peak load for HFD mice and a 9 N peak load for ND mice three times a week for two weeks, resulting in equal peak strains of about 2500 microstrain. At 16 weeks of age, mice were sacrificed, and tibiae and gonadal fat pads were dissected. Fat pads were weighed as an obesity indicator, and tibiae were imaged with microCT to measure bone structure. The left tibiae (nonloaded) were subsequently decalcified, stained with osmium, and scanned to quantify marrow fat. Results showed that HFD mice had larger tibial cross-sectional areas compared to ND mice, as well as greater marrow adiposity. However, there was no significant difference in the amount of bone adaptation in the cortical or trabecular bone between the two groups. This indicates that the bones of HFD and ND mice adapt equally well to loading.