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Effects of High-Fat Diet and Body Mass on Bone Morphology and Mechanical Properties in 1100 Advanced Intercross Mice.

ABSTRACT: Obesity is generally protective against osteoporosis and bone fracture. However, recent studies indicate that the influence of obesity on the skeleton is complex and can be detrimental. We evaluated the effects of a high-fat, obesogenic diet on the femur and radius of 1100 mice (males and females) from the Large-by-Small advanced intercross line (F34 generation). At age 5 months, bone morphology was assessed by microCT and mechanical properties by three-point bending. Mice raised on a high-fat diet had modestly greater cortical area, bending stiffness, and strength. Size-independent material properties were unaffected by a high-fat diet, indicating that diet influenced bone quantity but not quality. Bone size and mechanical properties were strongly correlated with body mass. However, the increases in many bone traits per unit increase in body mass were less in high-fat diet mice than low-fat diet mice. Thus, although mice raised on a high-fat diet have, on average, bigger and stronger bones than low-fat-fed mice, a high-fat diet diminished the positive relationship between body mass and bone size and whole-bone strength. The findings support the concept that there are diminishing benefits to skeletal health with increasing obesity. © 2019 American Society for Bone and Mineral Research.

SUBMITTER: Silva MJ

PROVIDER: S-EPMC6879418 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Effects of High-Fat Diet and Body Mass on Bone Morphology and Mechanical Properties in 1100 Advanced Intercross Mice.

Silva Matthew J MJ Eekhoff Jeremy D JD Patel Tarpit T Kenney-Hunt Jane P JP Brodt Michael D MD Steger-May Karen K Scheller Erica L EL Cheverud James M JM

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 20190107 4

Obesity is generally protective against osteoporosis and bone fracture. However, recent studies indicate that the influence of obesity on the skeleton is complex and can be detrimental. We evaluated the effects of a high-fat, obesogenic diet on the femur and radius of 1100 mice (males and females) from the Large-by-Small advanced intercross line (F<sub>34</sub> generation). At age 5 months, bone morphology was assessed by microCT and mechanical properties by three-point bending. Mice raised on a ...[more]

PMID: 30615803

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Project description:IntroductionKnowledge of bone structure-function relationships in mice has been based on relatively small sample sets that limit generalizability. We sought to investigate structure-function relationships of long bones from a large population of genetically diverse mice. Therefore, we analyzed previously published data from the femur and radius of male and female mice from the F34 generation of the Large-by-Small advanced intercross line (LGXSM AI), which have over a two-fold continuous spread of bone and body sizes (Silva et al. 2019 JBMR).MethodsMorphological traits, mechanical properties, and estimated material properties were collected from the femur and radius from 1113 LGXSM AI adult mice (avg. age 25 wks). Males and females fed a low-fat or high-fat diet were evaluated to increase population variation. The data were analyzed using principal component analysis (PCA), Pearson's correlation, and multivariate linear regression.ResultsUsing PCA groupings and hierarchical clustering, we identified a reduced set of traits that span the population variation and are relatively independent of each other. These include three morphometry parameters (cortical area, medullary area, and length), two mechanical properties (ultimate force and post-yield displacement), and one material property (ultimate stress). When comparing traits of the femur to the radius, morphological traits are moderately well correlated (r2: 0.18-0.44) and independent of sex and diet. However, mechanical and material properties are weakly correlated or uncorrelated between the long bones. Ultimate force can be predicted from morphology with moderate accuracy for both long bones independent of variations due to genetics, sex, or diet; however, predictions miss up to 50 % of the variation in the population. Estimated material properties in the femur are moderately to strongly correlated with bone size parameters, while these correlations are very weak in the radius.DiscussionOur results indicate that variation in cortical bone phenotype in the F34 LGXSM AI mouse population can be adequately described by a reduced set of bone traits. These traits include cortical area, medullary area, bone length, ultimate force, post-yield displacement, and ultimate stress. The weak correlation of mechanical and material properties between the femur and radius indicates that the results from routine three-point bending tests of one long bone (e.g., femur) may not be generalizable to another long bone (e.g., radius). Additionally, these properties could not be fully predicted from bone morphology alone, confirming the importance of mechanical testing. Finally, material properties of the femur estimated based on beam theory equations showed a strong dependence on geometry that was not seen in the radius, suggesting that differences in femur size within a study may confound interpretation of estimated material properties.

Project description:Fat mass may be a causal determinant of bone mass, but the evidence is conflicting, possibly reflecting the influence of confounding factors. The recent identification of common genetic variants related to obesity in children provides an opportunity to implement a Mendelian randomization study of obesity and bone outcomes, which is less subject to confounding and several biases than conventional approaches. Genotyping was retrieved for variants of two loci reliably associated with adiposity (the fat mass and obesity-related gene FTO and that upstream of the MC4R locus) within 7470 children from the Avon Longitudinal Study of Parents and Children (ALSPAC) who had undergone total body DXA scans at a mean of 9.9 yr. Relationships between both fat mass/genotypes and bone measures were assessed in efforts to determine evidence of causality between adiposity and bone mass. In conventional tests of association, both with and without height adjustment, total fat mass was strongly related to total body, spinal, and upper and lower limb BMC (ratio of geometric means [RGM]: 1.118 [95% CI: 1.112, 1.123], 1.110 [95% CI: 1.102, 1.119], 1.101 [95% CI: 1.093, 1.108], 1.146 [95% CI: 1.143, 1.155]; p < 10(-10) [adjusted for sex, height, and sitting height]). Equivalent or larger effects were obtained from instrumental variable (IV) regression including the same covariates (1.139 [95% CI: 1.064, 1.220], 1.090 [95% CI: 1.010, 1.177], 1.142 [95% CI: 1.049, 1.243], 1.176 [95% CI: 1.099, 1.257]; p = 0.0002, 0.03, 0.002, and 2.3(-6) respectively). Similar results were obtained after adjusting for puberty, when truncal fat mass was used in place of total fat, and when bone area was used instead of bone mass. In analyses where total body BMC adjusted for bone area (BA) was the outcome (reflecting volumetric BMD), linear regression with fat mass showed evidence for association (1.004 [95% CI: 1.002, 1.007], p = 0.0001). IV regression also showed a positive effect (1.031 [95% CI: 1.000, 1.062], p = 0.05). When MC4R and FTO markers were used as instruments for fat mass, similar associations with BMC were seen to those with fat mass as measured by DXA. This suggests that fat mass is on the causal pathway for bone mass in children. In addition, both directly assessed and IV-assessed relationships between fat mass and volumetric density showed evidence for positive effects, supporting a hypothesis that fat effects on bone mass are not entirely accounted for by association with overall bone size.

Dataset Information

Effects of High-Fat Diet and Body Mass on Bone Morphology and Mechanical Properties in 1100 Advanced Intercross Mice.

Publications

Effects of High-Fat Diet and Body Mass on Bone Morphology and Mechanical Properties in 1100 Advanced Intercross Mice.

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