Immature mice are more susceptible to the detrimental effects of high fat diet on cancellous bone in the distal femur

Abstract

With the increasing prevalence of obesity among children and adolescents, it is imperative to understand the implications of early diet-induced obesity on bone health. We hypothesized that cancellous bone of skeletally immature mice is more susceptible to the detrimental effects of a high fat diet (HFD) than mature mice, and that removing excess dietary fat will reverse these adverse effects. Skeletally immature (5 weeks old) and mature (20 weeks old) male C57BL/6J mice were fed either a HFD (60% kcal fat) or low fat diet (LFD; 10% kcal fat) for 12 weeks, at which point, the trabecular bone structure in the distal femoral metaphysis and third lumbar vertebrae were evaluated by micro-computed tomography. The compressive strength of the vertebrae was also measured. In general, the HFD led to deteriorations in cancellous bone structure and compressive biomechanical properties in both age groups. The HFD-fed immature mice had a greater decrease in trabecular bone volume fraction (BVF) in the femoral metaphysis, compared to mature mice (p=0.017 by 2-way ANOVA). In the vertebrae, however, the HFD led to similar reductions in BVF and compressive strength in the two age groups. When mice on the HFD were switched to a LFD (HFD:LFD) for an additional 12 weeks, the femoral metaphyseal BVF in immature mice showed no improvements, whereas the mature mice recovered their femoral metaphyseal BVF to that of age-matched lean controls. The vertebral BVF and compressive strength of HFD:LFD mouse bones, following diet correction, were equivalent to those of LFD:LFD mice in both age groups. These data suggest that femoral cancellous metaphyseal bone is more susceptible to the detrimental effects of HFD before skeletal maturity and is less able to recover after correcting the diet. Negative effects of HFD on vertebrae are less severe and can renormalize with LFD:LFD mice after diet correction, in both skeletally immature and mature animals.

High-Fat Diet Causes Bone Loss in Young Mice by Promoting Osteoclastogenesis Through Alteration of the Bone Marrow Environment

“…To investigate the mechanism of obesity-induced bone loss in children, we fed 5-week-old young mice (equivalent to 10 year-old children [29]) a high-fat diet (HFD) or low-fat diet (LFD) for 12-weeks, a standard duration that we used for HFD studies [19, 20, 30] and examined bone volume and bone morphology. HFD-fed mice had significantly increased body weight, and associated increased levels of fasting blood glucose, serum fatty acids, and serum leptin, confirming diet-induced obese characteristics (Figure 1A).…”

Inducible Models of Bone Loss

“…Other studies have also indicated that the response to HFD is age- and sex-dependent, as adolescent mice tend to be more susceptible than older mice (Inzana et al 2013) and males have demonstrated greater levels of bone loss on HFD than females (Gautam et al 2014). …”

The hunger games of skeletal metabolism

“…[66][67][68] The effects of diet-induced obesity are greater in immature mice than in older mice, as examined by Inzana et al, 69 who demonstrated that switching mice to a chow diet following a period of high-fat diet was able to restore the bone phenotype of older mice butnot immature mice. This suggests that high-fat diets cause greater damage in growing bones, which is concerning considering the current increases in the rate of childhood obesity in Western countries.…”