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, 156 (8), 2753-61

Exercise Regulation of Marrow Fat in the Setting of PPARγ Agonist Treatment in Female C57BL/6 Mice

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Exercise Regulation of Marrow Fat in the Setting of PPARγ Agonist Treatment in Female C57BL/6 Mice

Maya Styner et al. Endocrinology.

Abstract

The contribution of marrow adipose tissue (MAT) to skeletal fragility is poorly understood. Peroxisome proliferator-activated receptor (PPAR)γ agonists, associated with increased fractures in diabetic patients, increase MAT. Here, we asked whether exercise could limit the MAT accrual and increase bone formation in the setting of PPARγ agonist treatment. Eight-week-old female C57BL/6 mice were treated with 20-mg/kg · d rosiglitazone (Rosi) and compared with control (CTL) animals. Exercise groups ran 12 km/d when provided access to running wheels (CTL exercise [CTL-E], Rosi-E). After 6 weeks, femoral MAT (volume of lipid binder osmium) and tibial bone morphology were assessed by microcomputer tomography. Rosi was associated with 40% higher femur MAT volume compared with CTL (P < .0001). Exercise suppressed MAT volume by half in CTL-E mice compared with CTL (P < .01) and 19% in Rosi-E compared with Rosi (P < .0001). Rosi treatment increased fat markers perilipin and fatty acid synthase mRNA by 4-fold (P < .01). Exercise was associated with increased uncoupling protein 1 mRNA expression in both CTL-E and Rosi-E groups (P < .05), suggestive of increased brown fat. Rosi increased cortical porosity (P < .0001) but did not significantly impact trabecular or cortical bone quantity. Importantly, exercise induction of trabecular bone volume was not prevented by Rosi (CTL-E 21% > CTL, P < .05; Rosi-E 26% > Rosi, P < .01). In summary, despite the Rosi induction of MAT extending well into the femoral diaphysis, exercise was able to significantly suppress MAT volume and induce bone formation. Our results suggest that the impact of PPARγ agonists on bone and marrow health can be partially mitigated by exercise.

Figures

Figure 1.
Figure 1.
Mice treated with Rosi exercise similarly to CTLs. Eight-week-old C57BL/6 mice had access to running wheels at the start of the experiment. A, Food intake per group for the duration of the experiment (6 wk). B, Kilocalories consumed. C, Daily running distance. D, Body weight. Results are expressed as mean ± SEM.
Figure 2.
Figure 2.
Exercise suppresses MAT accumulation despite PPARγ agonist treatment. Visualization of osmium stain by μCT in (A) sagittal, (B) coronal, and (C) axial planes. Quantification of osmium as a measure of MAT in (D) whole femur, (E) diaphysis, (F) metaphysis, and (G) epiphysis. H, 3D representation of regions. Results are expressed as mean ± SD (n = 5/group). #, significant effect due to Rosi by two-way ANOVA; †, significant effect due to exercise by two-way ANOVA. Statistical significance for between-group comparisons is noted as follows: *, P < .05; **, P < .01; ***, P < .001; and ****, P < .0001.
Figure 3.
Figure 3.
Exercise increases trabecular bone quantity. Trabecular and cortical bone microarchitecture measured via μCT. Representative μCT 3D reconstructions for trabecular (A) and cortical (B) bone. C, Cortical porosity. D, Trabecular bone parameters measured by μCT include volume/total volume (BV/TV), trabecular number (Tb.N), Tb.Th, and trabecular spacing (Tb.Sp). E, Cortical bone parameters measured by μCT, including cortical bone area (Ct.Ar), cortical total area (Tt.Ar), Ct.Ar/Tt.Ar, and cortical thickness (Ct.Th). Results are expressed as mean ± SD (n = 5/group).). #, significant effect due to Rosi by two-way ANOVA; †, significant effect due to exercise by two-way ANOVA. Statistical significance for between-group comparisons is noted as follows: *, P < .05; **, P < .01; ***, P < .001; and ****, P < .0001.
Figure 4.
Figure 4.
Rosi and exercise effect on white and brown fat markers. Whole tibias were harvested and mRNA isolated from C57BL/6 mice after 6 weeks of running ± Rosi. Relative expression is shown by real-time PCR normalized to GAPDH. Results are expressed as mean ± SEM (n = 10/group).). #, significant effect due to Rosi by two-way ANOVA; †, significant effect due to exercise by two-way ANOVA. Statistical significance for between-group comparisons is noted as follows: *, P < .05; **, P < .01; ***, P < .001; and ****, P < .0001.
Figure 5.
Figure 5.
Fat pad lipogenic and thermogenic response. Perigonadal fat pads were harvested and mRNA isolated from C57BL/6 mice after 6 weeks of running ± Rosi. Relative expression is shown by real-time PCR normalized to GAPDH. Results are expressed as mean ± SEM (n = 5/group). #, significant effect due to Rosi by two-way ANOVA; †, significant effect due to exercise by two-way ANOVA. Statistical significance for between-group comparisons is noted as follows: *, P < .05; **, P < .01; ***, P < .001; and ****, P < .0001.

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