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

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.

Low intensity vibration mitigates tumor progression and protects bone quantity and quality in a murine model of myeloma

“…That said, it is interesting that the level of actual necrosis in the tibia of myeloma mice that served as sham control was higher than that measured in LIV, suggesting at least some capacity to deter the late stages of the pathology was evident. Alternatively, or in conjunction, there is evidence of spatial differences of marrow, not only within a given bone (62), but between bones (60), as well as the capacity of mechanical signals to influence bone morphology at these different sites. With evidence of the consequences of the disease evident in the axial skeleton, with some salutary benefit of LIV to protect skeletal components remote from the site of vibration, suggests circulatory factors may also be at play.…”

Development, regulation, metabolism and function of bone marrow adipose tissues

“…Mice with access to a wheel will voluntarily run ~10 km per day 35, 48 . This level of exercise reduces rBMA number and size in both lean and diet-induced obese mice 35 , suggesting that energy stored within marrow adipocytes is readily mobilized under these conditions.…”

Adipose, Bone, and Myeloma: Contributions from the Microenvironment

“…OVX-induced osteoporosis studies have demonstrated that bone loss can occur prior to increases in MAT [24]. Exercise has been shown to significantly suppress MAT volume and induce bone formation in certain mouse models, suggesting that a double-edged sword may be strengthening bones and decreasing MAT in MGUS or MM patients via diet and exercise to improve bone outcomes [25]. …”

“…In order to combat the potential that elevated MAT impacts tumor growth in MM, a number of approaches currently exist in the clinic. Weight loss via diet and exercise has been shown to decrease elevated MAT resulting from high fat diet or PPARγ agonists [25, 118]. Elevated MAT can also be treated with the anti-diabetic drug metformin, which is able to significantly decrease MAT in a diet-induced obesity mouse model (unpublished data).…”