Abstract
Based on body weight, morbidly obese leptin-deficient ob/ob mice have less bone than expected, suggesting that leptin plays a role in the skeletal response to weight bearing. To evaluate this possibility, we compared the skeletal response of wild type (WT) and ob/ob mice to hindlimb unloading (HU). Mice were individually housed at 32 °C (thermoneutral) from 4 weeks of age (rapidly growing) to 16 weeks of age (approaching skeletal maturity). Mice were then randomized into one of 4 groups (n = 10/group): (1) WT control, (2) WT HU, (3) ob/ob control, and (4) ob/ob HU and the results analyzed by 2-way ANOVA. ob/ob mice pair-fed to WT mice had normal cancellous bone volume fraction (BV/TV) in distal femur, lower femur length and total bone area, mineral content (BMC) and density (BMD), and higher cancellous bone volume fraction in lumbar vertebra (LV). HU resulted in lower BMC and BMD in total femur, and lower BV/TV in distal femur and LV in both genotypes. Cancellous bone loss in femur in both genotypes was associated with increases in osteoclast-lined bone perimeter. In summary, leptin deficiency did not attenuate HU-induced osteopenia in male mice, suggesting that leptin is not required for bone loss induced by unweighting.
Highlights
Ob mice become morbidly obese due to the combined influence of increased food intake and decreased energy expenditure[1]
Mice heterozygous for the ob gene have adipocytes with a reduced capacity to generate leptin but have near normal leptin levels due to compensatory increases in white adipose tissue (WAT) mass19. ob/+ mice exhibit an association between body weight and bone mass nearly identical to wild type (WT) mice
No significant difference in WAT weight was observed in response to hindlimb unloading (HU) but HU resulted in trends for lower body weight (p = 0.09) and blood glucose levels (p = 0.06)
Summary
Ob mice become morbidly obese due to the combined influence of increased food intake and decreased energy expenditure[1]. While the literature strongly supports an important role of leptin in increasing bone accrual prior to peak bone mass and in maintaining normal bone turnover, the hormone likely has additional, less well characterized, actions on bone metabolism. In this regard, there is conflicting evidence that leptin plays a role in mediating skeletal response to changes in body weight. It is possible that leptin is not required for skeletal adaptation to changes in weight but the hormone may enhance the magnitude of response by increasing sensitivity of bone to external loads
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