Leptin’s roles in bone growth and adipose tissue in ob/ob mice and their relationship to osteoporosis
Bartell, Shoshana Mal-Lee
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Disorders of body composition, specifically obesity and osteoporosis, have emerged in the last decade as major health concerns. The research was conducted to evaluate leptin’s role in bone growth, throughout the skeleton, and adipose tissue in ob/ob mice and their relationship to osteoporosis. The studies utilized a model of an aged (15-wk) obese ob/ob mice, who cannot produce leptin due to an inactivating mutation in the leptin gene. These mice have the skeletal abnormalities observed in an individual suffering from osteoporosis. Leptin treatment increased the expression levels of genes associated with osteogenesis (eg., Runx2), while those associated with osteoclastogenesis (eg., RANK) were decreased. This is consistent with the observed leptin-stimulated bone growth as demonstrated by the increased BMD, BMC, and mineral apposition rates (MAR) throughout the skeleton and the inclination of cells to differentiate into osteoblasts. Both central and systemic injections of leptin decreased adipogenesis in the bone marrow and adipose tissue, demonstrating an enhanced sensitivity to leptin-stimulated adipocyte apoptosis, which resulted in fat loss but not to the detriment of bone mass. These results indicate that increasing concentrations of leptin promoted expression of pro-osteogenic factors in the bone marrow and enhanced bone formation in ob/ob mice. Leptin induced adipocyte apoptosis in the bone marrow and adipose tissue, reduced cell differentiation into osteoclasts and adipocytes, and promoted osteoblast differentiation as demonstrated by changes in gene expression, bone histology, serum marker concentrations, and body composition. Both central and peripheral leptin treatment increased serum IGF-1 concentrations that most likely enhanced muscle and bone growth via muscle-derived mechanical stimuli. Thus, leptin exhibited characteristics important for the prevention of osteoporosis by preserving muscle mass, bone mass, and bone integrity as exhibited by the changes in gene expression, bone histology, serum marker concentrations, and body composition. Moreover, leptin administration reversed the primary osteoporosis-causing mechanisms, which future therapeutic treatments need to mimic to be effective agents and demonstrate that the ob/ob mouse is a useful model for studying osteoporosis.