The complex effects of leptin on bone metabolism through multiple pathways.

Leptin has recently emerged as a mediator of the protective effects of fat on bone tissue. However, it remains difficult to draw a clear picture of how leptin effects bone metabolism. From conflicting or apparently contradictory data, it is tempting to hypothesize that leptin exerts dual effects depending on bone tissue, skeletal maturity and/or signaling pathway. Early in life, leptin might stimulate bone growth and bone size through direct angiogenic and chondro-osteogenic effects. Later, it may decrease bone remodeling in the mature skeleton, when trabecular bone turnover is high, by stimulating the osteoprotegerin-RANK-ligand pathway. Leptin also exerts negative effects on bone formation through a hypothalamic pathway mediated downstream by the sympathetic nervous system. The two pathways could counterbalance each other, with the peripheral and positive effects being predominant when leptin central resistance occurs with obesity onset.