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Opposite Effects of Leptin on Bone Metabolism: A Dose-Dependent Balance Related to Energy Intake and Insulin-Like Growth Factor-I Pathway

Institut National de la Santé et de la Recherche Médicale, Unité 890, University Hospital, 42055 St-Etienne, France

Address all correspondence and requests for reprints to: Prof. Thierry Thomas, Institut National de la Santé et de la Recherche Médicale Unité 890, University Hospital, Boulevard Pasteur, 42055 St-Etienne Cedex 2, France. E-mail: thierry.thomas{at}univ-st-etienne.fr.

Published data describing leptin effects on bone are at variance with both positive and negative consequences reported. These findings are consistent with a bimodal threshold response to serum leptin levels. To test this theory, two groups of female rats (tail-suspended and unsuspended) were treated with ip leptin at two different doses or vehicle for 14 d. In tail-suspended rats, low-dose leptin compensated the decrease in serum leptin levels observed with suspension and was able to prevent the induced bone loss at both the trabecular and cortical level (assessed by three-dimensional microtomography). In contrast, high-dose leptin inhibited femoral bone growth and reduced bone mass by decreasing bone formation rate and increasing bone resorption in both tail-suspended and unsuspended groups. High- and low-dose leptin administration resulted in a reduced medullar adipocytic volume in all groups. High-dose leptin (but not low) induced a decrease in body-weight abdominal fat mass and serum IGF-I levels. Thus, the observed bone changes at high-dose leptin are at least partly mediated by a leptin-induced energy imbalance. In conclusion, a balance between negative and positive leptin effects on bone is dependent on a bimodal threshold that is triggered by leptin serum concentration. Also, the negative effects of high leptin levels are likely induced by reduced energy intake and related hormonal changes. The respective part of each pathway will be unraveled by additional studies.