What are the effects of leptin on bone and where are they exerted

In this issue of the Journal of Bone and Mineral Research, an article by Turner and colleagues addresses the important topic of the relationship between the adipocyte-derived hormone leptin, bone, and energy homeostasis. They report that the leptin-deficient and obese ob/ob mice and the leptin receptor–deficient db/db mice display an osteopetrotic-like skeletal phenotype at 15 weeks of age with high vertebral trabecular bone volume (BV/TV) despite a markedly decreased bone formation rate (BFR), as a result of decreased bone resorption. They also show that these phenotypes (low BFR and low resorption) can be corrected both by subcutaneous injections of leptin and by leptin hypothalamic gene therapy. Because this suggested that leptin can act both at the periphery and in the central nervous system to affect bone, they then performed marrow transplantation experiments in lethally irradiated mice. They report that transplantation of leptin receptor–deficient db/db bone marrow into lethally irradiated wild-type mice drastically reduces bone formation to levels indistinguishable from the db/db mice. Furthermore, mice engrafted with db/db marrow did not show overt alterations in energy homeostasis, suggesting that energy homeostasis is not affected by the changes in bone. They conclude that leptin acts on bone primarily through peripheral pathways and that its effects are to increase bone formation, but even more bone resorption. These results are in strong opposition with prevailing theories and call into question what leptin does in bone; ie, increasing or decreasing bone formation, and how it does it; ie, centrally through a hypothalamic relay or directly at the periphery. These findings raise several puzzling questions. First, the ob/ob and db/db skeletal phenotypes reported here are radically different from a previous report showing a 45% to 70% increase in BFR in ob/ob and db/db mice, respectively, compared to wildtype littermates. Second, the ability of peripheral leptin to affect bone, albeit supported by in vitro data published by others is in sharp contradiction with some in-depth studies from other laboratories. Third, peripheral leptin corrects the bone phenotype, although no significant alterations in energy homeostasis are noted, suggesting no direct link between bone and energy regulation in these leptin-deficient or leptin receptor–deficient mouse models. The original concept and the prevailing school of thought concerning the effects of the fat-derived hormone leptin on bone rely mainly on a series of pioneering and robust in vivo studies conducted by the Ducy and Karsenty groups (initially at the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; then at the Department of Pathology and Cell Biology [Ducy] and the Department of Genetics and Development [Karsenty], College of Physicians and Surgeons, Columbia University, New York, NY, USA). In 2000, these investigators presented their first in vivo evidence to the fact that bone gain in the ob/ob or db/db mice occurred despite gonadal failure, resulting from the absence of leptin signaling. Both ob/ob and db/dbmice exhibited high trabecular bone mass in the proximal tibiae and vertebrae, whereas intracerebroventricular (ICV) infusion of leptin into ovariectomized mice corrected this phenotype and resulted in a decreased BV/TV in both mutant and control groups. Interestingly, direct in vitro leptin treatment of primary ob/ob osteoblasts had no effect on collagen synthesis or mineralization, whereas db/db osteoblasts were indistinguishable from wild-type in culture, suggesting that leptin acted on bone solely via hypothalamic pathways. Moreover, the central action of leptin was proposed to target osteoblasts and not osteoclasts, because these authors found normal osteoclast function in the absence of leptin signaling. Subsequent work using b2-adrenergic receptor Adrb2-null mice or pharmacological treatment with b-blockers further supported the concept of a central inhibitory role of leptin on the skeleton, and proposed a model whereby activation of leptin receptors in the brain activates the sympathetic nervous system, which in COMMENTARY JBMR