Forging a link between brain and bone

March 27, 2002

The adipose-derived hormone leptin is well known for its influence on feeding behavior. Animals with genetic defects in leptin signaling become obese when supplied unlimited food. However, even when food supply is limited to prevent obesity, leptin still exerts profound effects on various organs, including the bones. These effects are mediated by the central nervous system, specifically hypothalamic neurons that respond to signals from neuropeptide Y (NPY), and, as Baldock and colleagues now show, they can be mimicked by defects in the NPY receptor Y2. The accelerated bone deposition in animals lacking leptin signaling might be thought to occur as a consequence of hormonal imbalance, possibly mediated by changes in corticosteroids or plasma calcium levels. However, Baldock et al. find no evidence for such a mechanism, and they suggest instead that rapid bone deposition and high trabecular bone volume result from direct neural control of bone growth. The absence of Y2, either specifically in the hypothalamus or throughout the body, yields the same increase in mineralized bone formation that was previously seen in leptin deficient animals. Double knockout animals, lacking both Y2 and leptin, show an identical bone phenotype, as expected if NPY signaling in the hypothalamus acts solely downstream of leptin. Baldock et al. speculate that autonomic nerves within the bone mediate the effects of hypothalamic signaling. How osteoclasts might recognize and respond to such stimuli remains an open question. Still, the emerging model of central control of bone metabolism clearly casts the genesis and control of osteoporosis in an entirely new light.
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