Leptin controls bone formation through a hypothalamic relay

Menopause favors osteoporosis and obesity protects from it. In an attempt to decipher the molecular bases of these two well-known clinical observations, we hypothesized that they meant that bone remodeling, body weight, and reproduction are controlled by identical endocrine pathways. We used mouse genetics as a tool to translate these clinical observations into a molecular hypothesis. The ob/ob and db/db mice were valuable models, since two of the three functions thought to be co-regulated are affected in these mice: they are obese and hypogonadic. Surprisingly, given their hypogonadism, both mouse mutant strains have a high bone mass phenotype. Subsequent analysis of the mechanism leading to this high bone mass revealed that it was due to an increase of bone formation. All data collected indicate that, in vivo, leptin does not act directly on osteoblasts but rather through a central pathway following binding to its specific receptors located on hypothalamic nuclei. This result revealed that bone remodeling, like most other homeostatic functions, is under hypothalamic control. The nature of the signal downstream of the hypothalamus is unknown but current experiments are attempting to identify it.