Leptin controls bone formation through a hypothalamic relay

Menopause favors osteoporosis and obesity protects from it. In an attempt t o decipher the molecular bases of these two well-known clinical observation s, we hypothesized that they meant that bone remodeling, body weight, and r eproduction are controlled by identical endocrine pathways. We used mouse g enetics 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 th e three functions thought to be co-regulated are affected in these mice: th ey are obese and hypogonadic. Surprisingly, given their hypogonadism, both mouse mutant strains have a high bone mass phenotype. Subsequent analysis o f 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 le ptin does not act directly on osteoblasts but rather through a central path way following binding to its specific receptors located on hypothalamic nuc lei. This result revealed that bone remodeling, like most other homeostatic functions, is under hypothalamic control. The nature of the signal downstr eam of the hypothalamus is unknown but current experiments are attempting t o identify it.