Figure 1. Leptin signaling in the central nervous system recruits the sympathetic nervous system to inhibit bone mass accrual.

Leptin, a hormone responsible for enforcing energy balance, is a powerful regulator of bone mass. Leptin signals in the dorsal raphe of the brainstem to inhibit serotonin synthesis by Tph2. Serotonergic neurons from the dorsal raphe synapse at several nuclei in the hypothalamus including the VMH. Htr2c signaling in the VMH inhibits sympathetic nervous system activity in the skeleton, thereby inhibiting bone mass accrual. Within the skeleton, the sympathetic nervous system releases norepinephrine, which signals on osteoblasts to stimulate bone resorption and inhibits bone formation. In mice, norepinephrine signals through Adrb2, but in humans, sympathetic norepinephrine signals through both Adrb1 and Adrb2. The effects of norepinephrine signaling on bone mass accrual are conserved between mice and humans. Altogether, this series of findings made several points. First, an energy metabolism hormone does regulate bone mass accrual, a process that consumes a great deal of energy. Second, the central nervous system controls bone mass. Third, the sympathetic nervous system is a powerful inhibitor of bone mass accrual.