Towards a serotonin-dependent leptin roadmap in the brain

Leptin exerts control over energy metabolism, reproduction and bone mass accrual, raising the question does leptin act through a common neuronal circuit to mediate these effects? Historically, the hypothalamus has been viewed as the site for leptin signaling in the brain. Recent genetic studies, however, indicate that these physiological functions, notably the regulation of appetite and bone mass accrual by leptin, take place for the most part through inhibition of serotonin (5-hydroxytryptamine) synthesis and release by brainstem neurons. Here, we review how these findings have redefined the roadmap of leptin signaling in the brain. This has led to proof-of-principle studies showing that selective inhibition of the leptin–serotonin axis is a viable therapeutic approach to treat appetite disorders.