Mediation of leptin regulation of bone mass by serotonin

Abstract

Recent observations demonstrated that leptin, an adipocyte-derived hormone, is a major regulator of bone remodeling through the sympathetic nervous system. However, the molecular mechanisms used by leptin to regulate sympathetic activity that inhibits bone formation remain elusive. My sponsor’s laboratory is studying the influence of neuropeptides on bone formation, whose expression is regulated by leptin. Among these, serotonin is an interesting candidate, because in patients serotonin reuptake inhibitors affect bone remodeling. 5-Ht2c is a serotonin receptor most highly expressed in the hypothalamus and 5-Ht2c -/- mice display a low bone mass due to a decrease in bone formation. Furthermore, expression of Tph2 (an enzyme responsible for serotonin production in the brain) and serotonin levels in the hypothalamus, are both elevated in leptin-deficient mice. These observations suggest that serotonin acts downstream of leptin and upstream of sympathetic activity to regulate bone formation. To test this hypothesis, I will generate Tph2-Egfp Knock-in mice to assess whether Tph2 regulates bone mass and sympathetic activity. Using axon tracing, I will test if axonal projections of Tph2-expressing neurons target 5-Ht2c-expressing neurons in the hypothalamus. Finally, I propose to genetically and physiologically determine whether leptin and serotonin act in the same pathway regulating bone formation.