Metabolic consequence of in vivo modulation of discrete serotonergic pathways.

Drugs augmenting serotonin bioavailability are among the most clinically effective compounds for weight loss and represent the gold-standard for obesity treatment research. Due to sibutramine's withdrawal from the clinic and the recent failure of the serotonin2C receptor agonist lorcaserin to achieve FDA approval, a major unmet clinical need has emerged. Here we propose a refined strategy to dissociate and manipulate a critical serotonin energy balance pathway in an effort to circumvent off-tar get effects produced by global serotonergic compounds and selective serotonin receptor agonists. Building on work generated in the previous funding period where we characterised a downstream pathway required for serotonin to regulate energy homeostasis, here we propose cutting-edge techniques coupled with recently developed tools to delineate and manipulate in real-time serotonin efferents providing these critical inputs to coordinate energy balance. Furthermore, we will interrogate the effect of dietary choice and adiposity on serotonin neuron sensitivity to these inputs and nutritional signals. Finally, we will delineate nutrients and nutritional cues that directly influence the sertotonin neuron activity, with the aim of revealing new system-specific targets for obesity pharmacotherapy.