Delineation of discrete brain circuitry regulating obesity and type 2 diabetes in mice. (360G-Wellcome-081713_Z_06_Z)

Recently, substantial support for central serotonin (through 5-HT2C and 5-HT1B receptors) and melanocortin (through melanocortin4 receptors (MC4Rs)) systems in the regulation of energy balance and insulin/glucose homeostasis has been reported in genetic and pharmacological studies. Linking these two key pathways together, my laboratory recently observed that 5-HT2C/1B receptor agonists promote hypophagia and produce improvements in insulin and glucose regulation in a MC4R-dependent manner. Here I propose to identify discrete populations of upstream serotonin- and downstream MC4R-expressing neurons underlying the serotonergic modulation of energy balance and glucose homeostasis and to determine the importance of activity at the endogenous melanocortin agonist (POMC/ -MSH)/antagonist (AgRP) and serotonin 5-HT2C/5-HT1B receptors in these effects. Finally, I will identify peripheral target tissues through which serotonin-MC4R pathways affect satiety and glucose metabolism. Aim 1 : To identify discrete populations of serotonin neurons involved in the modulation of energy balance and glucose homeostasis. Aim 2: To determine whether regulation of POMC/AgRP and activation of 5-HT2CR/5-HT1BR underlies serotonin s effects on energy balance and glucose homeostasis. Aim 3: To identify and characterize distinct populations of MC4R-expressing neurons critical for serotonin s effects on energy balance and glucose homeostasis. Aim 4: To identify key downstream periphera l mechanisms of central serotonin-MC4R-regulated satiety and glucose metabolism.