OR04-03 Calcitonin Receptor Expressing Neurons in the PVH Regulate Feeding Behavior

The paraventricular nucleus of the hypothalamus (PVH) is a brain region crucial for energy homeostasis. Abnormal PVH development or damage leads to hyperphagic obesity and energy expenditure deficits underscoring the importance of PVH neuronal activity in energy balance control. Application of salmon calcitonin (sCT) to the PVH suppresses feeding and calcitonin receptor (CalcR) is highly expressed in the PVH of rodents suggesting that CalcR-expressing PVH neurons contribute to energy homeostasis. In situ hybridization reveals that many CalcR(PVH) neurons express melanocortin-4 receptor (MC4R), a receptor required for normal feeding behavior. To investigate the physiologic roles of CalcR(PVH) neurons, we generated CalcR-2a-Cre knock-in mice to manipulate CalcR-expressing cells. Deletion of MC4R from CalcR expressing cells using Cre-loxP technology resulted in profound obesity in both male and female mice by 16 weeks of age. This weight gain was attributable to hyperphagia, as cumulative food intake of the MC4R deleted mice was significantly greater than the controls and energy expenditure measurements acquired through CLAMS analysis were not significantly different. To determine the brain regions engaged by CalcR(PVH) neurons, we used anterograde Cre-dependent viral tracing reagents injected into the PVH of CalcR-Cre mice, and found that CalcR(PVH) neurons project to brain regions implicated in energy balance control, including the nucleus of the solitary tract and the parabrachial nucleus. To assess the acute effects of activating CalcR(PVH) neurons, we used DREADD technology to chemogenetically activate CalcR(PVH) neurons. CalcR(PVH) neuron activation suppressed feeding but had no significant effect on energy expenditure. To determine if the activity of CalcR(PVH) neurons is required for energy homeostasis, we silenced them using Cre-dependent tetanus toxin virus. Male mice with tetanus toxin silenced CalcR(PVH) neurons were obese 7 weeks following injection in part due to greater cumulative food intake; CLAMS analysis revealed no differences in energy expenditure. Mice with silenced CalcR(PVH) neurons as well as mice with CalcR deleted from the PVH had normal anorectic responses to sCT, suggesting sCT-induced anorexia does not require CalcR(PVH) neurons or CalcR expression in the PVH. Taken together, these findings suggest CalcR(PVH) neurons are an essential component of feeding and energy homeostatic circuitry.