Ablation of oxytocin neurons causes a deficit in cold stress response

The paraventricular nucleus (PVN) is a critical locus of energy balance control.Three sets of neurons in the PVNare involved in regulating energy balance: oxytocin-expressing neurons (OXT-neurons), thyrotropinreleasing hormone-expressing neurons, and corticotrophin-releasing hormone-expressing neurons. To examine the role of OXT-neurons in energy balance, we ablated these neurons in mice by injecting diphtheria toxin into mice possessing both the oxytocin promoter driving cre expression and a creinducible diphtheria toxin receptor. Immunohistochemistry and real-time reverse transcriptase polymerase chain reaction confirmed that this injection caused a significant decrease in PVN OXT-neurons andOXT-mRNAabundance. OXT-neuron ablation did not alter food intake,weight, or energy expenditure at room temperature on either chow or a high-fat diet. To further characterize OXT-neuron-ablatedmice, we examined their response to 1) intraperitoneal cholecystokinin (CCK) injection and 2) thermogenic stress. OXT-neuron-ablatedmice had a blunted decrease in feeding response toCCK.When exposed to the extreme cold (4°C) for 3 hours, OXT-neuron-ablated mice had significant decreases in both rectal and brown adipose tissue temperature relative to controls, which was rescued by OXT treatment. Thermographic imaging revealed that OXT-neuron-ablatedmice had increased body surface temperature. Thus, we report that OXT-neuron ablation shows no role for OXT-neurons in energy homeostasis at neutral temperature but reveals a heretofore unappreciated role for OXT-neurons and oxytocin specifically in regulating the thermogenic stress response.