Melanocortin-4 receptor-expressing neurons in the paraventricular nucleus contribute to hypercapnic chemosensitivity

Obesity increases the risk of respiratory diseases associated with reductions in chemosensitivity. Evidence suggests that obesity causes changes in the brain that may underly a reduction in chemosensitivity. Melanocortin-4 Receptors (MC4R)—densely expressed in the paraventricular nucleus (PVN)—play a large role in bodyweight and energy regulation and are downregulated in an obese state. We sought to determine the extent to which chemogenetic activation or inhibition of MC4R-expressing neurons in the PVN (PVN MC4R ) affects chemosensitivity. Mice expressing cre-recombinase in MC4R-expressing neurons (MC4R-cre mice) were placed on either a chow (18% kcal from fat) or a high-fat diet (45% kcal from fat) for at least 12 weeks. Mice were then bilaterally injected with a cre-dependent DREADD virus targeted to the PVN. Lean mice received an inhibitory (hM4D(Gi)) while obese mice received an excitatory (hM3D(Gq)) virus. After recovery from surgery, and 30 minutes after an injection of clozapine-N-oxide or vehicle, the hypercapnic ventilatory response (HCVR) was measured at ZT 0-2 using whole-body plethysmography. As expected, the HCVR of vehicle-injected obese mice was reduced compared to vehicle-injected lean mice. Exciting the PVN MC4R neurons of obese mice improved their HCVR to a magnitude similar to lean controls. Moreover, inhibiting the PVN MC4R neurons of lean mice reduced the animal’s HCVR to the same degree as obesity. These results suggest that the relative activity of PVN MC4R neurons may contribute to the changes in chemosensitivity observed during obesity. National Institute of Health: R15HL170276-01 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.