Anatomical Determinants of Leptin and Melanocortins Regulation of Cardiovascular and Metabolic Autonomic Neurocircuitries

The central nervous system (CNS) autonomic network plays an important role in regulation of cardiovascular and metabolic functions. Leptin, a hormone secreted by adipose tissue, acts in the brain to regulate energy homeostasis, cardiovascular function, and several other physiological processes. The melanocortin system including the melanocortin-4 receptor (MC-4R) containing neurons is a key mediator of CNS leptin action. However, the anatomical substrates underlying cardiovascular and metabolic control by the leptin receptor (LepR) and MC-4R is unknown. We hypothesized that due to the physiological relationship between leptin and the melanocortin system that an anatomical relationship exists between the two. To test this, we utilized pseudorabies (PRV) tracing in mice bearing Cre-mediated expression of a fluorescent protein, td-Tomato. We assessed the presence of PRV-GFP injected into kidneys, or interscapular brown adipose tissue (iBAT) in td-Tomato labeled LepR or MC-4R neurons. At 5-6 days post-injection, we observed about 10% of LepR neurons that express PRV-GFP (after kidney or iBAT inoculation) in the preoptic nuclei and arcuate nucleus. Approximately 5% of LepR neurons in the lateral hypothalamic area, septal nucleus, ventral tegmental area, and nucleus tractus solitarius (nTS) were linked to kidney or iBAT. In contrast, about 10% of MC-4R neurons co-expressed PRV-GFP (after kidney or iBAT injection) in the periventricular nucleus of the hypothalamus and nTS. Interestingly, after injection into the kidneys, but not iBAT, PRV-GFP/MC-4R co-localization (5-10% of MC-4R neurons) was also detected in the agranular insular (AI) cortex and the amygdala (AMY). Many other common nuclei between the organ associated regions and either LepR neurons or MC-4R neurons such as the motor cortex and dorsal-medial hypothalamus did not appear to demonstrate any co-localization. Therefore, although LepR and MC-4R neurons are widely distributed throughout the brain those involved in regulation of cardiovascular or metabolic function appear to be localized to only a few specific areas. For most regions where LepR or MC-4R were co-expressed with PRV-GFP (kidney or iBAT), co-localization appeared to be mutually exclusive in that if co-localization was observed for either LepR neurons or MC-4R neurons then it was not observed for the other neuronal population. The only exception was the nTS which appeared to be a common nucleus for co-localization in that organ related neurons with LepR and those with MC-4R were both observed. All nuclei with LepR co-localization were common nuclei for kidney and iBAT inoculations. PVN and nTS are the two nuclei where MC4R neurons were commonly linked to both kidney and iBAT, but co-localization was also observed in the AI and AMY only after kidney inoculation. Our results suggest that LepR and MC-4R neurons may regulate cardiovascular and metabolic functions through a small number of distinct nuclei in the CNS autonomic network. Renal & Hypertension T32 DK007690; American Heart Association (834962) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.