Anatomical Substrate for Central Autonomic Control of Cardiovascular and Metabolic Functions by Leptin

Leptin, a hormone secreted by adipose tissue, is a critical signal influencing energy balance and blood pressure through modulation of the autonomic nervous system. However, the anatomical substrates for leptin regulation of the central autonomic network underlying cardiovascular and metabolic functions remains unknown. Here, we used a retrograde pseudorabies virus encoding a green fluorescent protein (PRV-GFP) in mice expressing a red fluorescent (td-Tomato) in leptin receptor (LepR) neurons to map the LepR neurons that project polysynaptically to the kidneys, liver, or the interscapular brown adipose tissue (iBAT). Mice expressing fluorescent tdTomato protein in the LepR neurons were sacrificed at 5, 6, or 7 days post-PRV-GFP injections, the brain imaged using confocal microscopy, and co-localization quantified of GFP and LepR neurons (tdTomato). We identified approximately 100 nuclei containing LepR neurons and more than 60 nuclei expressing GFP after PRV-GFP inoculation of the kidneys, liver, or iBAT. Interestingly, 42 nuclei contained both LepR and GFP neurons after PRV-GFP inoculation of either kidney, liver, or iBAT. Of these nuclei, we observed co-expression of tdTomato and GFP in only seven to eight nuclei dependent on the organ inoculated. After inoculation of PRV-GFP into kidneys, 26% of GFP expressing neurons in the preoptic nucleus (PO) co-localized with tdTomato corresponding to 9% of LepR expressing neurons. In the lateral hypothalamus (LH), 3% of GFP expressing neurons showed co-localization corresponding to 7% of LepR neurons. For the nucleus tract solitarius (NTS) 1% co-localization of GFP expressing neurons was observed corresponding to 4% of LepR neurons. For the liver, 35% co-localization was observed in the PO and 2.5% in the LH. For the iBAT, 20% co-localization was seen in the PO, 1.5% in the LH, and 8% in the NTS. Co-localization was also observed in other areas such as the septal nucleus, arcuate nucleus of the hypothalamus, dorsal and ventral medial hypothalamus, periaqueductal gray, and ventral tegmental area. Regardless of the organ inoculated, the soma sizes of organ associated neurons were different between various nuclei. For example, the soma size was significantly different between the LH and PO after liver and iBAT inoculation but not after kidney inoculation. In summary, LepR neurons projecting to the kidney, liver, or iBAT are present in specific regions such as the preoptic nucleus, some hypothalamic areas, and the NTS with the level of co-localization dependent on the organ. Our data suggest that although LepR neurons are distributed throughout the brain, those associated with the autonomic networks controlling cardiovascular and metabolic functions reside in specific regions of the brain. This work was partially supported by NIH (DK007690, DK112751, and HL162773), VA (BX004249 and BX006040), and the AHA Postdoctoral Fellowship (834962). 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.