Central Autonomic Network Underlying Cardiometabolic Coupling: Role of the Leptin Receptor Neurons
Authors: Williams Paul , Rahmouni Kamal , Guo Deng-Fu 
Published: May 2024

The autonomic network of the central nervous system (CNS) play an important role in the regulation of many physiological functions. Obesity is often associated with hypertension which is a serious medical condition that increase mortality. Therefore, obesity-induced hypertension may be the consequence of a cardiovascular-metabolic coupling in the CNS autonomic network. Leptin, a hormone secreted by adipose tissue, acts in the brain to regulate energy homeostasis, cardiovascular function, and several other physiological processes. We and others have previously shown the existence of shared nuclei in the autonomic network innervating organs such as the kidney, liver, and brown adipose tissue (BAT). However, whether there are shared neurons within these nuclei associated with these three organs and the anatomical substrates underlying cardiovascular and metabolic control by the leptin receptor (LepR)-containing neurons are unknown. To address this, two groups of wildtype mice received injections of pseudorabies virus (PRV) expressing a green fluorescent protein (GFP) into both kidneys and PRV expressing a red fluorescent protein (RFP) in either the interscapular BAT (iBAT) or the left lobe of the liver. Additionally, mice bearing Cre-mediated expression of a fluorescent protein, td-Tomato, in LepR neurons were injected with PRV in either the kidneys, liver, or iBAT. The animals were sacrificed 5-7 days post-injection and perfused. The brains were extracted, sectioned at 50 μm thickness, stained, and imaged with confocal microscopy. Sections were matched to the mouse brain atlas (Franklin & Paxinos) and neurons co-expressing GFP and RFP throughout the brain were identified. For the double-organ injections, soma morphology was measured using ImageJ software. We found several nuclei in which neurons were co-labeled with GFP (kidney) and RFP (BAT or liver). Co-expressing neurons were observed in areas such as the cortical regions (motor cortex and amygdala), hypothalamus (paraventricular nucleus (PVN), lateral hypothalamus (LH), and dorsomedial hypothalamus (DMH)), midbrain regions such as the periaqueductal gray, and brainstem nuclei such as the locus coeruleus (LC). In general, there appeared to be two scenarios for shared nuclei: 1) in regions such as LH, nucleus of the solitary tract, and dorsal motor nucleus of vagus there was little to very little co-expression, and 2) in regions such as PVN, DMH, LC, and motor cortex there was moderate to high levels of co-expression. Using the Kolmogorov-Smirnov test the kidney and iBAT soma sizes for the PVN, motor cortex, and LC were statistically different (p<0.05), but not for the LH (p>0.1). 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. Many other common nuclei between the organ associated regions and LepR neurons such as the amygdala and dorsal-medial hypothalamus did not appear to demonstrate any co-localization. This is the first study to provide anatomical evidence linking the autonomic networks regulating cardiovascular and metabolic functions. Moreover, our data show that although there is overlap of neurons in diverse nuclei there may also be a difference in morphological phenotype in the nuclei associated with cardiovascular vs metabolic functions. Our results suggest that leptin may couple cardiovascular and metabolic regulation through a small number of neurons in the CNS autonomic network. Renal & Hypertension T32 (DK007690), American Heart Association (834962), and Diabetes T32 (DK112751). This is the full abstract presented at the American Physiology Summit 2024 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.