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The Role of PVN MC4R Neural Pathway in Autonomic Control of Metabolic Homeostasis and Cardiovascular Function
Author(s) -
Singh Uday,
Saito Kenji,
Cui Huxing
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.05152
Subject(s) - rostral ventrolateral medulla , lateral parabrachial nucleus , hypothalamus , solitary tract , melanocortin , spinal cord , medicine , endocrinology , energy homeostasis , dorsal motor nucleus , nucleus , neuroscience , arcuate nucleus , homeostasis , biology , parabrachial nucleus , central nervous system , medulla oblongata , vagus nerve , receptor , stimulation
Central melanocortin pathways, mainly via acting on melanocortin‐4 receptor (MC4R), play an important role in both energy balance and sympathetic traffics affecting cardiovascular function. MC4R deficiency in both humans and rodents causes obesity, insulin resistance and diabetes while maintaining low to normal sympathetic tone and blood pressure, suggesting a critical role of MC4R signaling in metabolic homeostasis and obesity‐associated sympathetic overdrive and hypertension. MC4R is widely expressed in the brain including hypothalamic paraventricular nucleus (PVN) which functions as an integrative center for energy metabolism and autonomic regulation. However, whether and how PVN MC4R pathways contribute to the sympathetic control of cardiovascular function and metabolic homeostasis remain incompletely understood. In present study, we first comprehensively mapped afferent projections of PVN MC4R neurons by stereotaxically delivering Cre‐dependent AAV driving expression of eYFP into the PVN of MC4R‐Cre knock‐in mice, which allow targeted anterograde tract‐tracing of PVN MC4R neurons throughout the brain. In addition to known brain region for feeding behavior (i.e. parabrachial nucleus), we found broad innervations of PVN MC4R neurons to various brain regions important for autonomic‐cardiovascular control and energy metabolism, including but not limited to nucleus of solitary tractus , dorsal motor nucleus of vagus, rostral ventrolateral medulla (RVLM) and spinal cord. Using a combination of sophisticated viral tools, we further reveal that thoracic spinal cord‐projecting PVN MC4R neurons are exclusively located in the posterolateral PVN and send collateral projections to RVLM. Functionally, microinjection of synthetic MC4R agonist (MTII) into the PVN evokes renal sympathetic nerve activity in anesthetized mice and chemogenetic activation of PVN MC4R neurons elevates blood pressure and decreases food intake in freely moving animals. Additionally, genetic ablation of PVN MC4R neurons in adult mice using Cre‐dependent AAV expressing Casp3 causes hyperphagia and massive weight gain (over 80% increase within 6 weeks). These results provide an important insight into the role of PVN MCR neural circuits in regulating metabolic homeostasis and cardiovascular function. Optogenetic and chemogenetic studies are ongoing to functionally dissect the neural circuits downstream of PVN MC4R neurons. Support or Funding Information National Institute of Health (R01), AHA Postdoctoral Grant Award (19POST34450083)