Neuroanatomical organization and functional roles of PVN MC4R pathways in physiological and behavioral regulations

Abstract

Objective: The paraventricular nucleus of hypothalamus (PVN) is an integrative center in the brain orchestrating a wide range of physiological and behavioral responses. While the PVN melanocortin 4 receptor (MC4R) signaling (PVNMC4R+) is undoubtedly involved in feeding regulation, the neuroanatomical organization of PVNMC4R+ pathway and its role in diverse physiological and behavioral regulations have not been fully understood. Here we aimed to better characterize the input-output organization of PVNMC4R+ neurons and further test their potential functional roles beyond feeding. Methods: Using a combination of viral tools, we performed a comprehensive mapping of PVNMC4R+ circuits and tested the effects of chemogenetic activation of PVNMC4R+ neurons on thermogenesis, cardiovascular control and other behavioral regulations beyond feeding. Results: We found that PVNMC4R+ neurons broadly innervate many different brain regions known to be important not only for feeding but also for neuroendocrine and autonomic control of thermogenesis and cardiovascular function, including but not limited to preoptic area, median eminence, parabrachial nucleus, locus coeruleus, nucleus of solitary tract, ventrolateral medulla and thoracic spinal cord. Contrary to broad efferent projections, PVNMC4R+ neurons receive monosynaptic inputs from limited brain regions, including medial preoptic nucleus, arcuate and dorsomedial hypothalamic nuclei, and supraoptic nucleus. Consistent with broad efferent projections, chemogenetic activation of PVNMC4R+ neurons not only suppressed feeding but also led to an apparent increase in heart rate, blood pressure and brown adipose tissue thermogenesis. Strikingly, these physiological changes accompanied an unexpected repetitive bedding-removing behavior followed by hypoactivity and resting-like behavior. Conclusions: Our results clarify the neuroanatomical organization of PVNMC4R+ circuits and shed new light on the roles of PVNMC4R+ pathways in autonomic control of thermogenesis, cardiovascular function and other behavioral regulations.

Hypothalamic GPCR Signaling Pathways in Cardiometabolic Control

“…Moreover, pharmacological inhibition of MC4R restores normal BP in spontaneously hypertensive rats (SHR) with elevated SNA (da Silva et al, 2008). Consistent with these observations, our recent comprehensive anterograde tract-tracing revealed that PVN MC4R neurons densely innervate the ventrolateral medulla (VLM) and thoracic spinal cord (TSC) that are critical for sympathetic activation, and chemogenetic activation of PVN MC4R neurons not only suppresses feeding but also elevate BP and iBAT thermogenesis (Singh et al, 2021). These observations suggest the existence of distinct MC4R neuronal circuits for the regulation of different aspects of cardiometabolic homeostasis.…”

The rs17782313 polymorphism near MC4R gene confers a high risk of obesity and hyperglycemia, while PGC1α rs8192678 polymorphism is weakly correlated with glucometabolic disorder: a systematic review and meta-analysis

“…Melanocortin 4 receptor (MC4R), a member of the G proteincoupled receptor family and with alpha-melanocyte-stimulating hormone (a-MSH) as its ligand, is mainly distributed in the ventromedial hypothalamus and is a crucial modulator of food intake and energy homeostasis (13). Human MC4R gene is situated at the 18q21 region of chromosome 18.…”