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Sensory Circumventricular Organs, Neuroendocrine Control, and Metabolic Regulation

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Sensory Circumventricular Organs, Neuroendocrine Control, and Metabolic Regulation H OH metabolites OH Review Sensory Circumventricular Organs, Neuroendocrine Control, and Metabolic Regulation Jin Kwon Jeong , Samantha A. Dow and Colin N. Young * Department of Pharmacology and Physiology, School of Medicine and Health Sciences, The George Washington University, 2300 I St NW, Washington, DC 20037, USA; [email protected] (J.K.J.); [email protected] (S.A.D.) * Correspondence: [email protected]; Tel.: +1-202-994-9575; Fax: +1-202-994-287 Abstract: The central nervous system is critical in metabolic regulation, and accumulating evidence points to a distributed network of brain regions involved in energy homeostasis. This is accomplished, in part, by integrating peripheral and central metabolic information and subsequently modulating neuroendocrine outputs through the paraventricular and supraoptic nucleus of the hypothalamus. However, these hypothalamic nuclei are generally protected by a blood-brain-barrier limiting their ability to directly sense circulating metabolic signals—pointing to possible involvement of upstream brain nuclei. In this regard, sensory circumventricular organs (CVOs), brain sites traditionally recog- nized in thirst/fluid and cardiovascular regulation, are emerging as potential sites through which circulating metabolic substances influence neuroendocrine control. The sensory CVOs, including the subfornical organ, organum vasculosum of the lamina terminalis, and area postrema, are located outside the blood-brain-barrier, possess cellular machinery to sense the metabolic interior milieu, Citation: Jeong, J.K.; Dow, S.A.; and establish complex neural networks to hypothalamic neuroendocrine nuclei. Here, evidence Young, C.N. Sensory for a potential role of sensory CVO-hypothalamic neuroendocrine networks in energy homeostasis Circumventricular Organs, is presented. Neuroendocrine Control, and Metabolic Regulation. Metabolites Keywords: subfornical organ; organum vasculosum of the lamina terminalis; area postrema; hy- 2021, 11, 494. https://doi.org/ pothalamus; metabolism 10.3390/metabo11080494 Academic Editors: Giancarlo Panzica, Stefano Gotti, Paloma Collado Guirao 1. Introduction and Peter Meikle Precise and reciprocal interactions between the central nervous system (CNS) and Received: 10 June 2021 peripheral organs plays an integral role in whole body metabolic homeostasis, and impair- Accepted: 27 July 2021 ments in this CNS-peripheral communication are clearly implicated in the development Published: 29 July 2021 of metabolic disorders. This encompasses a wide range of conditions including obesity, type II diabetes, hypertriglyceridemia, non-alcoholic fatty liver disease, and insulin re- Publisher’s Note: MDPI stays neutral sistance, to name a few [1–6]. Within the CNS, a network of brain regions are involved with regard to jurisdictional claims in in metabolic regulation, however, it is generally accepted that metabolic information published maps and institutional affil- from both peripheral and central inputs will eventually be integrated into the hypotha- iations. lamus [4,5,7]. Hypothalamic nuclei, in particular the paraventricular nucleus (PVN) and supraoptic nucleus (SON), possess a wide array of neuroendocrine neurons, and therefore are considered as regions central to neuroendocrine regulation. However, the majority of circulating factors (hormones, adipokines, metabolites, etc.) cannot directly access Copyright: © 2021 by the authors. these hypothalamic nuclei as they are protected by the blood-brain barrier (BBB) and/or Licensee MDPI, Basel, Switzerland. substances are transported in limited quantity across the BBB; specialized endothelial This article is an open access article cells located between the bloodstream and brain as a protective barrier against circulating distributed under the terms and toxins and pathogens [8,9]. This suggests involvement of other brain region(s) upstream of conditions of the Creative Commons the PVN/SON in neuroendocrine-dependent metabolic homeostasis. In this regard, the Attribution (CC BY) license (https:// sensory circumventricular organs (CVOs) are a key candidate, considering that: (1) They creativecommons.org/licenses/by/ are located outside the BBB; (2) They possess the cellular machinery to detect circulating 4.0/). Metabolites 2021, 11, 494. https://doi.org/10.3390/metabo11080494 https://www.mdpi.com/journal/metabolites Metabolites 2021, 11, x FOR PEER REVIEW 2 of 16 Metabolites 2021, 11, 494 2 of 16 information, and; (3) They establish direct and/or indirect synaptic networks to hypotha- information, and; (3) They establish direct and/or indirect synaptic networks to hypothala- lamic neuroendocrine nuclei (Figure 1). Here, we will discuss existing anatomical, func- mic neuroendocrine nuclei (Figure1). Here, we will discuss existing anatomical, functional, tional, and circuit level evidence pointing to the involvement of sensory CVOs in neuro- and circuit level evidence pointing to the involvement of sensory CVOs in neuroendocrine endocrine regulated control of metabolism. regulated control of metabolism. Figure 1. Schematic illustration showing potential sensory CVO-hypothalamic networks involved in metabolism regulation. Figure 1. Schematic illustration showing potential sensory CVO-hypothalamic networks involved in metabolism regula- Eachtion. ofEach the of sensory the sensory CVOs CVOs possesses possesses the cellular the cellular machinery machinery to sense to multiple sense multiple metabolic metabolic factors, a factors, few of whicha few areof which shown are in theshown image. in the At image. the same At time,the same sensory time, CVOs sensory also CVOs establish also establish direct (solid direct line) (solid as well line) as as indirect well as indirect synapses synapses (dashed (dashed line) to hypothalamicline) to hypothalamic metabolic metabolic nuclei including nuclei including the PVN andthe SON.PVN and Multiple SON. investigations Multiple investigations have demonstrated have demon the involvementstrated the in- of thevolvement sensory of CVOs the sensory in metabolism CVOs in regulation, metabolism and regulation, further suggest and further that suggest hypothalamic that hypothalamic AVP and oxytocin AVP and (OXT) oxytocin may play(OXT) a keymay role. play Image a key wasrole. createdImage was with created Biorender.com. with Biorender.com. 2. Arcuate Nucleus Involvement in Metabolic Regulation Before discussingdiscussing a a neuroendocrine-metabolic neuroendocrine-metabolic role role of theof sensorythe sensory CVOs, CVOs, it is important it is im- topo considerrtant to consider what has what been has the been predominant the predominant focus of focus the field.of the Since field. theSince identification the identifica- of densetion of leptin dense receptors leptin receptors in hypothalamic in hypothalamic nuclei [ 10nuclei], numerous [10], numerous investigations investigations have focused have onfocused hypothalamic on hypothalamic neural neural circuits circuits in whole in whole body body metabolic metabolic regulation, regulation, in particular in particular an arcuatean arcuate nucleus-dependent nucleus-dependent axis axis [3,11 [3,11]]. The. The arcuate arcuate nucleus nucleus is a is small a small region region located located in the in mediobasalthe mediobasal hypothalamus hypothalamus adjacent adjacent to the to third the third ventricle ventricle (3V) and (3V) median and median eminence. eminence. While someWhile studiessome studies have proposed have proposed the arcuate the arcuate nucleus nucleus as a part as ofa part the CVOsof the [CVOs12], this [12] region, this inregion fact possessesin fact possesses an intact an BBB,intact and BBB, is and therefore, is therefore, fully protectedfully protected from from the circulation the circulation [13]. Nevertheless,[13]. Nevertheless, the arcuate the arcuate nucleus nucleus plays plays a key rolea key in role metabolic in metabolic regulation, regulation, due to due an ability to an ofability circulating of circulating factors factors to access to access the region the region through through the median the median eminence eminence and/or and/or median me- eminence-3Vdian eminence complex-3V complex [14,15 [14,15]]. The arcuate possesses two functionally opposing neuronal populations: neurons ex- pressing proopiomelanocortinproopiomelanocortin (POMC) (POMC) and and those those producing producin agouti-relatedg agouti-related peptide peptide (AgRP) and(AgRP) neuropeptide and neuropeptide Y (NPY) Y [3 (NPY),16,17]. [3,16,17] Although. Although these neuronal these neuronal populations populations synaptically synap- in- nervatetically innervate multiple multiple brain regions, brain hypothalamicregions, hypothalamic neuroendocrine neuroendocrine nuclei, particularly nuclei, particularly the PVN, Metabolites 2021, 11, 494 3 of 16 are main targets. Conversely, POMC and AgRP/NPY receive dense inputs from regions throughout the CNS (detailed in ref [18]). When activated by satiety signals, such as leptin, estrogen, and insulin, POMC neurons produce and release alpha-melanocyte stimulating hormone (α-MSH) into other brain regions (e.g., PVN) as a neurotransmitter to decrease appetite while also increasing energy expenditure [3,19]. On the other hand, AgRP/NPY neurons release hunger factor-induced inhibitory neurotransmitters to negatively regulate POMC neuronal activity (Jeong 2014). In brief, a balance between POMC and AgRP/NPY neurons is thought to be key to the modulation of energy homeostasis [16,17]. In addition to neuronal populations within the arcuate
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