Sensory Circumventricular Organs, Neuroendocrine Control, and Metabolic Regulation

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 recognized 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, and establish complex neural networks to hypothalamic neuroendocrine nuclei. Here, evidence for a potential role of sensory CVO-hypothalamic neuroendocrine networks in energy homeostasis is presented.

Pathophysiology and Therapy of Associated Features of Migraine

“…Both the nucleus tractus solitarius and dorsal motor nucleus of the vagus conform, along with the area postrema, the dorsal vagal complex, which is one of the main termination sites of the afferent fibres of the vagal nerve [ 67 ] and has a high distribution of dopamine D 2–4 receptors [ 68 ]. The area postrema is one of the sensory circumventricular organs with a possible chemoreceptive function, situated outside the blood–brain barrier and connected to the hypothalamus, which is thought to be essential in controlling neuroendocrine functions [ 69 ], is rich in type D 2 dopamine receptors [ 70 ] and is the brain area with the higher estimates of substance P [ 71 ].…”

Positioning-dependent bidirectional NELL2 signaling in the brain

“…However, a physiological NELL2 function has not been well determined in adult mammalian brains. Interestingly, our anatomical approaches to determining brain distribution of NELL2 revealed a relatively high expression of NELL2 in terms of both mRNA and protein levels in multiple cardiometabolic nuclei, including the subfornical organ (SFO), paraventricular and ventromedial hypothalamic nucleus (PVN and VMH, respectively), and the arcuate nucleus (ARC) in adult rodent brains (4,20). Especially in the ARC, NELL2 expression is detected on proopiomelanocortin (POMC) cells as well as cells expressing neuropeptide Y (NPY) (20).…”

“…Interestingly, our anatomical approaches to determining brain distribution of NELL2 revealed a relatively high expression of NELL2 in terms of both mRNA and protein levels in multiple cardiometabolic nuclei, including the subfornical organ (SFO), paraventricular and ventromedial hypothalamic nucleus (PVN and VMH, respectively), and the arcuate nucleus (ARC) in adult rodent brains (4,20). Especially in the ARC, NELL2 expression is detected on proopiomelanocortin (POMC) cells as well as cells expressing neuropeptide Y (NPY) (20). In the context of central cardiometabolism regulation, the SFO and ARC are believed to be the forebrain gates for circulating cardiometabolic signaling molecules, and transform the information into the deep brain regions, such as the PVN, to regulate neuroendocrine and autonomic outcomes for the preservation of cardiometabolic homeostasis (21,22).…”

“…In the context of central cardiometabolism regulation, the SFO and ARC are believed to be the forebrain gates for circulating cardiometabolic signaling molecules, and transform the information into the deep brain regions, such as the PVN, to regulate neuroendocrine and autonomic outcomes for the preservation of cardiometabolic homeostasis (21,22). Following these anatomical observations, studies utilizing the loss-of-function approach further demonstrated an involvement of NELL2 in metabolism regulation (20). Hypothalamus-targeted ablation of NELL2 biosynthesis in adult rats resulted in a reduction in daily food intake and body weight gain.…”

“…Especially in the ARC, NELL2 expression is detected on proopiomelanocortin (POMC) cells as well as cells expressing neuropeptide Y (NPY) ( 20 ). In the context of central cardiometabolism regulation, the SFO and ARC are believed to be the forebrain gates for circulating cardiometabolic signaling molecules, and transform the information into the deep brain regions, such as the PVN, to regulate neuroendocrine and autonomic outcomes for the preservation of cardiometabolic homeostasis ( 21 , 22 ). Following these anatomical observations, studies utilizing the loss-of-function approach further demonstrated an involvement of NELL2 in metabolism regulation ( 20 ).…”