MCH Neurons Regulate Permeability of the Median Eminence Barrier

Abstract

Summary Melanin-concentrating hormone (MCH)-expressing neurons are key regulators of energy and glucose homeostasis. Here, we demonstrate that they provide dense projections to the median eminence (ME) in close proximity to tanycytes and fenestrated vessels. Chemogenetic activation of MCH neurons as well as optogenetic stimulation of their projections in the ME enhance permeability of the ME by increasing fenestrated vascular loops and enhance leptin action in the arcuate nucleus of the hypothalamus (ARC). Unbiased phosphoRiboTrap-based assessment of cell activation upon chemogenetic MCH neuron activation reveals MCH-neuron-dependent regulation of endothelial cells. MCH neurons express the vascular endothelial growth factor A (VEGFA), and blocking VEGF-R signaling attenuates the leptin-sensitizing effect of MCH neuron activation. Our experiments reveal that MCH neurons directly regulate permeability of the ME barrier, linking the activity of energy state and sleep regulatory neurons to the regulation of hormone accessibility to the ARC.

What is the physiological role of hypothalamic tanycytes in metabolism?

“…During fasting, the tanycyte interface is reshaped to improve the access of metabolic signals to the ARH and to induce meal initiation (30). This reorganization could be induced by tanycytes themselves through metabolic sensing (30) as well as by neurons (32). Second, tanycytes are also able to modulate neuronal functions by releasing both orexigenic and anorexigenic molecules, what we will call "tanykines," into the hypothalamic parenchyma such as diazepam-binding inhibitor (DBI) (33,34), purines (26,28,35,36), triiodothyronine (T3) (37), chemerin (38), and prostaglandin E2 (PGE2) (39) (Fig.…”

Brain Barriers and brain fluids research in 2020 and the fluids and barriers of the CNS thematic series on advances in in vitro modeling of the blood–brain barrier and neurovascular unit

“…Neuronal regulation of brain endothelial function also occurs in areas without a BBB. Thus, Jiang et al [31] found that melanin-concentrating hormone-expressing neurons regulate the permeability of blood vessels of the median eminence via vascular endothelial growth factor signaling. Another type of BBB regulation can occur with parenchymal cell death.…”

Acute changes in systemic glycaemia gate access and action of GLP-1R agonist on brain structures controlling energy homeostasis

“…First order neurons, such as AgRPand POMC-neurons, have an exquisite location close to the capillary loops arising from the ME (Schaeffer et al, 2013), with a tightly regulated permeability that allows central access of circulating molecules via CVOs (Banks, 2019;Prevot et al, 2018). Permeability of the ME vascular loops reaching the ARC is tightly regulated by tanycytes, which are glucosesensing cells (Frayling et al, 2011) and one of the main sources of VEGF-A in the ME (Jiang et al, 2020;Langlet et al, 2013a;Langlet et al, 2013b). The tanycytes regulate the direct access of blood-borne molecules to ARC neurons by controlling capillary fenestration.…”

“…In conditions of nutrient overload or uncontrolled plasma glucose, systemic VEGF-A could bypass tanycytic-born VEGF-A signaling, thus leading to local adaptations in the ARC. A recent study shows that activation of melanin-concentrating hormone (MCH) neurons in the lateral hypothalamic area also regulates ME/ARC vessels' permeability possibly via the release of VEGF-A (Jiang et al, 2020). However, because insulin has been shown to have a strong inhibitory effect on MCH neurons (Silva et al, 2009), they are unlikely to be involved in the hypoglycemia/insulin-promoted facilitation of the access of GLP1-R agonists to the ARC.…”