MCH Neurons Regulate Permeability of the Median Eminence Barrier

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. [Display omitted] MCH neurons provide dense projections to the median eminenceMCH neuron activation promotes permeability of the median eminence barrierMCH neuron activation enhances microvessel fenestration in the MEMCH neuron activation enhances leptin action in the arcuate nucleus Melanin-concentrating hormone (MCH)-expressing neurons in the lateral hypothalamus are regulators of energy homeostasis and sleep. Here, Jiang et al. report that they provide dense projection to the median eminence. MCH neuron activation enhances permeability of the median eminence barrier through increasing microvessel fenestration, thus facilitating leptin access to the hypothalamus.