Figure 4.

Access of ghrelin signal to its neuronal targets. This schema summarizes the three hypothetic access routes of ghrelin toward its neuronal targets (cf Figure 2). First, ghrelin would be able to target neuronal networks thanks to specific transcellular transports at the level of blood–brain barrier (BBB) located on brain capillaries (purple arrows). Most ghrelin sensitive areas present blood–brain barrier vasculature and this route represent the main one described in all regions of the brain. However free-BBB regions, called the median eminence and the area postrema, are recorded in the hypothalamus and the brainstem respectively. These areas contain a rich fenestrated vasculature, which could represent a direct vascular route while allowing passive diffusion of peripheral ghrelin (red arrows). This route may be responsible of acute regulation and complete chronic feedback accomplished by uptake of circulating molecules via receptor-mediated transport across the blood–brain barrier. Finally, activation of brainstem areas by ghrelin may occur without the entrance of ghrelin in the brain, but through its binding to gastric vagal afferent neurons (orange). Acc, accumbens nucleus; ACh, acétylcholine; AgRP, agouti-related peptide; AP, area postrema; ARC, arcuate nucleus; CART, cocaine- and amphetamine-regulated transcript; CRH, corticotropin-releasing hormone; DA, dopamine; DYN, dynorphin; ENK, enkephalin; GABA, γ-aminobutyric acid; GHRH, growth-hormone-releasing hormone; GLU, glutamate; LDTg, laterodorsal tegmental area; LHA, lateral hypothalamic area; MCH, melanin-concentrating hormone; ME, median eminence; NPY, neuropeptide Y; NTS, nucleus of the solitary tract; POMC, pro-opiomelanocortin; PVN, paraventricular nucleus; TRH, thyrotropin releasing hormone; VMH, ventromedial nucleus; VTA, ventral tegmental area.