The Blood-Cerebrospinal Fluid (CSF) Barrier Transports Circulating Ghrelin Into The Brain

URIARTE, MAIA; DE FRANCESCO, PABLO NICOLÁS; CABRAL, AGUSTINA; FERNÁNDEZ, GIMENA; GARCÍA ROMERO, GUADALUPE; PERELLO, MARIO

Buenos Aires

Congreso; Reunión Conjunta de las Sociedades De Biociencias; 2017

Sociedad Argentina de Investigación Clínica (SAIC), SAIB, SAI, SAFIS, SAB, SAFE, SAH, SAP, SAA, SAB

Ghrelin is a stomach-derived orexigenic peptide hormone that mainly acts in the central nervous system. The mechanisms transporting plasma ghrelin to the brain are yet to be elucidated. The goal of the current study was to test the hypothesis that the CSF-blood barrier transports circulating ghrelin to the brain. First, we centrally infused a fluorescent ghrelin analog to mice and found that the tracer labeled the ependymal cells of the choroid plexus and the hypothalamic tanycytes, which form the CSF-blood barrier. Then, we performed a time course study by subcutaneously infusing the fluorescent ghrelin to mice. In this experiment, we found that the probe labeled the tanycytes and the choroid plexus at early time points (~5 min) while the hypothalamic periventricular brain parenchyma was labeled ~15 min after the injection. Notably, the ghrelin analog increased food intake in the mice when injected both centrally and peripherally (p≤0.01). In a subsequent experiment, we tested the effect of peripherally-injected ghrelin in mice that had been centrally- injected with a scrambled ghrelin peptide. We found that the ability of ghrelin to both increase food intake and activate the marker of neuronal activation, c-Fos, in the hypothalamus was impaired in mice previously injected with the scrambled peptide, as compared with the control animals (analyzed by two way anova, p˂0.0001), suggesting that the accessibility of ghrelin to the brain depends on a saturable mechanism. In order to test whether the access of circulating ghrelin to the brain parenchyma requires its passage thru the CSF, we centrally injected an anti-ghrelin antibody 15 min before a subcutaneous injection of ghrelin. Interestingly, the anti-ghrelin treatment decreased food intake (analyzed by two way anova, p˂0.05). Thus, we conclude that the cells of the CSF-blood barrier are involved in the blood to brain transport of ghrelin by a saturable mechanism, which would require passing through the CSF.