Ghrelin is a peptide hormone mainly secreted from gastrointestinal tract that acts via the growth hormone secretagogue receptor (GHSR), which is highly expressed in the brain. Strikingly, the accessibility of ghrelin to the brain seems to be limited and restricted to few brain areas. Previous studies in mice have shown that ghrelin can access the brain via the blood-cerebrospinal fluid (CSF) barrier, an interface constituted by the choroid plexus and the hypothalamic tanycytes. Here, we performed a variety of in vivo and in vitro studies to test the hypothesis that the transport of ghrelin across the blood-CSF barrier occurs in a GHSR-dependent manner. In vivo, we found that the uptake of systemically administered fluorescent ghrelin in the choroid plexus epithelial (CPE) cells and in hypothalamic tanycytes depends on the presence of GHSR. Also, we detected lower levels of CSF ghrelin after a systemic ghrelin injection in GHSR-deficient mice, as compared to WT mice. In vitro, the internalization of fluorescent ghrelin was reduced in explants of choroid plexus from GHSR-deficient mice, and unaffected in primary cultures of hypothalamic tanycytes derived from GHSR-deficient mice. Finally, we found that the GHSR mRNA is detected in a pool of CPE cells, but is nearly undetectable in hypothalamic tanycytes with current approaches. Thus, our results suggest that circulating ghrelin crosses the blood-CSF barrier mainly by a mechanism that involves the GHSR, and also possibly via a GHSR-independent mechanism.

Ghrelin 是一种主要从胃肠道分泌的肽激素，通过在大脑中高度表达的生长激素促分泌素受体 (GHSR) 发挥作用。引人注目的是，ghrelin 对大脑的可及性似乎是有限的，并且仅限于少数大脑区域。先前对小鼠的研究表明，ghrelin 可以通过血脑脊液 (CSF) 屏障进入大脑，该屏障由脉络丛和下丘脑单核细胞构成。在这里，我们进行了各种体内和体外研究，以检验生长素释放肽通过血脑脊液屏障的转运以 GHSR 依赖性方式发生的假设。体内，我们发现脉络丛上皮 (CPE) 细胞和下丘脑单核细胞中全身施用的荧光 ghrelin 的摄取取决于 GHSR 的存在。此外，与 WT 小鼠相比，我们在 GHSR 缺陷小鼠全身注射 ghrelin 后检测到较低水平的 CSF ghrelin。体外在 GHSR 缺陷小鼠的脉络丛外植体中，荧光 ghrelin 的内化减少，而在来自 GHSR 缺陷小鼠的下丘脑单核细胞原代培养物中不受影响。最后，我们发现在 CPE 细胞池中检测到 GHSR mRNA，但用目前的方法在下丘脑单核细胞中几乎检测不到。因此，我们的研究结果表明，循环的 ghrelin 主要通过涉及 GHSR 的机制穿过血脑脊液屏障，也可能通过不依赖 GHSR 的机制。