Analysis of brain nuclei accessible to ghrelin present in the cerebrospinal fluid

Abstract

Ghrelin is a stomach-derived peptide hormone that acts in the brain to regulate many important physiological functions. Ghrelin receptor, named the growth hormone secretagogue receptor (GHSR), is present in many brain areas with or without obvious direct access to ghrelin circulating in the bloodstream. Ghrelin is also present in the cerebrospinal fluid (CSF) but the brain targets of CSF ghrelin are unclear. Here, we studied which brain areas are accessible to ghrelin present in the CSF. For this purpose, we centrally injected mice with fluorescein-labeled ghrelin (F-ghrelin) peptide tracer and then systematically mapped the distribution of F-ghrelin signal trough the brain. Our results indicated that centrally injected F-ghrelin labels neurons in most of the brain areas where GHSR is present. Also, we detected F-ghrelin uptake in the ependymal cells of both wild type and GHSR-null mice. We conclude that CSF ghrelin is able to reach most of brain areas expressing GHSR. Also, we propose that the accessibility of CSF ghrelin to the brain parenchyma occurs through the ependymal cells in a GHSR-independent manner.

Diet-induced obesity causes ghrelin resistance in reward processing tasks

“…Interestingly, in the present study intra-VTA ghrelin robustly increased food intake in mice on both a chow and HFD suggesting HFD per sedoes not cause ghrelin resistance directly in the VTA. However, intra-VTA injection represents a non-physiological source of exogenous ghrelin into the VTA and studies show that peripheral ghrelin access into the brain is largely limited to the hypothalamus (Cabral et al, 2013;Cabral et al, 2014). When we performed linear regression analysis we observed a clear correlation between intra-VTA ghrelin-induced feeding and body weight in chow, but not HFD mice.…”

Ghrelin’s Orexigenic Effect Is Modulated via a Serotonin 2C Receptor Interaction

“…Moreover, a recent study by Bonn et al, demonstrates that the 5-HT2C receptor can also be found on NPY producing neurons 75,76 , which was previously not recognized. In addition, a significant number of neurons in the hippocampus express the GHS-R1a receptor 51,58,[77][78][79] as well as do most regions of the hypothalamus [50][51][52] . Specifically, in the arcuate nucleus, the GHS-R1a receptor is strongly expressed on NPY neurons, with 94% of the NPY neurons demonstrating GHS-R1a mRNA, but also on the POMC neurons , albeit only in 8% of the POMC neurons 80 .…”

“…Therefore, neurons were cultured from rat pups at E17 to ensure 5-HT2C receptor expression. Central expression of the GHS-R1a receptor was analysed using a variation of a recently described method using fluorescein-ghrelin 82 , a novel strategy to detect specific GHS-R1a receptor expression 58 Figure 5A). This is in line with previous findings from our lab and others demonstrating that a single administration of ghrelin causes an acute increase in food intake which is diminished over time 4,83 .…”

Role of AA-NAT and TPH1 in the Ghrelin-Dependent Regulation of Melatonin Secretion in Sheep during Different Seasons: An <em>In Vitro</em> Study

“…The PG is in direct contact with the CSF due to the incomplete ependymal lining in the pineal recess, an extension of the third ventricle [43]. Studies carried out on sheep [29], humans [44] and rodents [45] have confirmed the presence of GHRL in the CSF, through which, it is able to reach most of the forebrain, midbrain and hindbrain areas where GHSR-1a gene expression has been reported. Intracerebroventricular infusions of GHRL into the CSF allows GHRL to influence the PG directly or indirectly through the nerve centers of the brain, such as the mediobasal hypothalamus, that are functionally and anatomically connected with the PG, in which GHSR-1a has been identified [1].…”

“…Intracerebroventricular infusions of GHRL into the CSF allows GHRL to influence the PG directly or indirectly through the nerve centers of the brain, such as the mediobasal hypothalamus, that are functionally and anatomically connected with the PG, in which GHSR-1a has been identified [1]. Cabral et al [45] also detected GHRL uptake in the ependymal cells of the ventricular system of the brain, where GHSR-1a is presumably not present. The PG is rich in fenestrated capillaries and canaliculi, through which, even large molecules such as peptides and proteins, including GHRL, can probably penetrate from the CSF into the gland [43].…”