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Cited by 114Regulation of Appetite and ObesityBarrier Structure and Function StudiesDrug Transport and Resistance Mechanisms

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Ghrelin transport across the blood–brain barrier can occur independently of the growth hormone secretagogue receptor

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Rhea, Elizabeth M., Salameh, Therese S., Gray, Sarah, Niu, Jingjing, Banks, William A., Tong, Jenny·2018·Molecular Metabolism
DOI 10.1016/j.molmet.2018.09.007PMC PMC6308033
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Abstract

OBJECTIVE: The blood-brain barrier (BBB) regulates the entry of substrates and peptides into the brain. Ghrelin is mainly produced in the stomach but exerts its actions in the central nervous system (CNS) by crossing the BBB. Once present in the CNS, ghrelin can act in the hypothalamus to regulate food intake, in the hippocampus to regulate neurogenesis, and in the olfactory bulb to regulate food-seeking behavior. The goal of this study was to determine whether the primary signaling receptor for ghrelin, the growth hormone secretagogue receptor (GHSR), mediates the transport of ghrelin from blood to brain. METHODS: We utilized the sensitive and quantitative multiple-time regression analysis technique to determine the transport rate of mouse and human acyl ghrelin (AG) and desacyl ghrelin (DAG) in wildtype and Ghsr null mice. We also measured the regional distribution of these ghrelin peptides throughout the brain. Lastly, we characterized the transport characteristics of human DAG by measuring the stability in serum and brain, saturability of transport, and the complete transfer across the brain endothelial cell. RESULTS: We found the transport rate across the BBB of both forms of ghrelin, AG, and DAG, were not affected by the loss of GHSR. We did find differences in the transport rate between the two isoforms, with DAG being faster than AG; this was dependent on the species of ghrelin, human being faster than mouse. Lastly, based on the ubiquitous properties of ghrelin throughout the CNS, we looked at regional distribution of ghrelin uptake and found the highest levels of uptake in the olfactory bulb. CONCLUSIONS: The data presented here suggest that ghrelin transport can occur independently of the GHSR, and ghrelin uptake varies regionally throughout the brain. These findings better our understanding of the gut-brain communication and may lead to new understandings of ghrelin physiology.

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Crossref · 10.1016/j.molmet.2018.09.007

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Figure 1 Blood-to-brain influx of 125I-ghrelin peptides in WT and Ghsr null mice. No significant difference in A) mAG, B) hAG, C) mDAG, or D) hDAG influx was observed between WT (closed circles, n = 10–11) and Ghsr null mice (open circles, n = 6–9).
Figure 1 Blood-to-brain influx of 125I-ghrelin peptides in WT and Ghsr null mice. No significant difference in A) mAG, B) hAG, C) mDAG, or D) hDAG influx was observed between WT (closed circles, n = 10–11) and Ghsr null mice (open circles, n = 6–9).CC BY-NC-ND · PubMed Central
Figure 2 Characterization of 125I-hDAG. A) Stability in serum and whole brain (Whole Brain *p < 0.05 vs 2 and 6 min). B) Complete transfer across the brain endothelial cell (n = 3). C) Lack of saturable transport (One-Way ANOVA: p = 0.89, n = 9).
Figure 2 Characterization of 125I-hDAG. A) Stability in serum and whole brain (Whole Brain *p < 0.05 vs 2 and 6 min). B) Complete transfer across the brain endothelial cell (n = 3). C) Lack of saturable transport (One-Way ANOVA: p = 0.89, n = 9).CC BY-NC-ND · PubMed Central
Figure 3 Regional distribution of ghrelin peptides. Levels of 125I-ghrelin peptides were measured in each brain region after 10 min circulation. There were significant differences in the regional distribution of A) mAG, B) hAG, C) mDAG, and D) hDAG levels. There was also a difference due to genotype with B) hAG. (n = 5–7 per region per genotype).
Figure 3 Regional distribution of ghrelin peptides. Levels of 125I-ghrelin peptides were measured in each brain region after 10 min circulation. There were significant differences in the regional distribution of A) mAG, B) hAG, C) mDAG, and D) hDAG levels. There was also a difference due to genotype with B) hAG. (n = 5–7 per region per genotype).CC BY-NC-ND · PubMed Central
Figure 4 Pictorial representation of 125I-ghrelins brain distribution. A heat map was generated based on the data in Table 2. A–C) Data are collapsed across genotype. D–E) Data are separated for 125I-hAG due to statistically significant differences between genotypes.
Figure 4 Pictorial representation of 125I-ghrelins brain distribution. A heat map was generated based on the data in Table 2. A–C) Data are collapsed across genotype. D–E) Data are separated for 125I-hAG due to statistically significant differences between genotypes.CC BY-NC-ND · PubMed Central

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Metadata

Authors
Rhea, E. M., Salameh, T. S., Gray, S., Niu, J., Banks, W. A., & Tong, J.
Affiliations
  • University of Washington (US)
  • Duke University (US)
Corresponding author
Tong, Jenny
ORCID
Venue
Molecular Metabolism
Publisher
Elsevier BV
Published
2018-12
Volume
18
Pages
88-96
ISSN
2212-8778 (ISSN-L)
DOI
10.1016/j.molmet.2018.09.007
PMC
PMC6308033
OpenAlex
W2894219590
Cited by
114
References
51
Citations by year
2026: 13 · 2025: 12 · 2024: 26 · 2023: 13 · 2022: 12 · 2021: 18 · 2020: 10 · 2019: 8 · 2018: 2
FWCI
5.35
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Metabolism (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
National Institutes of Health (T32AG000057, RO1DK097550, T32DK007012, RO1AG046619)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Keywords
ghrelin, blood-brain barrier, growth hormone secretagogue receptor, acylated ghrelin, des-acyl ghrelin, brain regional distribution, olfactory bulb, gut-brain signaling, brain endothelial cells
MeSH terms
Animals, Blood-Brain Barrier, Capillary Permeability, Mice, Ghrelin, Receptors, Ghrelin

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