Ghrelin transport across the blood–brain barrier can occur independently of the growth hormone secretagogue receptor
Open accessAbstract
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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Ghrelin protects neurons from β-amyloid-induced toxicity.
“It binds to growth hormone secretagogue receptor (GHSR), and it has been shown to protect neurons from β-amyloid-induced toxicity, reduce tau phosphorylation, and enhance synaptic plasticity [20, 44–46].”
From Protective PLCG2 variants associate with a delayed onset of Alzheimer’s disease among heterozygous APOE ε4 carriers (2026) · cites this paper as [46]
The Introduction (page unavailable) says protective effects against cortical neuronal injury have been ascribed to desacyl ghrelin. It does not identify β-amyloid-induced toxicity as the cause of that injury, so it supports only the broader neuroprotection claim. (LLM, conf=0.82)
Experimental — accuracy not yet measuredGhrelin can pass through the blood-brain barrier, directly affecting brain cells.
“It has been shown that ghrelin can pass through the blood–brain barrier, directly affecting brain cells [46, 48–50].”
From Protective PLCG2 variants associate with a delayed onset of Alzheimer’s disease among heterozygous APOE ε4 carriers (2026) · cites this paper as [46]
Ghrelin binds to growth hormone secretagogue receptor (GHSR).
“It binds to growth hormone secretagogue receptor (GHSR), and it has been shown to protect neurons from β-amyloid-induced toxicity, reduce tau phosphorylation, and enhance synaptic plasticity [20, 44–46].”
From Protective PLCG2 variants associate with a delayed onset of Alzheimer’s disease among heterozygous APOE ε4 carriers (2026) · cites this paper as [46]
Ghrelin enhances synaptic plasticity.
“It binds to growth hormone secretagogue receptor (GHSR), and it has been shown to protect neurons from β-amyloid-induced toxicity, reduce tau phosphorylation, and enhance synaptic plasticity [20, 44–46].”
From Protective PLCG2 variants associate with a delayed onset of Alzheimer’s disease among heterozygous APOE ε4 carriers (2026) · cites this paper as [46]
The Introduction describes ghrelin’s effects on olfaction and other functions, but does not address synaptic plasticity. A References entry names a study of hippocampal spine synapse density; our copy does not report its findings or state that ghrelin enhances synaptic plasticity. Searches for “synaptic plasticity” and hippocampal spine synapse density found no decisive passage in the paper’s text. (LLM, conf=0.72)
Experimental — accuracy not yet measuredGhrelin reduces tau phosphorylation.
“It binds to growth hormone secretagogue receptor (GHSR), and it has been shown to protect neurons from β-amyloid-induced toxicity, reduce tau phosphorylation, and enhance synaptic plasticity [20, 44–46].”
From Protective PLCG2 variants associate with a delayed onset of Alzheimer’s disease among heterozygous APOE ε4 carriers (2026) · cites this paper as [46]
The Introduction discusses ghrelin’s receptor binding and a protective effect in cortical neuronal injury, while the Discussion addresses transport across the blood–brain barrier. Neither passage addresses tau phosphorylation; searches for “tau phosphorylation” and related terms found no such finding in our copy. (LLM, conf=0.75)
Experimental — accuracy not yet measured
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- [7]Muller T.D. Nogueiras R. Andermann M.L. Andrews Z.B. Anker S.D. Argente J. Ghrelin Molecular Metabolism 4 6 2015 437 460 [published Online First: Epub Date] 26042199 PMC4443295
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Reviewer #2 (Public Review): Neuronal migration depends on blood flow in the adult brain
Ogino, T., Saito, A., Sawada, M., et al. (2024) · eLife · doi:10.7554/elife.99502.1.sa0
Reviewer #1 (Public Review): Neuronal migration depends on blood flow in the adult brain
Ogino, T., Saito, A., Sawada, M., et al. (2024) · eLife · doi:10.7554/elife.99502.1.sa1
Neuronal migration depends on blood flow in the adult brainPreprint
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- 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
- Venue
- Molecular Metabolism
- Publisher
- Elsevier BV
- Published
- 2018-12
- Volume
- 18
- Pages
- 88-96
- ISSN
- 2212-8778 (ISSN-L)
- 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
- gold
- doi.org
- 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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