Extent and direction of ghrelin transport across the blood-brain barrier is determined by its unique primary structure
Abstract
The novel hormone ghrelin is a potent orexigen that may counterbalance leptin. Ghrelin is the only secreted molecule requiring post-translational acylation with octanoic acid to ensure bioactivity. Ghrelin, predominantly derived from the stomach, may target neuroendocrine networks within the central nervous system (CNS) to regulate energy homeostasis. This would require ghrelin to cross the blood-brain barrier (BBB). In mice, we examined whether ghrelin crosses the BBB and whether its lipophilic side chain is involved in this process. We found that saturable systems transported human ghrelin from brain-to-blood and from blood-to-brain. Mouse ghrelin, differing from human ghrelin by two amino acids, was a substrate for the brain-to-blood but not for the blood-to-brain transporter and so entered the brain to a far lesser degree. des-Octanoyl ghrelin entered the brain by nonsaturable transmembrane diffusion and was sequestered once within the CNS. In summary, we show that ghrelin transport across the BBB is a complex, highly regulated bidirectional process. The direction and extent of passage are determined by the primary structure of ghrelin, defining a new role for the unique post-translational octanoylation.
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Ghrelin 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 [49]
Peripherally produced ghrelin exerts appetite-inducing effects centrally after passing through the BBB.
“Peripherally produced ghrelin exerts its appetite-inducing effects centrally after passing through the BBB [112, 302-304].”
From Anxiety, depression, and the microbiome: A role for gut peptides (2018) · cites this paper as [112]
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- Authors
- Banks, W. A., Tschöp, M., Robinson, S. M., & Heiman, M. L.
- Affiliations
- St. Louis VA Medical Center (US)
- Eli Lilly (United States) (US)
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2002-08
- Volume
- 302
- Issue
- 2
- Pages
- 822-827
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W1985071684
- Cited by
- 691
- References
- 30
- Citations by year
- 2026: 14 · 2025: 14 · 2024: 12 · 2023: 14 · 2022: 27 · 2021: 15 · 2020: 22 · 2019: 22 · 2018: 37 · 2017: 51 · 2016: 24 · 2015: 28 · 2014: 24 · 2013: 39 · 2012: 40
- FWCI
- 17.42
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (R01AA12743, R01AA012743)
- National Institute of Neurological Disorders and Stroke (R0-1 NS41863, R01NS041863)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- ghrelin, blood-brain barrier, bidirectional transport, octanoylation, amino acid sequence, membrane diffusion, energy homeostasis, orexigenic hormones, leptin
- MeSH terms
- Animals, Blood-Brain Barrier, Brain, Humans, Kinetics, Peptides, Tissue Distribution, Peptide Hormones, Mice, Ghrelin
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