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.
Footnotes
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Supported by Veterans Affairs, R01 NS41863, R01AA12743, and Eli Lilly and Company.
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DOI: 10.1124/jpet.102.034827
- Abbreviations:
- CNS
- central nervous system
- CVO
- circumventricular organ
- BBB
- the blood-brain barrier
- h-ghrelin
- human ghrelin
- m-ghrelin
- mouse ghrelin
- des-m-ghrelin
- des-octanoyl mouse ghrelin
- %Inj/g
- percentage of the intravenously injected dose taken up into each gram of mouse brain
- LR-BSA
- lactated Ringer's and bovine serum albumin solution
- CSF
- cerebrospinal fluid
- Received February 19, 2002.
- Accepted March 27, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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