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Vol. 302, Issue 2, 822-827, August 2002
The Geriatric Research, Education, and Clinical Center, Veterans
Affairs Medical Center-St. Louis and the Division of Geriatrics,
Department of Internal Medicine, St. Louis University School of
Medicine, St. Louis, Missouri (W.A.B., S.M.R.); and Lilly Research
Laboratories, Eli Lilly and Company, Indianapolis, Indiana (M.T.,
M.L.H.)
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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