Abstract
The mouse mahogany gene encodes a protein that is involved in the suppression of diet-induced obesity. We studied the ability of its widely conserved C-terminal fragment to cross the blood-brain barrier (BBB) in mice. Multiple-time regression analysis showed that the entry rate (Ki) of 125I-mahogany (1377–1428) from blood-to-brain was 5.5 × 10−4ml/g · min. After coinjection of unlabeled mahogany (1377–1428), the Ki was significantly decreased, showing the self-inhibition characteristic of a saturable transport mechanism. The excess mahogany (1377–1428) did not change the influx rate of 99mTcalbumin, the vascular control, indicating a lack of disruption of the BBB. Statistically significant cross-inhibition was not seen with agouti-related protein (83–132), melanin-concentrating hormone, epidermal growth factor, leptin, a melanocortin-4 receptor antagonist, or α-melanocyte-stimulating hormone. HPLC showed that most of the injected 125I-mahogany (1377–1428) reached the brain intact, and capillary depletion with washout showed that most of it reached the parenchyma. There was no brain-to-blood efflux system for mahogany (1377–1428) but rather retention after i.c.v. administration, and the octanol/buffer partition coefficient showed low lipophilicity. Thus, the results show that the C-terminal peptide product encoded by the mahogany gene crosses the BBB by a transport mechanism that is saturable. The ability of this system to be regulated indicates the therapeutic potential of mahogany (1377–1428) in the treatment of obesity.
Footnotes
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Send reprint requests to: Abba J. Kastin, M.D., VA Medical Center, 1601 Perdido St., New Orleans, LA 70112-1262.
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↵1 This work was supported by the Department of Veterans Affairs and the National Institutes of Health (DK54880).
- Abbreviations:
- BBB
- blood-brain barrier
- MSH
- melanocyte-stimulating hormone
- MCH
- melanin-concentrating hormone
- MC4
- melanocortin-4
- AgRP
- agouti-related protein
- EGF
- epidermal growth factor
- Received March 17, 2000.
- Accepted April 27, 2000.
- U.S. Government
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