Mahogany (1377-1428) enters brain by a saturable transport system

The mouse mahogany gene encodes a protein that is involved in the suppressi on of diet-induced obesity. We studied the ability of its widely conserved C-terminal fragment to cross the blood-brain barrier (BBB) in mice. Multipl e-time regression analysis showed that the entry rate (K-i) of I-125-mahoga ny (1377-1428) from blood-to-brain was 5.5 X 10(-4) ml/g.min. After coinjec tion of unlabeled mahogany (1377-1428), the K-i was significantly decreased , showing the self-inhibition characteristic of a saturable transport mecha nism. The excess mahogany (1377-1428) did not change the influx rate of Tc- 99m-albumin, the vascular control, indicating a lack of disruption of the B BB. Statistically significant cross-inhibition was not seen with agouti-rel ated protein (83-132), melanin-concentrating hormone, epidermal growth fact or, leptin, a melanocortin-4 receptor antagonist, or alpha-melanocyte-stimu lating hormone. HPLC showed that most of the injected I-125-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. administ ration, and the octanol/buffer partition coefficient showed low lipophilici ty. Thus, the results show that the C-terminal peptide product encoded by t he mahogany gene crosses the BBB by a transport mechanism that is saturable . The ability of this system to be regulated indicates the therapeutic pote ntial of mahogany (1377-1428) in the treatment of obesity.