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 (K_i) of ¹²⁵I-mahogany (1377–1428) from blood-to-brain was 5.5 × 10⁻⁴ml/g · min. After coinjection of unlabeled mahogany (1377–1428), the K_i 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.