The agouti viable yellow (A^vy) spontaneous mutation generates an unusual mouse phenotype of agouti-colored coat and adult-onset obesity with metabolic syndrome. Persistent production of agouti signaling protein in A^vy mice antagonizes melanocortin receptors in the hypothalamus. To determine how this disruption of neuroendocrine circuits affects leptin transport across the blood-brain barrier (BBB), we measured leptin influx in A^vy and B6 control mice after the development of obesity, hyperleptinemia, and increased adiposity. After intravenous bolus injection, ¹²⁵I-leptin crossed the BBB significantly faster in young (2 month-old) B6 mice than in young A^vy mice or in older (8 month-old) mice of either strain. This difference was not observed by in-situ brain perfusion studies, indicating the cause being circulating factors, such as elevated leptin levels or soluble receptors. Thus, A^vy mice showed peripheral leptin resistance. The ObRa, main transporting receptor for leptin at the BBB, showed no change in the mRNA expression in the cerebral microvessels between the age-matched (2 month-old) A^vy and B6 mice. Higher ObRb mRNA was seen in the A^vy microvasculature with unknown significance. Immunofluorescent staining unexpectedly revealed that many of the ObR(+) cells were astrocytes, and that the A^vy showed a significant increase of ObR(+) astrocytes in the hypothalamus than the B6 mice. Although leptin permeation from the circulation was slower in the A^vy mice, the increased ObR expression in astrocytes and increased ObRb mRNA in microvessels suggest the possibility of heightened CNS sensitivity to circulating leptin.