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Astrocyte Leptin Receptor (ObR) and Leptin Transport in Adult-Onset Obese Mice

Blood-Brain Barrier Group, Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808

Address all correspondence and requests for reprints to: Weihong Pan, M.D., Ph.D., Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, Louisiana 70808. E-mail: weihong.pan{at}pbrc.edu.

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 iv 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. ObRa, the main transporting receptor for leptin at the BBB, showed no change in 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 mice showed significantly more 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 central nervous system sensitivity to circulating leptin.