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1 Geriatric Research, Education, and Clinical Center, Veterans Affairs Medical Center, St. Louis 63106; 2 Department of Internal Medicine, Division of Geriatrics, Saint Louis University School of Medicine, St. Louis Missouri 63104; and 3 Department of Pathology, Amgen, Inc., Thousand Oaks, California 91351
Impaired blood-brain barrier transport of leptin into the arcuate nucleus has been suggested to underlie obesity in humans and outbred aging mice. Here, we used a brain perfusion method in mice to measure transport rates and kinetic parameters for leptin at vascular concentrations between 0.15 and 130 ng/ml. Transport into whole brain was partially saturated at all concentrations, not only those seen in obesity. Leptin entered all regions of the brain, not only the hypothalamus, with entry and saturation rates differing among the brain regions. The value of the Michaelis-Menten constant of the transporter approximates normal serum levels and the maximum velocity value varies significantly among brain regions. These results suggest an important role for low serum levels signaling starvation status to the brain and show that the levels of leptin seen in obesity greatly saturate the transporter. Differences in regional uptake and saturation provide a mechanism by which leptin can control events mediated at the arcuate nucleus and other regions of the central nervous system with different regional thresholds for optimal function.
obesity; arcuate nucleus; hypothalamus; anorexia; peptide
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