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Department of Physiology, West Virginia University (S.M.H.), Morgantown, West Virginia 26506; Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center and Harvard Medical School (D.D.P., H.M., C.B., K.E.-H., J.S.F.), Boston, Massachusetts 02215; and Geriatric Research, Education, and Clinical Center, Veteran Affairs Medical Center and Department of Internal Medicine, Division of Geriatrics, St. Louis University School of Medicine (W.A.B.), St. Louis, Missouri 63104
Address all correspondence and requests for reprints to: Dr. Jeffrey S. Flier, Beth Israel Deaconess Medical Center, RN 325, 99 Brookline Avenue, Boston, Massachusetts 02215. E-mail: . jflier{at}caregroup.harvard.edu
Leptin deficiency causes obesity in rodents and humans, but circulating levels of leptin are paradoxically elevated in obesity. The mechanisms underlying this leptin resistance are unknown, but may involve reduced leptin transport across the blood-brain barrier via short isoforms of the leptin receptor (Ob-R). Here, we first quantified short Ob-R mRNA expression in isolated rat cerebral microvessels constituting the blood-brain barrier and found that Ob-Ra and Ob-Rc mRNA were abundantly expressed in similar amounts. Second, brain uptake of leptin was reduced in mice lacking Ob-R. Third, brain uptake of leptin in New Zealand Obese mice, a strain that responds to central, but not peripheral, leptin, was reduced, suggesting that their obesity is at least partly due to deficient leptin transport into the brain. Fourth, brain uptake of leptin was significantly reduced in diet-induced obese mice. Neither New Zealand Obese mice nor diet-induced obese mice exhibited significant decreases in Ob-R mRNA expression in isolated cerebral microvessels. These data support the ideas that short isoforms of Ob-R are involved in brain uptake of leptin and that impaired blood-brain barrier function contributes to the pathogenesis of obesity. However, the mechanisms by which obesity-related deficits in brain uptake of leptin occur remain to be defined.
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