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Simultaneous and Continuous 24-Hour Plasma and Cerebrospinal Fluid Leptin Measurements: Dissociation of Concentrations in Central and Peripheral Compartments

Center for Pharmacogenomics and Interdepartmental Clinical Pharmacology Center (M.-L.W., J.L., B.O.Y.), Neuropsychiatric Institute and David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California 90095; Division of Endocrinology (C.S.M.), Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215; Clinical Neuroendocrinology Branch (P.P., M.K., P.W.G.), National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892; and Department of Psychiatry (M.K.), Baltimore Veterans Affairs Medical Center and University of Maryland School of Medicine, Baltimore, Maryland 21201

Address all correspondence and requests for reprints to: Julio Licinio, M.D., Director, Center for Pharmacogenomics; and Interdepartmental Clinical Pharmacology Center, 3357A Gonda Center for Research on Genetics and Neuroscience, David Geffen School of Medicine at University of California, Los Angeles, 695 Charles Young Drive South, Los Angeles, California 90095-1761. E-mail: licinio{at}ucla.edu.

The entrance of leptin into the central nervous system is of physiological relevance to the regulation of food intake, energy balance, and neuroendocrine function. To our knowledge, the relation between plasma and lumbar cerebrospinal fluid (CSF) leptin has not been examined across the 24-h period. To evaluate the relation between plasma and CSF leptin across the 24-h period, we studied simultaneous and continuous plasma and CSF leptin in nine subjects. We measured plasma and lumbar CSF leptin every 30 min for 24 h. All subjects had diurnal periodicity in 24-h plasma leptin levels, but not in CSF levels, as assessed by analysis of covariance and cosinor analysis. Plasma leptin had a significant 24-h pattern (P = 0.001), but CSF leptin did not. A 25-fold range of plasma leptin concentrations was reflected by a less-than-2-fold range in lumbar CSF leptin concentrations. Nocturnal increases in plasma leptin concentrations were not accompanied by commensurate changes in CSF values. It appears that leptin enters the brain by a mechanism that is highly saturable at physiological leptin concentrations and that the dynamics of plasma leptin is not accompanied by similar dynamics in CSF leptin measured at the lumbar spinal level. Therefore, it is not possible to use plasma leptin levels to predict lumbar CSF leptin concentrations. Although we acknowledge that lumbar CSF concentrations do not fully reflect the dynamics of leptin in the brain, we suggest that the nocturnal saturability of leptin transport into the central nervous system might help explain the lack of responsiveness to the central physiologic effects of leptin in states of hyperleptinemia, such as obesity.

This work was supported by NIH Grants RR017365, MH062777, RR000865 (to M.-L.W.), GM61394, HL04526, RR16996, HG002500, RR017611, DK063240, DK58851 (to J.L.), and DK58785 (to C.M.) and by awards from the Dana Foundation, National Alliance for Research on Schizophrenia and Depression, and Amgen, Inc.

Abbreviations: ANCOVA, Analysis of covariance; BBB, blood-brain barrier; BMI, body mass index; CSF, cerebrospinal fluid.

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