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Effect of Leptin Replacement on Brain Structure in Genetically Leptin-Deficient Adults

Neuroimaging Research Branch (J.A.M.), National Institute on Drug Abuse, Department of Health and Human Services/National Institutes of Health, Baltimore, Maryland 21224; Neuropsychiatric Institute (E.D.L., B.O.Y., S.C., M.-L.W., J.L.), Department of Molecular and Medical Pharmacology (E.D.L.), David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90024; Department of Endocrinology and Metabolism (M.O., S.C.), Gulhane Haydarpasa Training Hospital, Acibadem-Istanbul, 34660 Turkey; and Amgen Inc. (A.M.D.), Thousand Oaks, California 91320

Address all correspondence and requests for reprints to: Edythe D. London, Ph.D., C8-532 NPI, David Geffen School of Medicine, University of California Los Angeles, 760 Westwood Plaza, Los Angeles, California 90024-1759. E-mail: elondon{at}mednet.ucla.edu.

The hormone leptin profoundly affects body weight and metabolism. Three human adults (two women, 35 and 40 yr old; one man, age 27) have been identified with a recessive mutation in the ob gene, which is homologous to the mutation in ob/ob mice, and produces leptin deficiency and morbid obesity. Because leptin replacement increases brain weight and changes brain protein and DNA content in ob/ob mice, we hypothesized that analogous treatment of leptin-deficient humans would alter brain tissue composition. Volumetric T1-weighted magnetic resonance images of the brain were acquired before and at 6 and 18 months after initiation of replacement therapy (daily sc injections of recombinant methionyl human leptin), which produced dramatic loss in body weight. We used voxel-based morphometry to test for increased gray matter tissue concentration after initiation of leptin replacement and detected increases at 6 months in the anterior cingulate gyrus, the inferior parietal lobule, and the cerebellum. These increases were maintained for over 18 months, with identical stereotaxic coordinates of the maxima for the effects. Our findings suggest that leptin can have sustained effects on tissue composition in the human brain and broaden the potential spectrum of leptin’s influence beyond feeding behavior and endocrine function.

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