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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 …