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Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center (R.S.A., C.B., J.S.F.); and the Endocrinology-Hypertension Division, Brigham and Women’s Hospital, Harvard Medical School (S.O.), Boston, Massachusetts 02215
Address all correspondence and requests for reprints to: Jeffrey S. Flier, M.D., Beth Israel Deaconess Medical Center, Division of Endocrinology, Research North, 99 Brookline Avenue, Boston, Massachusetts 02215. E-mail: jflier{at}caregroup.harvard.edu
The complete absence of leptin causes severe obesity in mice and humans, but its physiological roles are incompletely defined. Earlier studies reported decreased brain weight and impaired myelination in ob/ob and db/db mice. Here we have examined the effects of leptin deficiency and postnatal leptin treatment on brain weight, the expression of a broad array of neuronal and glial markers, and locomotor activity. ob/ob and db/db mice have reduced brain weight and an immature pattern of expression of synaptic and glial proteins, with growth-associated protein being elevated in the neocortex and hippocampus, and syntaxin-1, synaptosomal-associated protein-25, and synaptobrevin being decreased. The expression of myelin basic protein, proteolipid protein, and glial fibrillary acidic protein was also decreased in the neocortex, hippocampus, and striatum of ob/ob and db/db mice. Six weeks of leptin treatment initiated at week 4 increased brain weight and protein content, increased locomotor activity, and normalized levels of growth-associated protein, syntaxin-1, and synaptosomal-associated protein-25 in ob/ob mice without affecting synaptobrevin and glial proteins. In contrast with ob/ob and db/db mice, obese agouti (Ay/a) mice had normal brain weight and expression of synaptic and glial proteins. These findings suggest that leptin, a peripheral signal of energy stores in adult animals, is required for normal neuronal and glial maturation in the mouse nervous system.
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