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Molecular Endocrinology 15 (10): 1748-1757
Copyright © 2001 by The Endocrine Society

Conditional Deletion Of Brain-Derived Neurotrophic Factor in the Postnatal Brain Leads to Obesity and Hyperactivity

Maribel Rios, Guoping Fan, Csaba Fekete, Joseph Kelly, Brian Bates1, Ralf Kuehn, Ronald M. Lechan and Rudolf Jaenisch

Whitehead Institute for Biomedical Research (M.R., G.F., B.B., R.J.), Cambridge, Massachusetts 02142; Tupper Research Institute and Department of Medicine (C.F., J.K., R.M.L.), Division of Endocrinology, Diabetes, Metabolism and Molecular Medicine, New England Medical Center, Boston, Massachusetts 02111; Artemis Pharmaceuticals GmbH (R.K.), Cologne, Germany D-51063; Department of Neuroscience (R.M.L.), Tufts University School of Medicine, Boston, Massachusetts 02111; and Department of Biology (R.J.), Massachusetts Institute of Technology, Cambridge Massachusetts 02139

Address all correspondence and requests for reprints to: Dr. Rudolf Jaenisch, Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142. E-mail: jaenisch{at}wi.mit.edu

Brain-derived neurotrophic factor has been associated previously with the regulation of food intake. To help elucidate the role of this neurotrophin in weight regulation, we have generated conditional mutants in which brain-derived neurotrophic factor has been eliminated from the brain after birth through the use of the cre-loxP recombination system. Brain-derived neurotrophic factor conditional mutants were hyperactive after exposure to stressors and had higher levels of anxiety when evaluated in the light/dark exploration test. They also had mature onset obesity characterized by a dramatic 80–150% increase in body weight, increased linear growth, and elevated serum levels of leptin, insulin, glucose, and cholesterol. In addition, the mutants had an abnormal starvation response and elevated basal levels of POMC, an anorexigenic factor and the precursor for {alpha}-MSH. Our results demonstrate that brain derived neurotrophic factor has an essential maintenance function in the regulation of anxiety-related behavior and in food intake through central mediators in both the basal and fasted state.




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