Abstract 237 Genetic Basis of Disease I Platform, Monday, 5/3

Brain derived neurotrophic factor (BDNF) belongs to the nerve growth factor family of neurotrophins and it signals through a tyrosine kinase receptor, Trk B. BDNF has been implicated in numerous aspects of development of both the peripheral and central nervous system. Beyond development, few roles for BDNF in mature populations of neurons have been defined, though its expression remains high within the brain into adulthood.

Using a targeted gene deletion approach in mice, we have shown that mice deficient in a single allele of BDNF become either obese or hyperactive. The obesity in these mice is similar to human models of obesity in that they show significant hyperphagia and fat cell hypertrophy as well as leptin and insulin resistance. RNAse protection assays and in situ hybridization demonstrate a reduction in BDNF messenger RNA within discrete areas of the hypothalamic of both populations of mutant mice. Specifically, this decreased signal is seen in the lateral hypothalamic area (LHA), the paraventricular nucleus (PVN), and the ventromedial nucleus (VMH), which are areas within the hypothalamus implicated in feeding behavior and/or motor activity. Furthermore, there is differential expression between the fat and hyperactive mutants within the LHA, which is a negative regulator of activity and a positive regulator of appetite. This differential expression suggests a mechanism for this divergent phenotype. The obese phenotype is also reversible as infusion into the third cerebral ventricle of either BDNF or another Trk B ligand, NT-4, causes the fat mutants to decrease eating and lose weight to wildtype levels. Thus, the obese phenotype is not due to a development abnormality, and it is mediated through the Trk B receptor.

In humans, the BDNF gene is localized to 11p13, just distal to the loci for PAX-6 and WT-1. Deletion of this area results in a contiguous gene syndrome known as WAGR Syndrome whose hallmarks include Wilms' tumor, aniridia, and mental retardation. It has been suggested that some patients with WAGR syndrome are obese because of a deletion of another gene within 11p13. At least two such obese WAGR patients have been reported who have large deletions which encompass the BDNF locus.

Our in vivo study of BDNF deficient mice demonstrates that partial reduction of BDNF leads to obesity and hyperactivity in mice. Furthermore, it is a likely candidate for the obesity seen in WAGR patients, and may be responsible for obesity for more of the general population who have point mutations in the BDNF locus.