Molecular Mechanisms Regulating BDNF and Obesity

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DESCRIPTION (provided by applicant): Obesity and hyperphagia are phenotypes of conditional mutants lacking Brain-Derived Neurotrophic Factor (BDNF) in the brain after birth. Further investigation has also implicated the BDNF gene in both human obesity and anorexia. Since obesity is a trait regulated by many different genes, with allelic segregation of these genes giving rise to the severity of the phenotype in a continuous manner, we propose to investigate genetic interactions regulating obesity by focusing on genes that interact with BDNF. It should be noted, that this model of obesity is novel because it gives rise to an obese phenotype based on genotype alone, independent of the need for environmental influences. We are proposing that BDNF may interact with the hypothalamic-pituitary thyroid (HPT) axis to modulate hypothalamic energy regulation and food intake. We plan to utilize [microarrays] neuronal cell culture and in vivo manipulations to verify the interactions of BDNF with the HPT axis, while simultaneously identifying [novel] genes that may interact together or independently of BDNF expression to induce the obese phenotype observed in our quantitative trait animal model.