Previous studies have implicated brain-derived neurotrophic factor (BDNF) in the central control of food intake and body weight. The Bdnf gene produces two mRNA isoforms, one with a short 3'untranslated region (3'UTR), and the other with a long 3'UTR. Preliminary data indicate that the long BDNF 3'UTR is instrumental in local synthesis of BDNF protein in dendrites and in the regulation of energy homeostasis. The human BDNF 3'UTR has eight single nucleotide polymorphisms (SNPs), seven of which are in a sequence unique to the long 3'UTR. We hypothesize that SNPs that result in decreased dendritic BDNF mRNA will lead to increased weight gain because dendritic targeting of BDNF mRNA in the adult hypothalamus is necessary for mature neuronal morphology and body weight regulation.
Aim 1 will examine if SNPs in the BDNF 3'UTR affect dendritic targeting of BDNF mRNA in vitro, Aim 2 will examine if these SNPs impede dendritic targeting of hypothalamic BDNF mRNA in vivo and result in failure to regulate body weight, and Aim 3 will examine a possibly mechanism by which this might take place, specifically if dendritic BDNF mRNA is necessary for normal hypothalamic neuron morphological maturation. Public Health Relevance: The morbidity, mortality, and societal cost of obesity and its sequelae are a significant, increasing, and unresolved public health problem. Obese people are more likely to develop cardiovascular disease, high cholesterol, hypertension, and diabetes. The proposed studies have the potential to discover infomnation that will contribute to the development of effective medications and treatment plans for obesity.
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