Obesity is a risk factor for the development of type 2 diabetes, cardiovascular disease and other afflictions. This is troubling as close to 30% of the population in the United States is obese and 64% is overweight. The study of brain-derived neurotrophic factor (BDNF) and its receptor, TrkB, provides a new and promising avenue in obesity research. They mediate neuronal survival, differentiation, function and plasticity in the developing and mature brain. The relevance of this signaling pathway in the etiology of energy balance disorders is highlighted by the dramatic obesity exhibited by mice with brain-specific targeting of the Bdnf gene. Mutants display hyperphagic behavior and become hyperleptinemic, hyperinsulinemic and hyperglycemic, indicating that this neurotrophin is an essential regulator of food intake acting through as yet unknown mediators in the central nervous system. Human studies also show links between genetic alterations in the TrkB gene and hyperphagic behavior and obesity. This proposal outlines studies designed to ascertain the molecular and cellular mechanisms facilitating the satiety effects of the BDNF/TrkB signaling pathway in the adult animal. For this, the effects of energy signals on the expression and activity of BDNF and TrkB in distinct appetite-modulating regions of the brain will be evaluated. Moreover, the Bdnf gene will be targeted in adult animals in a site-specific manner in hypothalamic and caudal hindbrain nuclei associated with these processes. The impact of these manipulations on energy intake and expenditure will be evaluated. Finally, as BDNF has emerged as a prominent facilitator of synaptic plasticity, we will investigate whether it is required for synaptic plasticity- related processes in the hypothalamus thought to influence energy homeostasis. Together, these studies will distinguish developmental roles of BDNF from ones in the mature brain that influence body weight. This analysis will help clarify disease mechanisms and critical periods of intervention for obesity disorders. Moreover, they will bring us closer to novel strategies for the treatment of obesity and its associated syndromes.
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