Brain-derived neurotrophic factor (BDNF) and its TrkB receptor have been implicated in the control of energy balance in both humans and mice. Previous studies suggest that BDNF expressed in the ventromedial hypothalamus (VMH) plays a critical role in regulating energy balance. BDNF protein is synthesized in both neuronal somas and dendrites. In this application, we will examine the role of dendritic local BDNF synthesis in the control of energy balance.
Aim 1 is to determine if leptin regulates local synthesis of BDNF in dendrites. We will employ green fluorescence protein reporter constructs and synaptoneurosome preparations to examine the effect of leptin on dendritic transport and translation of BDNF mRNA.
Aim 2 is to determine if dendritically synthesized BDNF in the VMH regulates food intake and body weight. We will attempt to rescue the obese phenotype in a Bdnf mouse mutant which lacks dendritic local BDNF synthesis through viral expression of dendritically localized BDNF mRNA or somatically localized BDNF mRNA in the VMH.
Aim 3 is to examine if lack of local BDNF synthesis alters morphologies of dendritic spines of TrkB-expressing hypothalamic neurons. There are TrkB-expressing neurons in the hypothalamic nuclei important for the control of energy balance, such as the arcuate nucleus (ARC) and dorsomedial hypothalamus (DMH). We will examine spine morphologies of TrkB-expressing neurons in the ARC and DMH in the mouse mutant deficient in local BDNF synthesis.
Identification and characterization of new molecules and signaling pathways that control energy balance will offer opportunities for designing improved obesity treatments. If successful, findings from this proposed project will suggest that mutations in proteins involved in transport and translation of dendritic mRNA will increase susceptibility to obesity. Therefore, these proteins could be potential drug targets for obesity treatment.
| Liao, Guey-Ying; An, Juan Ji; Gharami, Kusumika et al. (2012) Dendritically targeted Bdnf mRNA is essential for energy balance and response to leptin. Nat Med 18:564-71 |
| Waterhouse, Emily G; Xu, Baoji (2009) New insights into the role of brain-derived neurotrophic factor in synaptic plasticity. Mol Cell Neurosci 42:81-9 |
