Close to a third of the population in the United States is obese and over 60% is overweight. This is an alarming trend as obesity significantly increases susceptibility to type 2 diabetes, cardiovascular disease and other medical disorders. Mounting evidence indicates that the brain-derived neurotrophic factor (BDNF)/TrkB pathway plays a critical part in energy balance regulation and is a promising target for novel therapies. Accordingly, reduced BDNF signaling in mice and humans results in hyperphagic behavior and dramatic obesity. It remained unclear whether BDNF, which supports neuronal survival, differentiation and synaptic plasticity, acted as a required satiety factor in the adult brain or as a developmental facilitator of feeding neural circuits. As part of the previously funded project, we showed that BDNF acts in the adult animal to promote satiety and that the ventromedial hypothalamus (VMH) is a critical source of this neurotrophin. Supportive evidence includes the robust effects of energy status on expression of BDNF and TrkB in the VMH and the hyperphagia and obesity elicited by selectively deleting BDNF in the VMH of adult mice. The cellular and molecular mechanisms underlying the anorexigenic effects of BDNF in the VMH remain to be elucidated. Our recent analysis of the transcriptome of cells laser-captured from the VMH of mice with central (BDNF2L/2LCk-cre) or VMH-specific depletion of BDNF revealed decreased expression of a2d-1 and of two other genes associated with obesity susceptibility in a recent large-scale human study. Our preliminary studies show that BDNF's anorexigenic effects are mediated by a2d-1, a high voltage-gated calcium channel subunit that enhances calcium currents and mediates excitatory synaptogenesis. We found that: i) selective a2d-1 inhibition by chronic gabapentin infusion into wild type VMH increased food intake and body weight and ii) viral-mediated a2d-1 delivery to the VMH of BDNF2L/2LCk-cre mutants ameliorated their hyperphagia and body weight gain. This competitive renewal proposal seeks to build on these findings by ascertaining cellular mechanisms underlying the effects of BDNF and a2d-1. Because calcium currents in VMH cells of BDNF mutants are normal, the satiety effects of a2d-1 might be related to its ability to induce excitatory synaptogenesis in a calcium-independent manner. Thus, Aim 1 will investigate the role of BDNF and a2d-1 in dynamic changes in VMH excitatory drive onto anorexigenic POMC neurons induced by nutritional cues using anatomical and electrophysiological approaches.
In Aim 2, we will investigate whether BDNF and a2d-1 also regulate excitatory drive onto anorexigenic VMH neurons.
In Aim 3, we will test whether the reduced expression of two other gene candidates in the BDNF mutant VMH contributes to the emergence of hyperphagic behavior and obesity and whether they act in common pathways with a2d-1 in the VMH. These studies will provide a mechanistic understanding of anorexigenic actions of BDNF and reveal novel avenues for the treatment of obesity.
Obesity is a pervasive disorder linked to serious medical complications and reaching epidemic proportions in the United States. New and efficacious treatment strategies are urgently needed. Dysregulation of brain- derived neurotrophic factor (BDNF) signaling in the brain contributes to excessive eating and body weight gain but the underlying disease mechanisms are poorly understood. We will examine candidate cellular and molecular mechanisms that might drive increases in food intake in individuals with deficient levels of BDNF. These investigations will facilitate the creation of new avenues for the treatment of obesity.
|Cordeira, Joshua W; Felsted, Jennifer A; Teillon, Sarah et al. (2014) Hypothalamic dysfunction of the thrombospondin receptor ?2?-1 underlies the overeating and obesity triggered by brain-derived neurotrophic factor deficiency. J Neurosci 34:554-65|
|Vithlani, Mansi; Hines, Rochelle M; Zhong, Ping et al. (2013) The ability of BDNF to modify neurogenesis and depressive-like behaviors is dependent upon phosphorylation of tyrosine residues 365/367 in the GABA(A)-receptor ýý2 subunit. J Neurosci 33:15567-77|
|Rios, Maribel (2013) BDNF and the central control of feeding: accidental bystander or essential player? Trends Neurosci 36:83-90|
|Rios, Maribel (2011) New insights into the mechanisms underlying the effects of BDNF on eating behavior. Neuropsychopharmacology 36:368-9|
|Cordeira, Joshua; Rios, Maribel (2011) Weighing in the role of BDNF in the central control of eating behavior. Mol Neurobiol 44:441-8|
|Klein, Anders B; Williamson, Rebecca; Santini, Martin A et al. (2011) Blood BDNF concentrations reflect brain-tissue BDNF levels across species. Int J Neuropsychopharmacol 14:347-53|
|Klein, A B; Santini, M A; Aznar, S et al. (2010) Changes in 5-HT2A-mediated behavior and 5-HT2A- and 5-HT1A receptor binding and expression in conditional brain-derived neurotrophic factor knock-out mice. Neuroscience 169:1007-16|
|Teillon, Sarah; Calderon, German A; Rios, Maribel (2010) Diminished diet-induced hyperglycemia and dyslipidemia and enhanced expression of PPARalpha and FGF21 in mice with hepatic ablation of brain-derived neurotropic factor. J Endocrinol 205:37-47|
|Cordeira, Joshua W; Frank, Lauren; Sena-Esteves, Miguel et al. (2010) Brain-derived neurotrophic factor regulates hedonic feeding by acting on the mesolimbic dopamine system. J Neurosci 30:2533-41|
|Unger, Thaddeus J; Calderon, German A; Bradley, Leila C et al. (2007) Selective deletion of Bdnf in the ventromedial and dorsomedial hypothalamus of adult mice results in hyperphagic behavior and obesity. J Neurosci 27:14265-74|