Poster abstracts
Poster number 71 submitted by Jacqueline Anderson
Metabolic effects of hypothalamic tropomyosin-receptor kinase B-full-length (TrkB.FL) overexpression in the BTBR murine model of autism
Jacqueline M. Anderson (Neuroscience Graduate Program), Lei Cao (Cancer Biology and Genetics)
Abstract:
An enriched environment (EE) has been found to induce an anti-obesity and anti-cancer phenotype in mice. Our lab previously elucidated the mechanism behind these effects, termed the hypothalamic-sympathoneural-adipocyte (HSA) axis, whereby hypothalamic brain-derived neurotrophic factor (BDNF) upregulation elevates sympathetic tone to adipocytes, leading to improved metabolic outcomes and an anticancer effect. Recently we investigated the effects of EE in BTBR T+ Itpr3tf/J (BTBR) mice, a model of autism spectrum disorder (ASD). We found that EE resulted in improved metabolic and behavioral outcomes and upregulation of gene expression of BDNF and its receptor, Ntrk2/TrkB, in several brain areas. Based on our past cancer and obesity studies identifying BDNF as the key brain mediator for improved metabolic and immunity outcomes, we hypothesized that BDNF-TrkB signaling was also important in the BTBR outcomes. The purpose of this current study was to investigate the role of TrkB signaling in improving metabolic and behavioral phenotypes in a diet-induced obesity BTBR mouse model. We placed eleven juvenile male BTBR mice on a high-fat diet and randomized mice to receive bilateral injections of either an adeno-associated virus (AAV) vector carrying TrkB.FL or YFP to the arcuate nucleus of the hypothalamus to locally overexpress neuronal TrkB.FL or YFP. We performed a variety of metabolic and behavioral tests over the course of five months while mice were maintained on a high fat diet. AAV-TrkB.FL treated mice showed lower weight gain, displayed increased metabolic expenditure, and had lower relative mass of liver and higher relative mass of brown adipose tissue (BAT) as compared to AAV-YFP treated mice. There were no significant differences between groups regarding anxiety and sociability behavioral tests. Western Blot showed a significantly lower pAKT/tAKT ratio in the hypothalamus of TrkB.FL treated animals. Analysis is underway to investigate gene expression of mediators involved in BDNF-TrkB signaling and to examine serum metabolic hormones. These preliminary results suggest that hypothalamic TrkB.FL upregulation affects protein levels of downstream signaling mediators in the BDNF-TrkB pathway and may play a role in improving metabolic outcomes in the BTBR mouse, but not behavioral outcomes.
Keywords: BTBR, obesity, AAV