Hypothalamic TrkB.FL overexpression improves metabolic outcomes in the BTBR mouse model of autism.

Scientists studied mice that model autism traits and tested whether boosting a specific brain protein (TrkB) in the hypothalamus could improve health outcomes. The treatment improved metabolism - mice gained less weight, burned more energy, and had better blood sugar control. However, it didn't change autism-like behaviors. This suggests the brain pathway studied affects physical health but not autism symptoms in this mouse model.

This preclinical study investigated whether overexpressing the TrkB receptor in the hypothalamus of BTBR mice (an autism model) could replicate the metabolic benefits observed with enriched environments. Researchers used viral vectors to increase TrkB expression and monitored metabolic and behavioral outcomes for 24 weeks. Results showed significant metabolic improvements including reduced weight gain, increased energy expenditure, better glucose control, and altered gene expression related to energy regulation. However, behavioral autism-like traits remained unchanged.

The findings suggest hypothalamic BDNF-TrkB signaling specifically influences metabolic health rather than core autism behaviors in this mouse model.

This research suggests metabolic and behavioral aspects of autism may involve different neural pathways. While not directly applicable to treatment, it contributes to understanding how brain signaling affects metabolism in autism models and supports investigating metabolic interventions separately from behavioral therapies.

Animal model findings may not translate to humans. Sample size not reported. Single intervention approach. Behavioral assessments limited to 24 weeks. BTBR mice may not fully represent human autism complexity.

BTBR T+ Itpr3tf/J (BTBR) mice are used as a model of autism spectrum disorder (ASD), displaying similar behavioral and physiological deficits observed in patients with ASD. Our recent study found that implementation of an enriched environment (EE) in BTBR mice improved metabolic and behavioral outcomes. Brain-derived neurotrophic factor (Bdnf) and its receptor tropomyosin kinase receptor B (Ntrk2) were upregulated in the hypothalamus, hippocampus, and amygdala by implementing EE in BTBR mice, suggesting that BDNF-TrkB signaling plays a role in the EE-BTBR phenotype. Here, we used an adeno-associated virus (AAV) vector to overexpress the TrkB full-length (TrkB.FL) BDNF receptor in the BTBR mouse hypothalamus in order to assess whether hypothalamic BDNF-TrkB signaling is responsible for the improved metabolic and behavioral phenotypes associated with EE.

Normal chow diet (NCD)-fed and high fat diet (HFD)-fed BTBR mice were randomized to receive either bilateral injections of AAV-TrkB.FL or AAV-YFP as control, and were subjected to metabolic and behavioral assessments up to 24 weeks post-injection. Both NCD and HFD TrkB.FL overexpressing mice displayed improved metabolic outcomes, characterized as reduced percent weight gain and increased energy expenditure. NCD TrkB.FL mice showed improved glycemic control, reduced adiposity, and increased lean mass. In NCD mice, TrkB.FL overexpression altered the ratio of TrkB.FL/TrkB.T1 protein expression and increased phosphorylation of PLCγ in the hypothalamus.

TrkB.FL overexpression also upregulated expression of hypothalamic genes involved in energy regulation and altered expression of genes involved in thermogenesis, lipolysis, and energy expenditure in white adipose tissue and brown adipose tissue. In HFD mice, TrkB.FL overexpression increased phosphorylation of PLCγ. TrkB.FL overexpression in the hypothalamus did not improve behavioral deficits in either NCD or HFD mice. Together, these results suggest that enhancing hypothalamic TrkB.FL signaling improves metabolic health in BTBR mice.