An ancient polymorphic regulatory region within the BDNF gene associated with obesity modulates anxiety-like behaviour in mice and humans.
Andrew R McEwanBenjamin HingJohanna C EricksonGreg HutchingsCharity UramaEmily Norton-HughesMariam D'IppolitoSusan BerryMirela DelibegovićFelix GrassmannAlasdair MacKenziePublished in: Molecular psychiatry (2024)
Obesity and anxiety are morbidities notable for their increased impact on society during the recent COVID-19 pandemic. Understanding the mechanisms governing susceptibility to these conditions will increase our quality of life and resilience to future pandemics. In the current study, we explored the function of a highly conserved regulatory region (BE5.1) within the BDNF gene that harbours a polymorphism strongly associated with obesity (rs10767664; p = 4.69 × 10 -26 ). Analysis in primary cells suggested that the major T-allele of BE5.1 was an enhancer, whereas the obesity-associated A-allele was not. However, CRISPR/CAS9 deletion of BE5.1 from the mouse genome (BE5.1KO) produced no significant effect on the expression of BDNF transcripts in the hypothalamus, no change in weight gain after 28 days and only a marginally significant increase in food intake. Nevertheless, transcripts were significantly increased in the amygdala of female mice and elevated zero maze and marble-burying tests demonstrated a significant increase in anxiety-like behaviour that could be reversed by diazepam. Consistent with these observations, human GWAS cohort analysis demonstrated a significant association between rs10767664 and anxiousness in human populations. Intriguingly, interrogation of the human GTEx eQTL database demonstrated no effect on BDNF mRNA levels associated with rs10767664 but a highly significant effect on BDNF-antisense (BDNF-AS) gene expression and splicing. The subsequent observation that deletion of BE5.1 also significantly reduced BDNF-AS expression in mice suggests a novel mechanism in the regulation of BDNF expression common to mice and humans, which contributes to the modulation of mood and anxiety in both species.
Keyphrases
- high fat diet induced
- weight gain
- insulin resistance
- stress induced
- endothelial cells
- weight loss
- metabolic syndrome
- poor prognosis
- gene expression
- type diabetes
- body mass index
- crispr cas
- sleep quality
- transcription factor
- binding protein
- birth weight
- induced pluripotent stem cells
- genome wide
- climate change
- pluripotent stem cells
- skeletal muscle
- dna methylation
- bipolar disorder
- copy number
- genome editing
- long non coding rna
- oxidative stress
- cell proliferation
- cell death
- functional connectivity
- wild type
- preterm birth
- cell cycle arrest
- drug induced