Abstract
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.
Original language | English |
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Number of pages | 11 |
Journal | Molecular Psychiatry |
Early online date | 16 Jan 2024 |
DOIs | |
Publication status | E-pub ahead of print - 16 Jan 2024 |
Bibliographical note
Open Access via the Springer Nature AgreementARM and AM were funded by a BBSRC project grant (BB/N017544/1) and Tenovus Scotland Grampian (award G19.08). GH was funded by Medical Research Scotland (PHD-50366-2021) and Wayne Gault of the Aberdeenshire Alcohol and Drugs Partnership. We thank the staff (Darrin Sheppard, Donna Wallace, Andrew Brown, Mark Herbert and Karen Heath) at the Medical Research Facility for their help and excellent advice in the completion of these studies. We also thank Giuseppe D’Agostino for his guidance and help throughout the study.