Changes in nucleus accumbens gene expression accompany sex-specific suppression of spontaneous physical activity in aromatase knockout mice

Abstract

Aromatase catalyzes conversion of testosterone to estradiol and is expressed in a variety of tissues, including the brain. Suppression of aromatase adversely affects metabolism and physical activity behavior, but mechanisms remain uncertain. The hypothesis tested herein was that whole body aromatase deletion would cause gene expression changes in the nucleus accumbens (NAc), a brain regulating motivated behaviors such as physical activity, which is suppressed with loss of estradiol. Metabolic and behavioral assessments were performed in male and female wild-type (WT) and aromatase knockout (ArKO) mice. NAc-specific differentially expressed genes (DEGs) were identified with RNAseq, and associations between the measured phenotypic traits were determined. Female ArKO mice had greater percent body fat, reduced spontaneous physical activity (SPA), consumed less energy, and had lower relative resting energy expenditure (REE) than WT females. Such differences were not observed in ArKO males. However, in both sexes, a top DEG was Pts, a gene encoding an enzyme necessary for catecholamine (e.g., dopamine) biosynthesis. In comparing male and female WT mice, top DEGs were related to sexual development/fertility, immune regulation, obesity, dopamine signaling, and circadian regulation. SPA correlated strongly with Per3, a gene regulating circadian function, thermoregulation, and metabolism (r = −0.64, P = .002), which also correlated with adiposity (r = 0.54, P = .01). In conclusion, aromatase ablation leads to gene expression changes in NAc, which may in turn result in reduced SPA and related metabolic abnormalities. These findings may have significance to post-menopausal women and those treated with an aromatase inhibitor.