Background

Female (F) rodents are more physically active than males (M) and are partially protected against metabolic dysfunction. The mechanism(s) are not fully understood, but we previously showed that ovariectomy in F rats caused significant mRNA changes in the nucleus accumbens (NAc) brain region, which correlated significantly with reduced physical activity (PA). This led us to hypothesize that sex differences in the NAc may help explain differences in PA and metabolism.

Methods

Differentially expressed genes (DEG) in NAc via RNAseq in M vs. F mice (n=5/grp; >2-fold change difference w/ FDR≤0.05) were determined to gain insight into brain-specific mechanism(s) behind sex differences in PA. We related those DEGs to systemic metabolism (body composition via EchoMRI & AT distribution; PA via metabolic chambers; HOMA-IR) and AT inflammation (q-rtPCR) in C57BL6J mice (n=10/group;12-16 wks; standard rodent chow). RNAseq data analyzed using R; for other variables, SPSS V.25, 2-tailed Student’s t-tests; bivariate Pearson’s correlations performed between key DEGs and outcome variables; alpha, P<0.05.

Results

F were significantly leaner and more physically active; had greater insulin sensitivity; lower AT inflammation; and greater AT UCP1 expression (P<0.05 compared to M in all cases). 48 DEGs in NAc were identified between M and F. Top DEGs were related to sexual development/fertility, inflammation, obesity, and AT metabolism; notably, functional over-enrichment analyses identified significant alterations in gene networks involved in the regulation of adipocyte metabolism (KEGG) and the circadian clock system (Panther). Of the top DEGs, PA correlated strongly with Per3, a gene associated with circadian function, thermoregulation, and metabolism (r=-0.64, P=0.002), which also correlated with adiposity (r=0.54, P=0.01).

Conclusions

Sex differences in NAc gene expression may explain sex differences in PA & metabolism. Estrogen’s regulation of circadian function may be a mechanism by which menopause reduces PA.