High-fat diet-induced changes in ovarian gene expression are restored with prolonged omega-3 fatty acid administration

Abstract

We have previously shown that high-fat diet (HFD) feeding leads to the alteration of ovarian gene expression, including genes involved in critical ovarian processes1. Supplementation with omega-3 fatty acids has been shown to improve ovarian reserve and function in advanced reproductive age2. We hypothesized that dietary intervention with docosahexaenoic acid (DHA) after HFD would reverse HFD-induced changes in ovarian gene expression. Prospective laboratory animal study. 5 wk old C57BL/6J mice were randomly assigned to receive 60% HFD (N = 45) or chow (N = 10) for 10 wks. After 10 wks, HFD mice were assigned to continue HFD (N = 15), or were switched to chow (N = 10), DHA enriched chow (N = 10, chow+DHA), or DHA enriched HFD (N = 10, HFD+DHA) for 10 wks. Chow mice remained on chow. Mice were sacrificed in diestrous and ovaries were collected. Three animals were randomly selected from each dietary group for RNA sequencing analysis of ovarian RNA, and STAR and cufflinks packages were used for analysis. Genes were considered differentially expressed (DE) after adjusting for false discovery rate (q < 0.05). Mice fed HFD for 10 wks weighed more than chow controls (29.4 ± 0.7 g, vs 21.8 ± 0.5 g, p < 0.0001). Diet reversal to chow or chow+DHA restored body weight to chow controls (24.6 ± 0.5 g, 24.4 ± 1.1 g, 24.5 ± 0.9 g respectively), while mice remaining on HFD or switched to HFD+DHA continued to gain weight (40.9 ± 2.1 g, 40.0 ± 1.9 g respectively, p < 0.0001). HFD feeding for 20 wks altered the expression of 17 genes (q < 0.05). Many HFD-induced DE genes were restored with reversal to chow diet (15/17 genes), to chow+DHA (10/17 genes), and to HFD+DHA (11/17 genes). Interestingly, each dietary intervention induced its own unique gene expression profile with 55 DE genes with reversal to chow, 21 DE genes with reversal to chow+DHA, and 15 DE genes with reversal to HFD+DHA compared to chow controls (q < 0.05). Prolonged HFD exposure alters ovarian gene expression, of which most, but not all, is reversed with switching to chow, chow+DHA, or HFD+DHA. Interestingly, each dietary intervention induces its own unique gene expression profile. Work is underway to determine the relation of genes with altered expression to ovarian function, providing novel insights into dietary impact on ovarian activity and aging.