Preconception Diet Interventions in Obese Outbred Mice and the Impact on Female Offspring Metabolic Health and Oocyte Quality

Abstract

Obese individuals often suffer from metabolic health disorders and reduced oocyte quality. Preconception diet interventions in obese outbred mice restore metabolic health and oocyte quality and mitochondrial ultrastructure. Also, studies in inbred mice have shown that maternal obesity induces metabolic alterations and reduces oocyte quality in offspring (F1). Until now, the effect of maternal high-fat diet on F1 metabolic health and oocyte quality and the potential beneficial effects of preconception dietary interventions have not been studied together in outbred mice. Therefore, we fed female mice a high-fat/high-sugar (HF/HS) diet for 7 weeks and switched them to a control (CONT) or caloric-restriction (CR) diet or maintained them on the HF/HS diet for 4 weeks before mating, resulting in three treatment groups: diet normalization (DN), CR, and HF/HS. In the fourth group, mice were fed CONT diet for 11 weeks (CONT). HF/HS mice were fed an HF/HS diet from conception until weaning, while all other groups were then fed a CONT diet. After weaning, offspring were kept on chow diet and sacrificed at 11 weeks. We observed significantly elevated serum insulin concentrations in female HF/HS offspring and a slightly increased percentage of mitochondrial ultrastructural abnormalities, mitochondrial size, and mitochondrial mean gray intensity in HF/HS F1 oocytes. Also, global DNA methylation was increased and cellular stress-related proteins were downregulated in HF/HS F1 oocytes. Mostly, these alterations were prevented in the DN group, while, in CR, this was only the case for a few parameters. In conclusion, this research has demonstrated for the first time that a maternal high-fat diet in outbred mice has a moderate impact on female F1 metabolic health and oocyte quality and that preconception DN is a better strategy to alleviate this compared to CR.

Keywords: diet intervention; epigenetics; metabolism; mitochondria; obesity; obesogenic diet; offspring; oocyte; preconception care; proteomics.

Figure 1

Overview of the experimental design. HF/HS = high-fat/high-sugar; DN = diet normalization; CR = caloric restriction; CONT = control; w = weeks.

Figure 2

Female offspring body weight at birth (0 weeks), weaning (3 weeks), and adult age (8 weeks and 11 weeks) from offspring born to HF/HS = high-fat/high-sugar diet, DN = diet normalization, CR = caloric restriction, or CONT = control diet. At birth, mice were weighed collectively per litter (n = 4 litters/treatment), while, at the other time points, all mice were weighed individually (n = 16–20/treatment). Each data point shows mean +/− SEM.

Figure 3

Serum insulin concentrations in female offspring born to HF/HS = high-fat/high-sugar diet, DN = diet normalization, CR = caloric restriction, or CONT = control diet (n = 10/treatment). Each bar shows mean +/− SEM. Significant differences (p ≤ 0.05) are shown by different letters (a or b).

Figure 4

Global DNA methylation levels in oocytes from offspring born to HF/HS = high-fat/high-sugar diet, DN = diet normalization, CR = caloric restriction, or CONT = control diet (n = 49–77 oocytes/treatment; n = 4 litters/treatment). Each bar shows mean +/− SEM. Significant differences (p ≤ 0.05) are shown by different letters (a or b).

Figure 5

Pathways in which the 17 observed DRPs were enriched (n = 3 pools/treatment, n = 64–309 oocytes/pool).