Hepatic Gene Expression Changes in Adult Mice After Maternal Calorie Restriction

Objectives: Maternal malnutrition during pregnancy results in developmental programing of offspring that increases risk for later metabolic disease. The offspring's diet further influences these risks, but less is known about the interactions of prenatal and postnatal nutrition exposures into adulthood. Methods: Pregnant C57BL/6J mice were randomized to 30% calorie restriction (CR) or ad libitum food (control) starting at day 10 of gestation. At 21 days of life, offspring were weaned to control (CON, 7% calories from fat) or HFD (45% calories from fat) diet. At age 16-18 weeks, female and male control and CR offspring (n = 6/group) were euthanized. Whole livers were collected, weighed, and flash frozen. mRNA-sequencing was conducted using Illumina methodology. Differentially regulated genes (DEGs) were defined using the limma-voom pipeline as ±1.2-fold change and adjusted p < 0.1. Pathways represented by up- and down-regulated DEGs were identified using Enrichr. Expression of individual genes of interest were compared by fetal growth and postnatal diet by two-way ANOVA. Results: At day 18.5, CR fetuses weighed an average of 19% less than controls, but did not differ at age 16 weeks within diet groups. Relative liver weight also did not differ between groups. Among females, no genes had padj < 0.01 (n = 1,065 with p < 0.05). Comparing CR to control males, there were 5,844 DEGs for those fed CON-diet, and 153 for those fed HFD. The top upregulated pathways in CR-CON livers related to cell cycle and inflammation. Top upregulated pathways in CR-HFD related to fatty acid degradation including PPAR signaling. Expression of PPARγ, a regulator of hepatic lipid metabolism, was 4-fold higher (p = 0.0014) in CR-CON male livers. Expression of PPARα, which is involved in regulation of fatty acid oxidation and triglyceride levels, was 1.5-fold lower in CR-CON male livers. TNFα expression was higher 6.8-fold higher in CR-CON versus control-CON males. Conclusions: Maternal calorie restriction resulted in substantial differences in hepatic gene expression related to fatty acid metabolism, insulin sensitivity, and inflammation in adult male offspring. Additional work is needed to determine a mechanistic role for these changes in metabolic outcomes. Funding Sources: NIDDK, Ludeman Family Center for Women's Health Research.