RSS-Feed abonnieren
DOI: 10.1055/s-0034-1372029
A high-fat diet during pregnancy and lactation targets GIP-regulated metabolic pathways in male offspring in mice
Introduction: Offspring exposed to high fat diet (HFD) during pregnancy (IU) and lactation (L) are at risk of developing obesity in adulthood. Inhibition of glucose dependent insulinotropic polypeptide receptor signaling (Gipr-/-) in mice is protective of HFD induced obesity. We reported that Gipr-/- exposed to HFD during IU/L are no longer protected from diet induced obesity in adulthood. We now tested the hypothesis if these programming effects are due to altered promoter methylation of key genes of lipid metabolism which causes a decrease in gene expression.
Methods: Female GIP receptor heterozygous (Gipr+/-) mice were fed either HFD or control (C) diet prior to mating with Gipr+/- male mice and during IU/L. Male Gipr-/- offspring were kept on normal chow for 22 weeks after weaning, followed by HFD for additional 20 weeks. This resulted into Gipr-/- exposed to either C (KO Ciu-HF) or HFD (KO HFiu-HF) during IU/L and HFD later in adulthood. Wild type (WT) male mice fed C diet during IU/L and HFD in adulthood served as controls (WT Ciu-HF). At 45 weeks of age, body fat content, adipocyte size and expression and DNA-methylation of genes of fatty acid oxidation in muscle were analyzed.
Results: KO HFiu-HF had increased body fat content (P < 0.05) and larger adipocytes (P < 0.005) compared to KO Ciu-HF. Gene expression of PPARα (2.45-fold) and CPT-1β (1.53-fold) was massively increased in KO Ciu-HF compared to WT Ciu-HF mice (P < 0.05), but down regulated by 45.2% for PPARα and by 41.0% for CPT-1β in KO HFiu-HF compared to KO Ciu-HF (P < 0.05) in muscle. One CpG-site for PPARα and three CpG-sites for CPT-1β showed a decrease in methylation in KO Ciu-HF compared to WT Ciu-HF and a renewed increase in KO HFiu-HF as seen in WT Ciu-HF. CpG-methylation correlated inversely with gene expression.
Conclusion: HFD during IU/L induces epigenetic modifications leading to decreased peripheral fatty acid oxidation that reverses the protection of diet induced obesity in Gipr-/- mice.