Abstract 12540: Epigenetic Modulation of Macrophage Polarization Toward a Proinflammatory Phenotype Increases the Susceptibility to Insulin Resistance in Adult Offspring of High-fat Diet Fed-dams

Abstract

Background: Maternal high-fat diet (HFD) has been shown to promote the development of metabolic disorders such as obesity and insulin resistance in adult offspring; however, its underlying mechanisms remains undefined. Method and Result: Eight-week-old female wild-type mice were fed a HFD or normal diet (ND) one week prior to mating, and received either HFD or ND during gestation and lactation. Offspring of both groups were fed a ND after weaning and then fed a HFD from 8 to 20 weeks of age. After 4 weeks of HFD feeding, insulin tolerance test in male offspring of HFD-fed dams (O-HFD) showed a significantly impaired insulin sensitivity compared with those of ND-fed dams (O-ND), which was more prominent after 8 weeks of HFD feeding. In contrast, glucose tolerance did not differ between the 2 groups after 4 and 8 weeks of HFD feeding. The weight of epididymal white pads and adipocyte size were comparable between the 2 groups. Although the fraction of macrophages (F4/80 + CD11b + ) in epididymal white pads assessed by flow cytometry did not differ between the 2 groups, the ratio of M1/M2 macrophages (M1:CD11c + CD206 - , M2:CD11c - CD206 + ) was markedly increased in O-HFD compared with O-ND (18.3 vs. 1.6, O-HFD vs. O-ND; P < 0.05). We examined the effect of maternal HFD on the bone marrow (BM) monocytosis and macrophage polarization in adult offspring before HFD feeding. The fraction of BM pro-monocyte (CD11b high Ly-6G low ) did not differ between the 2 groups; however, BM-derived macrophages (BMDMs) in O-HFD showed a higher expression levels of M1 marker genes after stimulation of IFN-γ, concomitant with the lower expression levels of M2 marker genes after stimulation of IL-4. Further, BMDMs in O-HFD showed a 2.9-fold increase in the mRNA expression levels of histone deacetylase 3 ( HDAC3 ) after stimulation of IL-4 ( P < 0.05), whereas its expression was decreased by 64 % in O-ND ( P < 0.05). Conclusion: Our findings demonstrated for the first time that BMDMs in adult offspring of HFD-fed dams are likely to be polarized toward a proinflammatory phenotype, thereby contributing to the increased susceptibility to insulin resistance. Modulation of epigenetic-mediated macrophage polarization could be a potential therapeutic target for preventing metabolic disorders.