Abstract
Abnormal polarization of adipose tissue macrophages (ATMs) results in low-grade systemic inflammation and insulin resistance (IR), potentially contributing to the development of diabetes. However, the underlying mechanisms that regulate the polarization of ATMs associated with gestational diabetes mellitus (GDM) remain unclear. Thus, we aimed to determine the effects of abnormal fatty acids on macrophage polarization and development of insulin resistance in GDM. Levels of fatty acids and inflammation were assessed in the serum samples and adipose tissues of patients with GDM. An in vitro cell model treated with palmitic acid was established, and the mechanisms of palmitic acid in regulating macrophage polarization was clarified. The effects of excessive palmitic acid on the regulation of histone methylations and IR were also explored in the high-fat diet induced GDM mice model. We found that pregnancies with GDM were associated with increased levels of serum fatty acids, and inflammation and IR in adipose tissues. Increased palmitic acid could induce mitochondrial dysfunction and excessive ROS levels in macrophages, leading to abnormal cytoplasmic and nuclear metabolism of succinate and α-ketoglutarate (αKG). Specifically, a decreased nuclear αKG/succinate ratio could attenuate the enrichment of H3K27me3 at the promoters of pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, leading to cytokine secretion. Importantly, GDM mice treated with GSK-J4, an inhibitor of histone lysine demethylase, were protected from abnormal pro-inflammatory macrophage polarization and excessive production of pro-inflammatory cytokines. Our findings highlight the importance of the metabolism of αKG and succinate as transcriptional modulators in regulating the polarization of ATMs and the insulin sensitivity of adipose tissue, ensuring a normal pregnancy. This novel insight sheds new light on gestational fatty acid metabolism and epigenetic alterations associated with GDM.
Schematic illustration showing how abnormal FFA concentrations regulate M1 type macrophage polarization and insulin resistance in GDM. In women with GDM, the levels of FFAs are elevated. These elevated FFAs can be absorbed by monocytes, leading to mitochondrial dysfunction and a decreased ratio of αKG/succinate. The decreased αKG/succinate ratio results in a lower enrichment of H3K27me3 in the promoter of pro-inflammatory cytokines, leading to M1 type macrophage polarization and insulin resistance in adipose tissues. Thus, elevated FFAs in GDM might induce adipose tissue insulin resistance by promoting macrophage polarization by influencing αKG/succinate metabolism and H3K27me3 modification. [Display omitted]
•Pregnancies with GDM are associated with increased levels of serum fatty acid.•Excess PA disturbs macrophage αKG/succinate metabolism and promoters' enrichment of H3K27me3 at pro-inflammatory cytokines.•GDM mice induced by a high-fat diet treated with the GSK-J4 inhibitor partially restore insulin sensitivity.