Maternal Fine Particulate Matter Exposure Impairs Inguinal White Adipose Tissue Plasticity in Middle-Aged Male Mouse Offspring.

Abstract

The rising prevalence of metabolic diseases represents a global health challenge, among which metabolically unhealthy normal-weight individuals constitute a largely ignored subgroup. Fine particulate matter (PM_2.5), which contains substantial nanoscale particulate matter, is a recognized extrinsic environmental trigger of metabolic disorders in both obese and nonobese situations, whereas the loss of plasticity in inguinal white adipose tissue (iWAT) is a critical intrinsic pathological feature of metabolic diseases. However, the long-term metabolic effects of maternal PM_2.5 exposure on nonobese offspring, particularly in iWAT plasticity, and underlying cellular mechanisms remain poorly understood. Here, we revealed that maternal PM_2.5 exposure induced insulin resistance in middle-aged male mouse offspring and identified iWAT as a susceptible adipose depot with impaired plasticity, which is characterized by adipocyte hypertrophy, inflammation, fibrosis, and metabolic dysfunction. Using single-cell RNA sequencing on iWAT from middle-aged male mouse offspring, we found that maternal PM_2.5 exposure altered the fate decisions of adipose-derived stem cells from adipogenesis to fibrosis through increasing CD142⁺ adipogenesis-regulatory cell expansion and inducing fibrogenesis in DPP4⁺ adipose stem cells. Mechanistically, maternal PM_2.5 exposure induced IgG production from plasma cells, which promoted fibrogenesis in DPP4⁺ adipose stem cells by activating macrophages. This process was further exacerbated by monocyte- and macrophage-mediated inflammation. Finally, maternal PM_2.5 exposure induced endothelial cell heterogeneity shifts and dysfunction, facilitating immune cell recruitment and naïve B cell differentiation into plasma cells, ultimately initiating IgG-triggered plasticity impairment. This study provided insights into the adverse effects of maternal exposure to environmental pollution on the metabolic health of offspring at single-cell resolution.