Mechanistic aspects of sex-specific prenatal programming of adipose tissue development by obesogenic exposure in a human cell model

The incidence of maternal obesity is steadily increasing globally ([1] [2] [3]). Both preclinical and clinical studies indicate that maternal obesity influences fetal programming of energy metabolism, including the plasticity of adipocyte development, promoting an early onset of obesity and type 2 diabetes (T2D) ([4] [5] [6]). Our previously established mouse model of obesity in pregnancy indicated sex-specific programming of adipose tissue. Obesogenic exposure in utero reduced the adipocyte size in adult female but not male offspring, accompanied by hyperglycemia ([7]). The dysfunctional adipocyte phenotype was aggravated by postnatal high-calorie diet (HCD) feeding, which led to severe adiposity and T2D symptoms in female adult offspring. However, the precise early mechanisms linking prenatal obesogenic exposure to the subsequent development of obesity and T2D in offspring later in life remain incompletely understood.

To gain insights into the molecular mechanisms, we performed a multi-omics analysis of murine female embryonic adipocyte precursors, exposed to an HCD in utero. Our analyses revealed epigenetic changes evident in genes associated with fat cell differentiation and regulation at embryonic day E13.5, and proteomics data pointed to a dysregulation in fatty acid and lipid metabolic processes. Notably, transcription of aldehyde dehydrogenases (Aldh) 1a1 and Aldh1a7 was downregulated. In vitro, Aldh1a7 siRNA knockdown in murine 3T3-L1 cells confirmed impaired early adipogenesis, pointing to a yet unknown molecular pathway. Further analyses revealed that Aldh1a7 knockdown in differentiating 3T3-L1 cells prompted an upregulation of a signaling cascade to maintain the preadipocyte state, including an upregulation of Aldh1a1 mRNA expression. In contrast, knockdown of Aldh1a1 in murine 3T3-L1 cells had no effect on early adipocyte differentiation. However, during differentiation of the human white preadipocyte cell line SGBS, knockdown of Aldh1a1 reduced lipid droplet formation and mRNA expression of key adipogenesis driver genes. In addition, reduced lipid storage persisted until maturation of SGBS cells.

In conclusion, we show that Aldh1a1 is essential for the early human adipocyte differentiation, similar to Aldh1a7 in a murine environment. Further research involving estrogen signaling is expected to help clarifying the underlying mechanistic aspects of the dysregulation of aldehyde dehydrogenases during adipogenesis and the female-specific impaired adipocyte phenotype.

Publikationsverlauf

Artikel online veröffentlicht:
28. Mai 2025

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