Frontiers in Cell and Developmental Biology · 5 authors, 3 centres
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This study found that maternal diabetes and obesity in mice cause excessive lipid accumulation in the visceral yolk sac, the early placenta. The excess lipids form larger droplets that are less likely to be processed by lysosomes, suggesting a defect in lipid breakdown. This impaired lipid processing may reduce nutrient supply to the embryo, potentially explaining the increased risk of birth defects like neural tube defects in diabetic and obese pregnancies.
**Background:** Maternal diabetes and obesity are known risk factors for structural birth defects, including neural tube defects (NTDs) and cardiovascular malformations. The underlying mechanisms are unclear, but nutrient excess, particularly hyperglycemia, is thought to play a role. During early post-implantation development, the embryo receives nutrients through the yolk sac, which functions as a primitive placenta. The visceral yolk sac consists of an endodermal layer for nutrient uptake and a mesodermal layer for transport to the embryo. Prior in vitro studies using rat conceptuses cultured in high glucose showed yolk sac abnormalities, including reduced lipid droplet content and fatty acid uptake. However, these studies were confounded by the use of adult serum and high oxygen conditions, which differ from the hypoxic in vivo environment. This study aimed to re-evaluate yolk sac abnormalities in vivo using two mouse models of diabetic pregnancy and a model of maternal obesity.
**Methods:** Three mouse models were used: (1) Streptozotocin (STZ)-induced diabetes in FVB/N mice, (2) spontaneously diabetic non-obese diabetic (NOD) mice, and (3) FVB/N mice fed a high-fat-high-sucrose diet (HFD) for 4 weeks prior to mating to model obesity. Visceral yolk sacs were isolated at embryonic day 8.5 (E8.5). Lipid droplets were stained with Bodipy and nuclei with DAPI. Three-dimensional confocal imaging and volumetric analysis were performed using Imaris software to quantify lipid droplet number, size, and total lipid volume relative to DAPI. Immunohistochemistry and immunofluorescence were used to assess expression of lipid transporters (ApoA1, ApoB, SR-B1) and endodermal markers (Folate receptor α, Cubilin). Lysosomal processing was evaluated by co-staining live yolk sacs with LysoTracker (lysosomes) and Bodipy (lipids), and colocalization was quantified using ImageJ. RNA sequencing data from NOD yolk sacs were analyzed for expression of lipid-related genes.
**Key Results:** In both diabetic models (FVB-STZ and NOD) and the HFD obesity model, yolk sacs showed significantly increased lipid accumulation compared to controls. The ratio of lipid (Bodipy) to DAPI voxel volume was significantly higher in diabetic FVB (p<0.05), diabetic NOD (p<0.05), and HFD (p<0.05) yolk sacs. Lipid droplets were not only more numerous but also larger in size, with a shift toward larger volume ranges in all experimental groups. Expression of lipid transporters ApoA1, ApoB, and SR-B1 was detected in the yolk sac, but their protein levels did not differ significantly between control and experimental groups in any model. RNA sequencing of NOD yolk sacs confirmed no significant differences in expression of 77 lipid-related genes (adjusted p-values >0.05). Colocalization of lipid droplets with lysosomes was significantly decreased in yolk sacs from diabetic FVB (p<0.05), diabetic NOD (p<0.05), and HFD-fed dams (p<0.05) compared to controls, indicating impaired lipid processing.
**Clinical Implications:** This study demonstrates that maternal diabetes and obesity lead to excessive lipid accumulation in the visceral yolk sac due to defective lysosomal processing, rather than increased expression of lipid transporters. The accumulation of large lipid droplets may inhibit lipophagy, creating a negative feedback loop that further impairs lipid breakdown. Since the yolk sac is critical for supplying nutrients (including lipids, cholesterol, and fat-soluble vitamins) to the developing embryo, this defect could result in deficiencies of essential nutrients like vitamin E and cholesterol, which are known to be required for neural tube closure. The findings align with prior studies showing that supplementation with arachidonic acid, vitamin E, or prostaglandin E2 can reduce malformation rates in diabetic pregnancies. The results suggest that therapies aimed at enhancing lipid processing or release from yolk sac cells could potentially lower the risk of neural tube defects in pregnancies complicated by diabetes or obesity. Future studies should investigate whether similar lipid accumulation occurs in human yolk sacs and whether interventions can restore nutrient transport to the embryo.