Aberrant lipid accumulation in the mouse visceral yolk sac resulting from maternal diabetes and obesity

Abstract

Maternal diabetes and obesity in pregnancy are well-known risk factors for structural birth defects, including neural tube defects and congenital heart defects. Progeny from affected pregnancies are also predisposed to developing cardiometabolic disease in later life. Based upon in vitro embryo cultures of rat embryos, it was postulated that nutrient uptake by the yolk sac is deficient in diabetic pregnancies. In contrast, using two independent mouse models of maternal diabetes, and a high-fat diet-feeding model of maternal obesity, we observed excessive lipid accumulation at 8.5 days in the yolk sac. The numbers as well as sizes of intracellular lipid droplets were increased in yolk sacs of embryos from diabetic and obese pregnancies. Maternal metabolic disease did not affect expression of lipid transporter proteins, including ApoA1, ApoB and SR-B1, consistent with our earlier report that expression of glucose and fatty acid transporter genes was also unchanged in diabetic pregnancy-derived yolk sacs. Colocalization of lipid droplets with lysosomes was significantly reduced in the yolk sacs from diabetic and obese pregnancies compared to yolk sacs from normal pregnancies. We therefore conclude that processing of lipids is defective in pregnancies affected by maternal metabolic disease, which may lead to reduced availability of lipids to the developing embryo. The possible implications of insufficient supply of lipids -and potentially of other nutrients-to the embryos experiencing adverse pregnancy conditions are discussed.

Differential responses to maternal diabetes in embryo and visceral yolk sac

“…However, lack of differential expression of hemoglobin genes in our yolk sac profiles (data not shown) underscores that blood island formation is not affected by the exposure to maternal diabetes at the somite stages we investigated. In addition, even though we detected significant accumulation of lipid droplets in yolk sacs under diabetic conditions as early as E8.5 (Zhang et al, 2023), this is not reflected in altered transcriptome profiles. Implications for understanding molecular mechanisms underlying adverse outcomes in pregnancies complicated by maternal diabetes…”

“…Finally, it should be kept in mind that our investigation was conducted in the NOD mouse strain, which spontaneously develops diabetes that includes immune system involvement also found in human type I diabetes. Similarities to chemically (i.e., Streptozotocin) induced models of diabetes in other mouse strains exist at the cellular level, both related to impaired migration of mesodermal cells ( Salbaum et al, 2015 ) and to excessive lipid accumulation in the visceral yolk sac ( Zhang et al, 2023 ), with commonalities at the transcriptomic level remaining to be determined. Furthermore, we focused on only those conceptuses that contained morphologically normal embryos.…”

“…Furthermore, based upon culture of rat and mouse conceptuses, prior work proposed that compromised yolk sac function would deprive the embryo of critical nutrients, such as arachidonic acid ( Pinter et al, 1986a ) and prostaglandin ( Piddington et al, 1996 ; Wentzel and Eriksson, 2005 ), leading to the “yolk sac hypothesis of diabetic embryopathy” ( Reece et al, 1994 ). Our own recent work demonstrated excess accumulation of lipids in visceral yolk sac in two independent mouse models of diabetic pregnancy ( Zhang et al, 2023 ), indicating altered nutrient availability to the embryo from the yolk sac at time points as early as E7.5 and E8.5. However, comprehensive gene expression profiles from yolk sac at such early stages, under conditions of maternal diabetes, have not been reported to date.…”

Diabetes Mellitus and Pregnancy: An Insight into the Effects on the Epigenome

“…So equipped, scientists have attempted to explain the mechanisms responsible for these alterations. Although the results obtained are diverse, it has been possible, in animal studies, to infer the mechanisms of diabetes [18].…”