Background It is now understood that it is the quality rather than the absolute amount of adipose tissue that confers risk for obesity-associated disease. Adipose-derived stem cells give rise to adipocytes during the developmental establishment of adipose depots. In adult depots, a reservoir of progenitors serves to replace adipocytes that have reached their lifespan and for recruitment to increase lipid buffering capacity under conditions of positive energy balance. Main The adipose tissue expandability hypothesis posits that a failure in de novo differentiation of adipocytes limits lipid storage capacity and leads to spillover of lipids into the circulation, precipitating the onset of obesity-associated disease. Since adipose progenitors are specified to their fate during late fetal life, perturbations in the intrauterine environment may influence the rapid expansion of adipose depots that occurs in childhood or progenitor function in established adult depots. Neonates born to mothers with obesity or diabetes during pregnancy tend to have excessive adiposity at birth and are at increased risk for childhood adiposity and cardiometabolic disease. Conclusion In this narrative review, we synthesize current knowledge in the fields of obesity and developmental biology together with literature from the field of the developmental origins of health and disease (DOHaD) to put forth the hypothesis that the intrauterine milieu of pregnancies complicated by maternal metabolic disease disturbs adipogenesis in the fetus, thereby accelerating the trajectory of adipose expansion in early postnatal life and predisposing to impaired adipose plasticity.

Background: Exposure to high maternal adiposity in utero is a significant risk factor for the later-life development of metabolic syndrome (MetS), including non-alcoholic fatty liver disease (NAFLD). We have previously shown that high pre-pregnancy adiposity programs adipose tissue dysfunction in the offspring, leading to spillover of fatty acids into the circulation, a key pathogenic event in obesity-associated MetS. Herein, we hypothesized that programming of adipose tissue dysfunction in offspring born to overweight dams increases the risk for developing NAFLD. Results: Females heterozygous for leptin receptor deficiency (Hetdb) were used as a model of high pre-pregnancy adiposity. Wild-type (Wt) offspring born to Hetdb pregnancies gained significantly more body fat following high fat/fructose diet (HFFD) compared to Wt offspring born to Wt dams. HFFD increased circulating free fatty acids (FFA) in male offspring of control dams, while FFA levels were similar in HFFD-fed offspring from Wt dams compared to CD or HFFD-Wt offspring from Hetdb dams. Despite female-specific protection from diet-induced FFA spillover, both male and female offspring from Hetdb dams were more susceptible to diet-induced hepatosteatosis. Lipidomic analysis revealed that CD-offspring of overweight dams had decreased hepatic PUFA levels compared to control offspring. Changes to saturated fatty acids (SFA) and the de novo lipogenic (DNL) index were diet driven; however, there was a significant effect of the intrauterine environment on FA elongation and Capital Greek Δ9 desaturase activity. Conclusion: High maternal adiposity during pregnancy programs a susceptibility to diet-induced hepatosteatosis.

The syncytiotrophoblast is a human epithelial cell that is bathed in maternal blood on the maternal-facing surface of the human placenta. It therefore acts as a barrier and exchange interface between the mother and fetus. Syncytiotrophoblast dysfunction is a feature of pregnancy pathologies, like preeclampsia. Dysfunctional syncytiotrophoblasts display a loss of microvilli, which is a marker of aberrant apical–basal polarization, but little data exist about the regulation of syncytiotrophoblast polarity. Atypical PKC isoforms are conserved polarity regulators. Thus, we hypothesized that aPKC isoforms regulate syncytiotrophoblast polarity. Using human placental explant culture and primary trophoblasts, we found that loss of aPKC activity or expression induces syncytiotrophoblast gasdermin-E-dependent pyroptosis, a form of programmed necrosis. We also establish that TNF-α induces an isoform-specific decrease in aPKC expression and gasdermin-E-dependent pyroptosis. Therefore, aPKCs are homeostatic regulators of the syncytiotrophoblast function and a pathogenically relevant pro-inflammatory cytokine leads to the induction of programmed necrosis at the maternal–fetal interface. Hence, our results have important implications for the pathobiology of placental disorders like preeclampsia.