Ruano, S. H. | Search bioRxiv

bioRxiv2026

Effects of a Maternal Ketogenic Diet on Maternal and Offspring Metabolic Health in Mice

Ketogenic (keto) diets have gained popularity due to their potential benefits on weight loss and metabolic conditions. However, the consequences of consuming a keto diet before, during, and after pregnancy on maternal and offspring health remain incompletely understood. To investigate this, female Swiss Webster mice were randomly assigned to either a keto or control diet. After 6 weeks on diet, females were mated and maintained on their respective diets throughout pregnancy and lactation. In experiment 1, glucose tolerance tests (GTT) were performed on pregnant dams at gestational day (GD) 16.5. At GD 17.5, dams were euthanized, urine was collected for ketone analysis, and fetal and placental weights were recorded. In experiment 2, dams delivered naturally and one male and one female offspring per dam were retained and weighed weekly. At 12 weeks of age, offspring underwent GTT, followed by euthanasia and serum collection for insulin and leptin analysis. Compared with controls, keto dams exhibited increased body weight, impaired glucose tolerance, elevated urinary ketones, and reduced circulating insulin during late gestation (p<0.05). Fetuses from keto dams were significantly smaller (p<0.05), whereas placental weight and placental efficiency were unchanged. Offspring from keto dams weighed less than controls during early postnatal development but demonstrated catch-up growth by 12 weeks of age. At 12 weeks, keto offspring exhibited a modest but statistically significant improvement in glucose tolerance compared to control offspring (p<0.05). Male keto offspring had significantly decreased serum insulin (p<0.05) compared to male control offspring, while no differences were observed in females. Serum leptin levels did not differ between diet groups, although sex differences present in control offspring were not observed in keto offspring. Together, these findings suggest that maternal ketogenic diet consumption is associated with altered maternal glucose homeostasis during pregnancy and reduced fetal growth in this mouse model. Although offspring exhibited only modest metabolic alterations during early adulthood, the observed changes in growth trajectory and sex-specific metabolic profiles support further investigation into the long-term consequences of maternal ketogenic diet exposure during pregnancy.

physiology↗

bioRxiv2025

Complement activation in maternal and placental pathology of preeclampsia

Preeclampsia is a multifactorial, pregnancy-related disorder characterized by new-onset hypertension and proteinuria, with distinct early- and late-onset forms linked to varying placental and maternal pathologies. While complement system dysregulation has been implicated in the pathogenesis of preeclampsia, its causal relationship and molecular mechanisms remain unclear. In mice, complement receptor 1-related protein y (Crry) functions as a critical complement regulator at the fetal-maternal interface, essential for early embryonic survival. Complete Crry deficiency is embryonically lethal, complicating in vivo studies of complement activation in pregnancy. Using an alternative strategy, we developed a placenta-specific, doxycycline-inducible shRNA mouse model utilizing Cyp19-driven Cre recombinase and a Tet-On system to downregulate Crry in a dose-dependent manner 9.5 days post coitus, effectively restricting complement activation to the placenta. Using this model, we demonstrate that early gestation but sustained placental complement activation impairs maternal heart and liver adaptation, reduces placental efficiency, and causes fetal growth restriction, mimicking early-onset preeclampsia. Conversely, delayed complement activation induces a phenotype more consistent with late-onset preeclampsia features without placental pathology. In early-onset preeclampsia-like phenotype, the fetal growth restriction is accompanied by placental glycogen storage deficiency, and impaired hormonal function. Maternal glucose metabolism is not affected but compensatory adaptations in lipid metabolism occur although insufficient to offset fetal growth restriction. This novel model reveals that the timing of placental complement activation dictates the spectrum of preeclampsia-like pathology, providing mechanistic insights into the pathophysiology of preeclampsia.

immunology↗