Maternal Obesity Programs Glucose Intolerance in Pregnant Female Offspring

Maternal obesity is a known risk factor for metabolic dysfunction in offspring; however, its effect on metabolism during pregnancy in female offspring remains unclear. This study investigated how maternal obesity, induced by high-fat (HF) feeding in C57BL/6J mice, affects the metabolic adaptation to pregnancy in female offspring. Dams were fed an HF diet (60% fat) or chow for 3 months before and during pregnancy. Offspring of HF diet-fed dams (OF-HFD) exhibited reduced fetal growth, followed by rapid postnatal catch-up and increased adult adiposity, compared with offspring of chow-fed dams (OF-CD), despite having similar baseline glucose and insulin levels. During pregnancy, OF-HFD exhibited diminished increases in maternal body fat, blood triglycerides, and insulin concentrations, accompanied by glucose intolerance. In cultured islets, glucose-stimulated insulin secretion was markedly reduced in pregnant OF-HFD, despite unchanged β-cell mass or proliferation. Hepatic triglyceride secretion was decreased, whereas liver insulin signaling was enhanced, suggesting alterations in lipid and glucose metabolism. Feeding OF-HFD an HF diet before and during pregnancy further impaired fetal growth. These findings indicate that maternal obesity impairs the metabolic adaptation to pregnancy in female offspring, characterized by insulin insufficiency and disrupted lipid homeostasis. This may initiate a transgenerational cycle of metabolic dysfunction, potentially increasing the risk of gestational diabetes in subsequent generations. Our findings underscore the need for more research to explore these mechanisms in humans and develop strategies to reduce the long-term effects of maternal obesity.

Maternal high-fat (HF) diet induces adiposity in first-generation (F1) female offspring, impairing metabolic adaptations during pregnancy. F1 offspring from HF diet-fed dams show diminished fat gain and reduced serum triglycerides, disrupting nutrient availability for fetal growth. Impaired insulin production in F1 pregnancy leads to glucose intolerance, driven by reduced insulin secretion despite normal β-cell mass. Unlike male offspring, F1 females exhibit resistance to fat expansion under HF diet challenge, suggesting sex-specific programming. These findings underscore a transgenerational cycle of metabolic dysfunction, highlighting the need for interventions against maternal obesity.