Transient fetal hyperglycemia reprograms adipogenesis, lipogenesis, and insulin signaling in zebrafish.

Gestational diabetes mellitus (GDM) exposes the fetus to chronic hyperglycemia and increases the risk of later metabolic disease. The mechanisms by which early hyperglycemia reprograms lipid and glucose metabolism remain unclear, largely due to maternal and placental confounders in mammalian models. To overcome these limitations, we developed a zebrafish model that isolates fetal hyperglycemia and enables direct investigation of its developmental and long-term metabolic effects. To mimic late-onset GDM, zebrafish embryos were exposed at 4 days post-fertilization to glucose concentrations comparable to those reported in umbilical cord blood from poorly controlled diabetic pregnancies. Developmental, metabolic, and molecular outcomes were assessed across the life course, including lipid accumulation, adipocyte differentiation, and expression of genes regulating lipogenesis and insulin signaling. To determine the role of acetyl-CoA carboxylase (ACC), embryos were exposed to hyperglycemia in the presence of an ACC inhibitor. Transient embryonic hyperglycemia induced persistent activation of de novo lipogenesis, increased adipocyte formation, and sustained upregulation of lipid storage pathways. These effects persisted into adulthood and were accompanied by hepatic lipid accumulation and insulin resistance. Hyperglycemic exposure reprogrammed key metabolic regulators (acaca, fasn, insr) and reduced phosphorylated AKT, indicating a stable shift toward lipogenic and insulin-desensitized states. Inhibition of ACC during glucose exposure prevented these long-term metabolic alterations. Transient fetal hyperglycemia, independent of maternal or placental influences, durably reprograms lipid metabolism and insulin responsiveness, providing direct evidence that early hyperglycemic exposure promotes lifelong susceptibility to metabolic disease.