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Mounting evidence supports an instructive role for metabolism in stem cell fate decisions. However, much is yet unknown about how fetal metabolism changes during mammalian development and how altered maternal metabolism shapes fetal metabolism. Here, we present a descriptive atlas of in vivo fetal murine metabolism during mid-to-late gestation in normal and diabetic pregnancy. Using 13C-glucose and LC-MS, we profiled the metabolism of fetal brains, hearts, livers, and placentas harvested from pregnant dams between embryonic days (E)10.5 and 18.5. Comparative analysis of our large metabolomics dataset revealed metabolic features specific to fetal tissues developed under a hyperglycemic environment as well as metabolic signatures that may denote developmental transitions during euglycemic development. We observed sorbitol accumulation in fetal tissues and altered neurotransmitter levels in fetal brains isolated from dams with maternal hyperglycemia. Tracing 13C-glucose revealed disparate nutrient sourcing in fetuses depending on maternal glycemic states. Regardless of glycemic state, histidine-derived metabolites accumulated during late development in fetal tissues and maternal plasma. Our rich dataset presents a comprehensive overview of in vivo fetal tissue metabolism and alterations occurring as a result of maternal hyperglycemia.

Glycolysis is a universal metabolic process that breaks down glucose to produce cellular energy currency ATP and biomass precursors1. The Entner-Doudoroff pathway is a glycolytic pathway that parallels the textbook glycolysis but yields half as many ATP2. In organisms that possess both glycolytic pathways, such as Escherichia coli, inactivating the less energy-efficient Entner-Doudoroff pathway does not alter growth rates3. The benefit of the Entner-Doudoroff pathway has instead been hypothesized to be metabolic flexibility as an auxiliary enzyme-efficient catabolic route4. However, its raison d'être remains incompletely understood. Here we identify the advantage of employing parallel glycolytic pathways under dynamic nutrient environments. Upon carbon and nitrogen upshifts, wild-type cells accelerate growth faster than those with the Entner-Doudoroff pathway knocked out. Using stable isotope tracers and mass spectrometry, we find that the Entner-Doudoroff pathway flux increases disproportionately faster than that of the textbook glycolysis during nutrient upshifts. We attribute the fast response time of the Entner-Doudoroff pathway to its strong thermodynamic driving force and concerted regulation facilitating glucose uptake. Intermittent supply of nutrients manifests this evolutionary advantage of the parallel glycolysis. Thus, the dynamic nature of an ostensibly redundant pathway's role in promoting rapid adaptation constitutes a metabolic design principle.