Metabolic switch from glycogen to lipid in the liver maintains glucose homeostasis in neonatal mice

Neonates strive to acquire energy when the continuous transplacental nutrient supply ceases at birth, whereas milk consumption takes hours to start. Using murine models, we report the metabolic switches in the first days of life, with an unexpected discovery of glucose as the universal fuel essential for neonatal life. Blood glucose quickly drops as soon as birth, but immediately rebounds even before suckling and maintains stable afterward. Meanwhile, neonatal liver undergoes drastic metabolic changes, from extensive glycogenolysis before suckling to dramatically induced fatty acid oxidation (FAO) and gluconeogenesis after milk suckling. Unexpectedly, blocking hepatic glycogenolysis only caused a transient hypoglycemia before milk suckling without causing lethality. Limiting lipid supply in milk (low-fat milk, [LFM]) using Cidea-/- mice, however, led to a chronic and severe hypoglycemia and consequently claimed neonatal lives. While fat replenishment rescued LFM-caused neonatal lethality, the rescue effects were abolished by blocking FAO or gluconeogenesis, pointing to a funneling of lipids and downstream metabolites into glucose as the essential fuel. Finally, glucose administration also rescued LFM-caused neonatal lethality, independent on FAO or gluconeogenesis. Therefore, our results show that the liver works as an energy conversion center to maintain blood glucose homeostasis in neonates, providing theoretical basis for managing infant hypoglycemia.