Ketone bodies in the developing brain: Sex-specific metabolic pathways during the neonatal period

The developing central nervous system (CNS) relies on tightly regulated metabolic substrates, including glucose, lactate, and ketone bodies (KBs), to energy demands, brain maturation and neural circuit formation. Disruptions in substrate flow availability during early life can lead to long-lasting brain functional and structural impairments. Among these substrates, KBs serve as a critical alternative fuel during the neonatal period, sustaining cerebral energy demands under conditions of limited glucose availability and metabolic stress. Mounting evidence highlights pronounced sex-specific differences in brain development and vulnerability to injury, with males showing increased susceptibility to neurodevelopmental disorders, whereas females exhibit greater metabolic flexibility during hypoglycemia and oxidative stress. Despite this, most neuroscience and metabolic research remains male-focused, limiting our understanding of female-specific cerebral metabolic adaptations. This review examines KB metabolism across major neural cell types (astrocytes, neurons, oligodendrocytes and microglia) during neurodevelopment, with a particular focus on sex-specific differences in substrate utilization, metabolic signaling and cellular resilience. Understanding these distinctions is critical, as even subtle energetic impairments during early brain development may contribute to neurological disorders with sex-biased prevalence. Addressing this gap may ultimately facilitate the development of more precise, sex-specific therapeutic strategies for neurodevelopmental disorders.