Introduction and Objective: Late-stage pregnancy induces a physiological shift toward accelerated starvation, characterized by attenuated glucose use, enhanced fatty acid oxidation, and elevated circulating ketones. Ketones cross the placenta and remain key substrates postnatally, with the neonatal brain consuming ~50% of hepatic output to sustain lipid biosynthesis and energy demands. The consequences of supraphysiological ketone exposure during these windows remain poorly defined, despite growing adoption of ketosis-inducing interventions.Methods: Wild-type breeder dams received the DL-β-hydroxybutyrate precursor 1,3-butanediol (BD) during gestation, lactation, or both.Results: BD did not alter maternal weight, glycemia, or fatty acid levels, but elevated ketonemia to 2.4±0.69 mM in late-gestation dams versus 0.6±0.07 mM in controls. Enantiomeric profiling revealed selective accumulation of non-physiological L-β-hydroxybutyrate over gestation. Offspring were longitudinally assessed for somatic growth, glucose homeostasis, and brain lipid composition. Lactation-only exposure produced a transient growth deficit at postnatal day 21 (P21) with full recovery by P91, reflecting developmental plasticity. Male offspring exposed during lactation or both windows exhibited improved glucose tolerance. Brain lipidomics revealed increases in polyunsaturated fatty acid abundance across paradigms and sexes, driven by enrichment of very-long-chain PUFA within the lysophosphatidylcholine and lysophosphatidylethanolamine lipid classes, which are central to membrane remodeling and neurodevelopmentConclusion: These findings establish exogenous ketone exposure as a timing-dependent developmental metabolic signal, producing transient somatic changes alongside persistent alterations in glucose regulation and brain lipid architecture, and provide a preclinical framework for evaluating the safety and therapeutic potential of ketone supplementation during pregnancy and lactation.
A. Hayir: None. R. Ankeriasniemi: None. K. Fulghum: None. P. Crawford: None. P. Puchalska: None.
Medical School (AP-0924-03MIDB) seed grant, NIH grant (DK091538), NIH grant (AG069781)
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