Maternal High‐Fat Diet, During Preimplantation or Gestation/Lactation, Alters Mouse Offspring Metabolic, Molecular and Locomotor Phenotypes

Maternal nutrition during offspring development influences the offspring physiology and risk of long‐term chronic disease. Here, we investigate the effects of maternal high‐fat diet during distinct developmental windows (preimplantation alone, EmbHFD; or throughout gestation and lactation, HFD) on adult offspring metabolic, molecular and motor behavioural outcome. Our mouse model, utilising healthy nonobese MF1 mothers, induced distinct offspring outcomes dependent upon dietary duration with some sex‐specific effects. EmbHFD offspring had high serum leptin (females), elevated systolic blood pressure (SBP), low locomotory activity and diminished motor coordination. Similarly, HFD offspring not only had raised serum leptin, high SBP and poor motor coordination but also experienced excess weight gain, deficits in energy metabolism, reduced relative brown adipose tissue (BAT) mass (females) and increased muscle lipid accumulation. Transcriptomic profiling of HFD female offspring revealed upregulation of thermogenic and lipid‐handling genes (e.g., Ucp1 and ApoE ) in BAT alongside downregulation of mitotic regulators, suggesting impaired regenerative capacity. Collectively, these findings demonstrate, first, the risk to offspring of even transient maternal fatty diet without maternal obesity. Second, they highlight the sensitivity of periconceptional nutrition on the emergence of offspring multisystem metabolism and physiology, supporting the Developmental Origins of Health and Disease (DOHaD) concept.