Key points Maternal obesity predisposes to metabolic dysfunction in male and female offspring Maternal high‐fat diet consumption prior to and throughout pregnancy and lactation accelerates offspring metabolic ageing in a sex‐dependent manner This study provides evidence for programming‐ageing interactions Abstract Human epidemiological studies show that maternal obesity (MO) shortens offspring life and health span. Life course cellular mechanisms involved in this developmental programming‐ageing interaction are poorly understood. In a well‐established rat MO model, female Wistar rats ate chow (controls (C)) or high energy, obesogenic diet to induce MO from weaning through pregnancy and lactation. Females were bred at postnatal day (PND) 120. Offspring (F1) of mothers on control diet (CF1) and MO diet (MOF1) delivered spontaneously at terms. Both CF1 and MOF1 ate C diet from weaning throughout the study. Offspring were killed at PND 36, 110, 450 and 650. We determined body and liver weights, liver and serum metabolite concentrations, hormones and oxidative stress biomarkers. Male and female CF1 body weight, total fat, adiposity index, serum leptin, insulin, insulin resistance, and liver weight, fat, triglycerides, malondialdehyde, reactive oxygen species and nitrotyrosine all rose with differing ageing trajectories. Female CF1 triglycerides were unchanged with age. Age‐related increases were greater in MOF1 than CF1 in both sexes for all variables except glucose in males and females and cholesterol in males. Cholesterol fell in CF1 females but not MOF1. Serum corticosterone levels were higher in male and female MOF1 than CF1 and declined with age. DHEA serum levels were lower in male and female MOF1 than CF1. Liver antioxidant enzymes decreased with age (CF1 and MOF1). Conclusions: exposure to the developmental challenge of MO accelerates progeny ageing metabolic and endocrine profiles in a sex specific manner, providing evidence for programming‐ageing interactions.

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Maternal nutritional challenges during fetal and neonatal development result in developmental programming of multiple offspring organ systems including brain maturation and function. A maternal low-protein diet during pregnancy and lactation impairs associative learning and motivation. We evaluated effects of a maternal low-protein diet during gestation and/or lactation on male offspring spatial learning and hippocampal neural structure. Control mothers (C) ate 20% casein and restricted mothers (R) 10% casein, providing four groups: CC, RR, CR, and RC (first letter pregnancy, second lactation diet). We evaluated the behavior of young adult male offspring around postnatal day 110. Corticosterone and ACTH were measured. Males were tested for 2 days in the Morris water maze (MWM). Stratum lucidum mossy fiber (MF) area, total and spine type in basal dendrites of stratum oriens in the hippocampal CA3 field were measured. Corticosterone and ACTH were higher in RR vs. CC. In the MWM acquisition test CC offspring required two, RC three, and CR seven sessions to learn the maze. RR did not learn in eight trials. In a retention test 24 h later, RR, CR, and RC spent more time locating the platform and performed fewer target zone entries than CC. RR and RC offspring spent less time in the target zone than CC. MF area, total, and thin spines were lower in RR, CR, and RC than CC. Mushroom spines were lower in RR and RC than CC. Stubby spines were higher in RR, CR, and RC than CC. We conclude that maternal lowprotein diet impairs spatial acquisition and memory retention in male offspring, and that alterations in hippocampal presynaptic (MF), postsynaptic (spines) elements and higher glucocorticoid levels are potential mechanisms to explain these learning and memory deficits.

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