Abstract-Maternal obesity is increasingly prevalent and may affect the long-term health of the child. We investigated the effects of maternal diet-induced obesity in mice on offspring metabolic and cardiovascular function. Female C57BL/6J mice were fed either a standard chow (3% fat, 7% sugar) or a palatable obesogenic diet (16% fat, 33% sugar) for 6 weeks before mating and throughout pregnancy and lactation. Offspring of control (OC) and obese dams (OO) were weaned onto standard chow and studied at 3 and 6 months of age. OO were hyperphagic from 4 to 6 weeks of age compared with OC and at 3 months locomotor activity was reduced and adiposity increased (abdominal fat pad mass; PϽ0.01). OO were heavier than OC at 6 months (body weight, PϽ0.05). OO abdominal obesity was associated with adipocyte hypertrophy and altered mRNA expression of ␤-adrenoceptor 2 and 3, 11␤HSD-1, and PPAR-␥ 2. OO showed resistance artery endothelial dysfunction at 3 months, and were hypertensive, as assessed by radiotelemetry (nighttime systolic blood pressure at 6 months [ Key Words: obesity Ⅲ pregnancy Ⅲ developmental programming Ⅲ metabolic syndrome Ⅲ appetite Ⅲ blood pressure Ⅲ mouse O besity among women of reproductive age is presenting a critical challenge to health care. 29% of USA women aged 20 to 39 years are reported to be clinically obese 1 and there is serious concern in many European countries over the increasing obesity among young women. 2 While obesity is associated with increased risk of almost every common complication of pregnancy, obesity in the mother may play a direct role in transmission of an obesogenic and diabetogenic trait from generation to generation. Increasing evidence suggests that children born of pregnancies complicated by either obesity or related gestational diabetes mellitus (GDM) are at increased risk of obesity, impaired glucose tolerance, and other facets of the metabolic syndrome. 3 Animal models have proven invaluable in interrogation of associations between maternal diet and body composition and offspring phenotype. 4 Those studies which have addressed effects of maternal calorific excess, including several from our laboratory, have generally fed rats diets rich in animal fat. 4 -7 Because young women of reproductive age often consume excessive amounts of sugars as well as fats, 8 the relevance of a diet rich in fat alone is limited. In this study, we induced obesity by feeding mice a highly palatable diet rich in sugars and animal fat, and addressed the hypothesis that diet-induced obesity during pregnancy can transmit a propensity for adiposity, glucose intolerance, and cardiovascular dysfunction to the offspring. Obesity was induced in female mice and offspring cardiovascular and metabolic function

Hypothalamic systems which regulate appetite may be permanently modified during early development. We have previously reported hyperphagia and increased adiposity in the adult offspring of rodents fed an obesogenic diet prior to and throughout pregnancy and lactation. We now report that offspring of obese (OffOb) rats display an amplified and prolonged neonatal leptin surge, which is accompanied by elevated leptin mRNA expression in their abdominal white adipose tissue. At postnatal Day 30, before the onset of hyperphagia in these animals, serum leptin is normal, but leptin-induced appetite suppression and phosphorylation of STAT3 in the arcuate nucleus (ARC) are attenuated; the level of AgRP-immunoreactivity in the hypothalamic paraventricular nucleus (PVH), which derives from neurones in the ARC and is developmentally dependent on leptin, is also diminished. We hypothesise that prolonged release of abnormally high levels of leptin by neonatal OffOb rats leads to leptin resistance and permanently affects hypothalamic functions involving the ARC and PVH. Such effects may underlie the developmental programming of hyperphagia and obesity in these rats.

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During pregnancy, infection or immune responses induce cytokine release, which might influence fetal neurodevelopment, leading to neurodegenerative disease in adulthood. Because the hippocampus is a key area for learning and memory, we evaluated 4- and 24-wk-old rats for the effects of early and late prenatal exposure to interleukin-6 (IL-6) on hippocampal morphology, expression of mRNA for IL-6, the gamma-aminobutyric acid receptor (GABA(Aalpha5)), the NR1 subunit of the N-methyl-D-aspartate receptor, and glial fibrillary acidic protein (GFAP), caspase-3 protein and mRNA levels, and learning abilities. Late exposure increased serum IL-6 and hippocampal expression of IL-6 mRNA at 4 and 24 wk. All adult rats showed neuronal loss in the hilus and astrogliosis; males had losses mainly in the CA2 and CA3 regions, and females in CA1. Expression of GABA(Aalpha5), NR1, and GFAP mRNA increased in late-exposed males and females at 4 and 24 wk. mRNA and protein levels of the apoptosis marker caspase-3 were increased in all late-exposed rats except males at 4 wk. Evaluation of hippocampus-dependent working memory in the Morris water maze at 20 wk of age showed increases in escape latency and time spent near the pool wall in all IL-6 adult rats, especially females. These findings suggest that fetal IL-6 exposure, especially in late pregnancy, leads to increased IL-6 levels in the circulation and hippocampus, abnormalities of hippocampal structural and morphology, and decreased learning during adulthood.

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