DataSheet_1_Maternal High-Fat Diet During Pre-Conception and Gestation Predisposes Adult Female Offspring to Metabolic Dysfunction in Mice.pdf

The risk of obesity in adulthood is subject to programming in the womb. Maternal obesity contributes to programming of obesity and metabolic disease risk in the adult offspring. With the increasing prevalence of obesity in women of reproductive age there is a need to understand the ramifications of maternal high-fat diet (HFD) during pregnancy on offspring’s metabolic heath trajectory. In the present study, we determined the long-term metabolic outcomes on adult male and female offspring of dams fed with HFD during pregnancy. C57BL/6J dams were fed either Ctrl or 60% Kcal HFD for 4 weeks before and throughout pregnancy, and we tested glucose homeostasis in the adult offspring. Both Ctrl and HFD-dams displayed increased weight during pregnancy, but HFD-dams gained more weight than Ctrl-dams. Litter size and offspring birthweight were not different between HFD-dams or Ctrl-dams. A significant reduction in random blood glucose was evident in newborns from HFD-dams compared to Ctrl-dams. Islet morphology and alpha-cell fraction were normal but a reduction in beta-cell fraction was observed in newborns from HFD-dams compared to Ctrl-dams. During adulthood, male offspring of HFD-dams displayed comparable glucose tolerance under normal chow. Male offspring re-challenged with HFD displayed glucose intolerance transiently. Adult female offspring of HFD-dams demonstrated normal glucose tolerance but displayed increased insulin resistance relative to controls under normal chow diet. Moreover, adult female offspring of HFD-dams displayed increased insulin secretion in response to high-glucose treatment, but beta-cell mass were comparable between groups. Together, these data show that maternal HFD at pre-conception and during gestation predisposes the female offspring to insulin resistance in adulthood.</p

Critical Role for Macrophages in the Developmental Programming of Pancreatic β-cell Area in Offspring of Gestational Hypertension

Preeclampsia is a pregnancy-specific complication with long-term negative outcomes for offspring including increased susceptibility to type 2 diabetes (T2D) in adulthood. In rat Reduced Uteroplacental Perfusion Pressure (RUPP) model of chronic placental ischemia, maternal hypertension in conjunction with intrauterine growth restriction mimics aspects of preeclampsia and resulted in female embryonic day (e)19 offspring with reduced β-cell area and increased β-cell apoptosis compared to offspring of Sham pregnancies. Decreased pancreatic β-cell area persists to Postnatal Day (PD)13 in females and could influence whether T2D develops in adulthood. Macrophage changes also occur in islets in T2D. Therefore, we hypothesized that macrophages are crucial to reduction in pancreatic β-cell area in female offspring following chronic placental ischemia. The macrophage marker CD68 mRNA expression was significantly elevated in e19 and PD13 islets isolated from female RUPP offspring compared to Sham. Postnatal injections of clodronate liposomes into female RUPP and Sham offspring on PD2 and PD9 significantly depleted macrophages compared to animals injected with control liposomes. Depletion of macrophages rescued reduced β-cell area and increased β-cell proliferation and size in RUPP offspring. Our studies suggest that the presence of macrophages is important for reduced β-cell area in female RUPP offspring and changes in macrophages could contribute to development of T2D in adulthood.</p