Abstract
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.
Highlights
The Barker hypothesis described that there are critical and sensitive time points during development and different timing of exposure in utero could lead to altered phenotypes that can impact the metabolic health trajectory of the offspring in adulthood [1]
The body weight at postnatal day 1 (P1) in high-fat diet (HFD) offspring was normal compared to Ctrl offspring (p=0.10, Figure 1D)
Pancreatic beta-cell ratio at P1 was significantly decreased in HFD offspring compared to Ctrl (Figure 1J), alpha-cell ratio was comparable between the groups (Figures 1K, L and Supplemental Figure 1A)
Summary
The Barker hypothesis described that there are critical and sensitive time points during development and different timing of exposure in utero could lead to altered phenotypes that can impact the metabolic health trajectory of the offspring in adulthood [1]. Studies demonstrate that different timing of exposure in utero could lead to altered phenotypes in the offspring depending on what cells and tissues are developing at that time of insult. We and others have shown that pancreatic beta-cells are very sensitive to nutrient changes in utero, such that maternal low-protein diet throughout pregnancy reduces beta-cell mass at birth and impairs glucose homeostasis of the adult offspring. Maternal low-protein diet during pregnancy (starting at embryonic day 0.5, LP0.5) reduces beta-cell mass of offspring at birth and impairs insulin secretion in adulthood [3]. Effects of undernutrition during gestation in the Dutch Famine cohort had small-for-gestational age (SGA) weights and had higher prevalence of obesity and glucose intolerance in adulthood [5]
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