Offspring from maternal nutrient restriction in mice show variations in adult glucose metabolism similar to human fetal growth restriction

Abstract

Fetal growth restriction (FGR) is a pregnancy condition in which fetal growth is suboptimal for gestation, and this population is at increased risk for type 2 diabetes as adults. In humans, maternal malnutrition and placental insufficiency are the most common causes of FGR, and both result in fetal undernutrition. We hypothesized that maternal nutrient restriction (MNR) in mice will cause FGR and alter glucose metabolism in adult offspring. Pregnant CD-1 mice were subjected to MNR (70% of average ad libitum) or control (ad libitum) from E6.5 to birth. Following birth, mice were fostered by mothers on ad libitum feeds. Weight, blood glucose, glucose tolerance and tissue-specific insulin sensitivity were assessed in male offspring. MNR resulted in reduced fetal sizes but caught up to controls by 3 days postnatal age. As adults, glucose intolerance was detected in 19% of male MNR offspring. At 6 months, liver size was reduced (P = 0.01), but pAkt-to-Akt ratios in response to insulin were increased 2.5-fold relative to controls (P = 0.004). These data suggest that MNR causes FGR and long-term glucose intolerance in a population of male offspring similar to human populations. This mouse model can be used to investigate the impacts of FGR on tissues of importance in glucose metabolism.

Metabolic and fecal microbial changes in adult fetal growth restricted mice

“…We also report impaired glucose handling in FGR HFD males compared to control HFD males, without differences in females. Prior work, including in a model similar to ours, 43 also showed impaired glucose handling in FGR males at 6 to 9 months of age, 12 , 43 though there was no consideration of sex as a biologic variable. Sex differences in response to HFD are well documented in mice, generally demonstrating relative protection in females.…”

“…Studying animals until 6–9 months of age may clarify the true extent of FGR’s longstanding effects. 12 , 43 While the tests we performed give broad information about glucose handling, future studies with insulin tolerance testing and/or metabolic clamp studies 11 , 46 may further characterize the effects of FGR on glycemic control and elucidate underlying mechanisms. Our use of 16 S sequencing did not allow for identification of specific species nor functional changes of bacteria.…”

Dysregulation of miRNA–mRNA expression in fetal growth restriction in a caloric restricted mouse model

“…We chose maternal malnutrition as it is both a significant risk factor for FGR and, arguably, it is more physiological than other models described. This model results in reduced fetal weight and has metabolic sequelae to include glucose intolerance, impaired cognitive function and chronic diseases such as hypertension and coronary artery disease in response to reduced calories compared to mice that receive adequate nutrition 14 , 56 , 57 . Nevertheless, studies to include additional modeling strategies such as maternal hypoxia would strengthen the validity of our results.…”

Gestational Early-Time Restricted Feeding Results in Sex-Specific Glucose Intolerance in Adult Male Mice

“…Undernutrition [ 49 – 51 ], overnutrition [ 52 , 53 ], placental insufficiency [ 54 , 55 ], and chronodisruption [ 15 , 16 , 42 , 56 ] during pregnancy have all been reported to induce offspring glucose intolerance. The extent to which male-predominate phenotypes and female resilience to changes are difficult to deduce as many groups either study male offspring exclusively [ 51 , 57 ] or analyze males and females together [ 50 , 58 ].…”