Preconception Prebiotic and Sitagliptin Treatment in Obese Rats Affects Pregnancy Outcomes and Offspring Microbiota, Adiposity, and Glycemia

Abstract

Maternal obesity is associated with increased risk of pregnancy complications and greater risk of obesity in offspring, but studies designed to examine preconception weight loss are limited. The objective of this study was to determine if a combined dietary [oligofructose (OFS)] and pharmacological (sitagliptin) preconception intervention could mitigate poor pregnancy outcomes associated with maternal obesity and improve offspring metabolic health and gut microbiota composition. Diet-induced obese female Sprague-Dawley rats were randomized to one of four intervention groups for 8 weeks: (1) Obese-Control (consumed control diet during intervention); (2) Obese-OFS (10% OFS diet); (3) Obese-S (sitagliptin drug); (4) Obese-OFS + S (combination treatment). Two reference groups were also included: (5) Obese-HFS (untreated obese consumed high fat/sucrose diet throughout study); (6) Lean-Control (lean reference group that were never obese and consumed control diet throughout). Offspring consumed control diet until 11 weeks of age followed by HFS diet until 17 weeks of age. The Obese-OFS + S rats lost weight during the intervention phase whereas the OFS and S treatments attenuated weight gain compared with Obese-HFS (p < 0.05). Gestational weight gain was lowest in Obese-OFS + S rats and highest in Obese-HFS rats (p < 0.05). Prepregnancy intervention did not affect reproductive parameters but did affect pregnancy outcomes including litter size. Male Obese-OFS offspring had significantly lower percent body fat than Obese-HFS at 17 weeks. Female Obese-S and Obese-OFS offspring had significantly lower fasting glucose at 17 weeks compared with Obese-Control and Obese-HFS. Clostridium cluster XI was higher in Obese-HFS and Obese-S dams at birth compared with all other groups. Dams with an adverse pregnancy outcome had significantly lower (p = 0.035) Lactobacillus spp. compared with dams with normal or small litters. At weaning, male offspring of Obese-HFS had higher levels of Methanobrevibacter than all other groups except Obese-S and female Obese-HFS offspring had higher Enterobacteriaceae compared with all other groups. At 11 and 17 weeks of age, Bacteroides/Prevotella spp. was significantly lower in male and female offspring of Obese-HFS dams compared with all other groups except Obese-OFS + S. Modest weight loss induced with a diet-drug combination did not affect maternal fecundity but did have sex-specific effects on offspring adiposity and glycemia that may be linked to changes in offspring microbiota.

Figure 7: Effect of maternal sitagliptin on intestinal IL-6 and TNF-α expression in male offspring.

“…HFD increased energy intake and body weight gain during pregnancy, whereas sitagliptin intervention significantly reduced energy intake and body weight gain during pregnancy. A previous study also provided evidence that preconception sitagliptin treatment reduced body weight gain during pregnancy in a HFD-induced obese rodent model (Dennison, Eslinger & Reimer, 2017). In addition, we found that sitagliptin intervention improved maternal glucose homeostasis.…”

“…We found that maternal sitagliptin intervention attenuated glucose metabolism and insulin resistance in male offspring at weaning. However, intervening before pregnancy with sitagliptin did not have a significant effect on glucose metabolism (Dennison, Eslinger & Reimer, 2017). These different results may be due to differences in sitagliptin treatment time and duration.…”

“…Recently, Professor Reimer et al administered sitagliptin to high-fat diet (HFD)-induced obese rats before pregnancy. Their results showed that this intervention strategy did not have lasting effects on fasting blood glucose in offspring (Dennison, Eslinger & Reimer, 2017). Another group reported that sitagliptin attenuates severe acute pancreatitis-associated intestinal inflammation in vivo and in vitro (Zhou et al, 2019).…”

Maternal Inulin Supplementation Alters Hepatic DNA Methylation Profile and Improves Glucose Metabolism in Offspring Mice

“…treatment moderated glucose intolerance and insulin resistance caused by maternal HF diet exposure. Several studies had drew the similar conclusion about the benefit of inulin (Hallam and Reimer, 2014;Dennison et al, 2017). However, recent one study found that C57BL/6J mice fed a HF diet could be susceptible to liver cancer upon consumption of inulin (Singh et al, 2018).…”

“…Unlike the postnatal period, few studies have focused on the effect of inulin treatment in utero on infants. Maternal oligofructose treatment in obese female rats during gestation and lactation reduced offspring blood glucose in 17-week-old rats through the gut microbiota (Dennison et al, 2017). Metabolite production by the gut microbiome may affect epigenetic changes.…”