Attenuated effects of bile acids on glucose metabolism and insulin sensitivity in a male mouse model of prenatal undernutrition

Prenatal undernutrition and low birth weight are associated with risk of type 2 diabetes and obesity. Prenatal caloric restriction results in low birth weight, glucose intolerance, obesity, and reduced plasma bile acids (BA) in offspring mice. Since BAs can regulate systemic metabolism and glucose homeostasis, we hypothesized that BA supplementation could prevent diet-induced obesity and glucose intolerance in this model of developmental programming. Pregnant dams were food restricted by 50% from gestational days 12.5-18.5. Offspring of both undernourished (UN) and control (C) dams given unrestricted diets were weaned to high fat diets with- or without supplementation with 0.25% w/w ursodeoxycholic acid (UDCA), yielding 4 experimental groups: C, UN, C+UDCA, and UN+UDCA. Glucose homeostasis, bile acid composition, liver and intestinal gene expression, and microbiota composition were analyzed in the 4 groups. While UDCA supplementation ameliorated diet-induced obesity in controls (C), there was no effect in UN mice. UDCA similarly lowered fasting insulin, and improved glucose tolerance, pyruvate tolerance, and liver steatosis in C, but not UN animals. Bile acid composition differed significantly, and liver and ileal expression of genes involved in bile acid metabolism (Cyp7b1, Shp) were differentially induced by UDCA in C vs. UN animals. Bacterial taxa in fecal microbiota correlated with treatment groups and metabolic parameters. In conclusion, prenatal undernutrition alters responsiveness to the metabolic benefits of bile acid supplementation, with “resistance” to the weight-lowering and insulin sensitizing effects of UDCA supplementation. Our findings suggest that bile acid metabolism may be a previously unrecognized contributor to developmentally-programmed diabetes risk.