Attenuated Effects of Bile Acids on Glucose Metabolism and Insulin Sensitivity in a Male Mouse Model of Prenatal Undernutrition

Abstract

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 (BAs) in offspring mice. Because 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 to 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 four experimental groups: C, UN, C + UDCA, and UN + UDCA. Glucose homeostasis, BA composition, liver and intestinal gene expression, and microbiota composition were analyzed in the four groups. Although UDCA supplementation ameliorated diet-induced obesity in C mice, 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. BA composition differed significantly, and liver and ileal expression of genes involved in BA 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 BA supplementation, with resistance to the weight-lowering and insulin-sensitizing effects of UDCA supplementation. Our findings suggest that BA metabolism may be a previously unrecognized contributor to developmentally programmed diabetes risk.

Targeting the alternative bile acid synthetic pathway for metabolic diseases

“…In this study, FXR acted as a transcription factor for BA synthetic enzymes and transporter proteins, thereby maintaining homeostasis through BA synthesis, influx, and efflux (Mueller et al, 2015 ). Consistent with our observations, Ma et al ( 2017 ) reported that UDCA supplementation increased CYP7B1 mRNA levels and improved fasting glucose levels and hepatic steatosis in a diet-induced NAFLD model mouse. Our study showed that UDCA administration in mice enhanced CYP7B1 expression but reduced CYP8B1 expression, leading to an elevated non-12-OH/12-OH BA ratio and a decrease in diet-induced obesity.…”

The role of CD36-Fabp4-PPARγ in skeletal muscle involves insulin resistance in intrauterine growth retardation mice with catch-up growth

“…Barker et al [ 15 ] firstly proposed the “thrifty phenotype” hypothesis, stating that the fetal under-nutrition can compel the body to store fat (after improvement of the nutritional environment) rather than muscle. This adaptive adjustment in the fetus is more likely to lead to obesity, IR, and type 2 diabetes [ 7 ]. Our study found that in the LBW mice with a high-fat diet, glucose regulation was more seriously disrupted in adulthood and IR was more evident, which were consistent with the findings of previous studies [ 6 , 16 ].…”

“…Ye et al observed that catch-up growth in early childhood and disorders involving in glucose and lipid metabolism in adulthood were accompanied by impaired IGFBP3/IGF-1/IRS-1/Akt signaling pathway in the liver [ 6 ]. In the early stage of our study, we found that deoxycholic acid and cholic acid levels in the blood of LBW mice were significantly lower than those of normal birth weight mice, suggesting that cholic acid metabolism might play a role in adult type 2 diabetes mellitus caused by LBW [ 7 ]. However, the mechanisms inducing IR and the development of diabetes in LBW individuals remain unclear.…”

Exploring the Multi-Tissue Crosstalk Relevant to Insulin Resistance Through Network-Based Analysis

“…Previous studies have shown strong causative relation between restricted intrauterine growth and adult metabolic reprograming in rodents ( 17 , 18 ). To reduce the potential impact of uneven intrauterine nutrition accompanied by different litter size, we used a previously developed ICR mouse model ( 19 ). Adult (6- to 8-week-old) male and female ICR mice were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. and caged.…”