Increased placental nutrient transport in a novel mouse model of maternal obesity with fetal overgrowth

Abstract

Objective: To identify possible mechanisms linking obesity in pregnancy to increased fetal adiposity and growth, a unique mouse model of maternal obesity associated with fetal overgrowth was developed, and the hypothesis that maternal obesity causes up-regulation of placental nutrient transporter expression and activity was tested.

Methods: C57BL/6J female mice were fed a control (C) or a high-fat/high-sugar (HF/HS) pelleted diet supplemented by ad libitum access to sucrose (20%) solution, mated, and studied at embryonic day 18.5.

Results: HF/HS diet increased maternal fat mass by 2.2-fold (P < 0.01) and resulted in glucose intolerance with normal fasting glucose. Maternal circulating insulin, leptin, and cholesterol were increased (P < 0.05) whereas total and high-molecular-weight adiponectin was decreased (P < 0.05). HF/HS diet increased fetal weight (+18%, P = 0.0005). In trophoblast plasma membranes (TPM) isolated from placentas of HF/HS-fed animals, protein expression of glucose transporter (GLUT) 1 and 3, sodium-coupled neutral amino acid transporter (SNAT) 2, and large neutral amino acid transporter 1 (LAT1) was increased. TPM System A and L amino acid transporter activity was increased in the HF/HS group.

Conclusions: Up-regulation of specific placental nutrient transporter isoforms may constitute a mechanism underlying fetal overgrowth in maternal obesity.

© 2015 The Obesity Society.

Figures

Figure 1

Body composition of mice fed a control or high fat/high sugar diet (HF/HS). When females on the HF/HS diet had increased 25% in body weight dual-energy X-ray absorptiometry (DEXA, A) and whole body quantitative magnetic resonance imaging (qMRI, B) was performed (n=5/group). Values are given as means + SEM; *P

Figure 2

Daily calorie (A) and food intake (B) in pregnant mice fed control (n=15) or HF/HS (n=15) diet. Data was collected by weighing the remaining pelleted food at the end of each of the following gestational periods: E 0.5 to 6.5, E 7.5 to 13.5 and E 14.5 to 17.5. In addition, the amount of consumed sugar was determined every day at the time of refreshing the sucrose water. This information was used to calculate the average daily food and calorie intake for the entire gestation period. Values are given as means + SEM; *P

Figure 3

Maternal glucose tolerance test (A) at E18.5 after a 4-hour fast in mice fed a control or HF/HS diet. An i.p. injection of 2 g/kg of a 30% glucose solution was given, and blood glucose was determined in samples obtained from the tail vein 0-90 min after glucose administration. Histogram (B) summarize the area under curve of GTT. Values are means ± SEM; n= 4 (Control) and 5 (HF/HS). *P

Figure 4

Fetal (A) and placental (B) weights determined at E18.5 in mice fed a control and HF/HS diet. Values are means + SEM, n= 12 in each group, *P

Figure 5

TPM nutrient transporter isoform expression (A-F) and activity (G-H). A and B). Protein expression of System A amino acid transporter isoforms in TPM. Representative Western blots for (A) SNAT2 and 4 in TPM isolated from control and HF/HS diet fed animals at E 18.5. Histogram (B) summarizes the Western blotting data from control (C, n = 6) and HF/HS (n = 6). Equal loading was performed. After normalization to β-actin, the mean density of C samples was assigned an arbitrary value of 1. Values are given as means + SEM; *P G and H). TPM system A and L activity. System A transport activity (G) was determined as sodium dependent [14C]-MeAIB uptake, and System L transport (H) was measured as [3H]-L-leucine uptake in isolated TPM vescicles. MeAIB, 2-Methylaminoisobutyric acid; Leu, Leucine. Values are given as means + SEM; n=6/group; *P < 0.05 vs. control; unpaired Student's t-test.