Downregulation of peroxisome proliferator-activated receptor gamma in the placenta correlates to hyperglycemia in offspring at young adulthood after exposure to gestational diabetes mellitus

Abstract

Aims/introduction: Children who are exposed to gestational diabetes mellitus (GDM) in utero are at high risk of developing related illnesses, such as type 2 diabetes mellitus in young adulthood, but the underlying mechanism and related predictive biomarkers are not known.

Materials and methods: The present study identified the related biomarkers of hyperglycemia in young adults from the relationship between fetal blood glucose and placental lipid transporters at messenger ribonucleic acid (mRNA) and protein expression levels. We recruited patients from a prospective cohort, and determined the mRNA and protein levels of placental fatty acid transporters. Diet-induced mouse models of GDM were established, and the mRNA and protein levels of the same transporters in placentas were validated.

Results: Only the mRNA levels of peroxisome proliferator-activated receptor gamma correlated with the levels of neonatal blood glucose in GDM patients using linear regression and Spearman's correlation analyses (r = 0.774, P = 0.001). The mRNA levels of peroxisome proliferator-activated receptor gamma, matrix metalloproteinase-2 and fatty acid transport protein-6 correlated with blood glucose levels in mouse offspring (r = 0.82, P = 0.001, r = 0.737, P = 0.006 and r = -0.891, P = 0.001, respectively) at young adulthood using the same analyses. Notably, we observed significantly higher blood glucose levels in GDM offspring at 12 weeks-of-age compared with the control and rosiglitazone-supplemented groups (P < 0.05).

Conclusions: The downregulation of peroxisome proliferator-activated receptor gamma in the placenta might predict hyperglycemia in offspring at young adulthood.

Keywords: Gestational diabetes mellitus; Hyperglycemia; Peroxisome proliferator-activated receptor gamma.

Figure 1

The messenger ribonucleic acid (mRNA) and protein expression of human placental fatty acid transport regulators. (a) The mRNA expression levels were detected using real‐time polymerase chain reaction. (b) The protein expression levels were detected using western blot analysis, and representative images from three independent experiments are shown **P < 0.01; *P < 0.05. FABPpm, plasma membrane fatty acid binding protein; FAT, fatty acid translocase; FATP, fatty acid transport protein; GDM, gestational diabetes mellitus; MMP, metalloproteinase; PPARγ, peroxisome proliferator‐activated receptor‐γ.

Figure 2

The messenger ribonucleic acid (mRNA) and protein expression of placental fatty acid transport regulators in the animal model. (a) The mRNA expression levels were detected using real‐time polymerase chain reaction. (b) The protein expression levels were detected using Western blot analysis, and representative images from three independent experiments are shown. **P < 0.01; *P < 0.05. FABPpm, plasma membrane fatty acid binding protein; FAT, fatty acid translocase; FATP, fatty acid transport protein; GDM, gestational diabetes mellitus; MMP, metalloproteinase; PPARγ, peroxisome proliferator‐activated receptor‐γ; RSG, rosiglitazone.

Figure 3

(a) Maternal bodyweights of C57BL/6 mice in different groups. Bodyweights were measured during pregnancy (gestation day [GD]0, GD10, GD12, GD14, GD16 and GD18). The diet‐induced gestational diabetes mellitus (GDM) dam weight increased significantly compared with the controls at different time‐points. Maternal bodyweights increased slightly, but significantly, in the GDM + rosiglitazone (RSG) group compared with the controls at different time‐points. (b) Maternal blood glucose levels of C57BL/6 mice in different groups. Blood glucose concentrations were measured during pregnancy (GD0, GD10, GD12, GD14, GD16 and GD18). The GDM group showed significantly higher blood glucose levels compared with the control dams. Blood glucose levels decreased obviously after RSG intervention to a level that was not significantly different compared with the control dams after GD12. The (c) fetal bodyweight, (d) crown‐rump length, the (e) placental weight and (f) placental diameter of C57BL/6 mice in different groups. The fetal bodyweight, crown‐rump length and placental weight in the GDM and GDM + RSG group decreased significantly compared with the controls, but the placental diameter was not different. (g) Blood glucose levels of C57BL/6 mice at young adulthood in different groups (n = 12 per group). Values are presented as the mean ± standard error of the mean. ***P < 0.001; **P < 0.01; *P < 0.05.

Figure 4

Relationship between newborn plasma glucose levels and the messenger ribonucleic acid expression levels of placental fatty acid transporters and their related regulators. Linear regression and Spearman's correlation analyses were used to evaluate the relationship. Only the messenger ribonucleic acid of peroxisome proliferator‐activated receptor‐γ (PPARγ) in gestational diabetes mellitus (GDM) patients correlated to the levels of neonatal blood glucose (r = 0.774, P = 0.001). FABPpm, plasma membrane fatty acid binding protein; FAT, fatty acid translocase; FATP, fatty acid transport protein; MMP, metalloproteinase.

Figure 5

Relationship between mouse offspring plasma glucose levels and the messenger ribonucleic acid expression levels of placental fatty acid transporters and their related regulators at young adulthood (n = 12 per group). Linear regression and Spearman's correlation analyses were used to evaluate the relationship. The messenger ribonucleic acid levels of peroxisome proliferator‐activated receptor‐γ (PPARγ), metalloproteinase (MMP)2 and fatty acid transport protein (FATP)‐6 correlated to the levels of mouse offspring blood glucose (r = 0.82, P = 0.001, r = 0.737, P = 0.006 and r = −0.89, P = 0.001, respectively). FABPpm, plasma membrane fatty acid binding protein; FAT, fatty acid translocase; RSG, rosiglitazone.