Folic Acid Prevents High-Fat Diet-Induced Postpartum Weight Retention in Rats, Which Is Associated with a Reduction in Endoplasmic Reticulum Stress-Mediated Hepatic Lipogenesis

Abstract

Background: Proactively preventing postpartum weight retention (PPWR) is one of the effective intervention strategies to reduce the occurrence of obesity in women. Population studies have shown that serum folate levels are closely related to body weight. The regulation of folic acid on lipid metabolism has been fully confirmed in both in vivo and in vitro studies. For many years, folic acid supplementation has been widely used in periconceptional women due to its role in preventing fetal neural tube defects. However, whether folic acid supplementation prior to and throughout pregnancy exerts preventive effects on PPWR remains uncertain. This study aims to investigate the preventive effect of folic acid on PPWR in rats and further explore the underlying mechanisms.

Methods: In this study, pregnant rats were administered one of the dietary schedules: control diet (CON), high-fat diet (HF), control diet combined with folic acid (FA) and high-fat diet combined with folic acid (HF + FA).

Results: We discovered that folic acid supplementation inhibited high-fat diet-induced elevations in body weight, visceral fat weight, liver weight, hepatic lipid levels and serum lipid levels at 1 week post-weaning (PW). Western blot analysis showed that folic acid supplementation inhibited the expression of endoplasmic reticulum (ER) stress-specific proteins including GRP78, PERK, eIF2α, IRE1α, XBP1 and ATF6, subsequently decreasing the expression of proteins related to lipid synthesis including SREBP-1c, ACC1 and FAS.

Conclusions: In conclusion, folic acid supplementation prior to and throughout pregnancy exerts preventive effects on high-fat diet-induced PPWR in rats, and the mechanism is associated with the inhibition of ER stress-mediated lipogenesis signaling pathways in the liver. Folic acid supplementation may serve as a potential strategy for preventing PPWR. In the future, the effectiveness of folic acid in PPWR prevention can be further verified by population studies.

Keywords: endoplasmic reticulum stress; folic acid; postpartum weight retention.

Figure 1

Folic acid supplementation altered the body weights of dams and the birth weights of pups. (A) Body weights of dams. (B) Gestational weight gain. (C) Numbers of pups. (D) Birth weights of pups. (E) Lactational weight loss. (F) Weight loss from weaning to 1 week post-weaning. (G) Body weight changes throughout the experiment. (H) Rates of body weight changes throughout the experiment. Values are presented as the mean ± SD (n = 10). ^a p < 0.05 indicates significant differences in comparison to the CON group. ^b p < 0.05 indicates significant differences in comparison to the HF group. ^c p < 0.05 indicates significant differences in comparison to the FA group.

Figure 2

Changes in water intake, food intake and energy intake. (A) Water intake. (B) Food intake. (C) Energy intake. Values are presented as the mean ± SD (n = 10). ^a p < 0.05 indicates significant differences in comparison to the CON group. ^b p < 0.05 indicates significant differences in comparison to the HF group. ^c p < 0.05 indicates significant differences in comparison to the FA group.

Figure 3

Folic acid supplementation ameliorated serum biochemical profiles in dams. (A) Serum TGs. (B) Serum Hcy. Values are presented as the mean ± SD (n = 10). ^a p < 0.05 indicates significant differences in comparison to the CON group. ^b p < 0.05 indicates significant differences in comparison to the HF group. ^c p < 0.05 indicates significant differences in comparison to the FA group.

Figure 4

Folic acid supplementation reduced fat weight and the fat index in dams. (A) Perirenal fat weight. (B) Perirenal fat index. (C) Mesenteric fat weight. (D) Mesenteric fat index. (E) Periovarian fat weight. (F) Periovarian fat index. (G) Total visceral fat weight. (H) Total visceral fat index. (I) Adipocyte size. (J) Pathological changes in periovarian fat. H&E staining of perirenal fat was photographed at 400× magnification. Scale bar = 100 μm. Adipocyte size was measured by using ImageJ software (version 1.8.0). Values are presented as the mean ± SD (n = 10). ^a p < 0.05 indicates significant differences in comparison to the CON group. ^b p < 0.05 indicates significant differences in comparison to the HF group. ^c p < 0.05 indicates significant differences in comparison to the FA group.

Figure 5

Folic acid supplementation reduced liver weight and the liver index and ameliorated hepatic lipids profiles in dams. (A) Liver weight. (B) Liver index. (C) Hepatic TGs. (D) Pathological changes in the liver. H&E staining of the liver tissue was photographed at 200 × magnification. Scale bar = 100 μm. Values are presented as the mean ± SD (n = 10). ^a p < 0.05 indicates significant differences in comparison to the CON group. ^b p < 0.05 indicates significant differences in comparison to the HF group. ^c p < 0.05 indicates significant differences in comparison to the FA group.

Figure 6

Folic acid supplementation alleviated hepatic oxidative stress in dams. (A) Hepatic MDA. (B) Hepatic GSH-Px. (C) Hepatic SOD. (D) Hepatic CAT. Values are presented as the mean ± SD (n = 10). ^a p < 0.05 indicates significant differences in comparison to the CON group. ^b p < 0.05 indicates significant differences in comparison to the HF group. ^c p < 0.05 indicates significant differences in comparison to the FA group.

Figure 7

Folic acid supplementation alleviated hepatic ER stress and reduced lipid synthesis in dams. (A,B) Protein expression levels related to ER stress. (C) Protein expression levels related to lipid synthesis. Values are presented as the mean ± SD (n = 3). ^a p < 0.05 indicates significant differences in comparison to the CON group. ^b p < 0.05 indicates significant differences in comparison to the HF group. ^c p < 0.05 indicates significant differences in comparison to the FA group.

Figure 8

Potential mechanism underlying the preventative effect of folic acid on PPWR.