Omega-3 fatty acids prevent gestational diabetes mellitus via modulating lipid metabolism

doi:10.21203/rs.3.rs-3796352/v1

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Omega-3 fatty acids prevent gestational diabetes mellitus via modulating lipid metabolism

https://doi.org/10.21203/rs.3.rs-3796352/v1

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Background

The incidence rate of gestational diabetes mellitus (GDM) is still high among pregnant women in the second trimester of pregnancy. This study explored the therapeutic effects of omega-3 fatty acids (ω-3 FAs) on GDM at the cellular and animal levels.

Methods

THP1 cells were stimulated with phorbol 12-myristate 13-acetate (PMA) to induce M0 macrophage. The transformation of M0 macrophages into M2 macrophages was observed after ω-3 FAs treatment. Then, macrophages induced by ω-3 FAs were co-cultured with hepatocytes HepG2, and the glycolipid metabolism in hepatocytes was assessed. By establishing a GDM mouse model, the impact of ω-3 FAs on liver function in GDM pregnant mice and offspring was evaluated.

Results

At the cellular level, we found that ω-3 FAs can promote the transformation of M0 macrophages into anti-inflammatory M2 macrophages, and the transformed M2 macrophages can prevent excessive accumulation of lipid droplet in hepatocyte cell line HepG2, by promoting β-oxidation and reducing lipid synthesis of hepatocyte, thereby protecting hepatic function. Supplementation of ω-3 FAs in pregnant GDM mice significantly reduced fasting blood glucose levels, GTT and ITT indexes, and lipid accumulation in the liver, and effectively prevented liver fibrosis. ω-3 FAs also had positive effects on the offspring of GDM pregnant mice, demonstrated by reducing birth mortality and improving glycemic stabilization.

Conclusion

This study suggests that ω-3 FAs prevent GDM via modulating lipid metabolism and may provide a strategy for translational medicine that can treat GDM and offspring.

Gestational diabetes mellitus

omega-3 fatty acids

Lipid Metabolism

glucose metabolism

anti-inflammation

Gestational diabetes mellitus (GDM) is a disease of high incidence during pregnancy, which seriously affects the life safety and health of pregnant women and may affect the fetus. Prevalence of GDM is as high as 2–25% globally, and this wide range of incidence may be due to inconsistent evaluation criteria around the world[1–6]. GDM mainly occurs in the second or third trimester. Pregnant women with GDM exhibit glucose intolerance and insulin deficiency, vitamin D deficiency, deficiency of omega-3 fatty acids, and etc[7–11]. The insulin produced by the pancreas of pregnant women with GDM is not enough to resist the insulin inhibition effect caused by hormones produced by the placenta, such as oestrogen, human placental lactogen and cortisol. This condition persists from the time when a woman is first diagnosed with GDM until she gives birth[12–15]. Many factors are associated with GDM, such as obesity, non-white ethnicity, increased maternal age, family history of diabetes and history of giving birth to large infants. GDM even has long-term effects on pregnant women after childbirth, with the incidence of developing type 2 diabetes as high as 50% after 5 years of pregnancy and even 70% after 22–28 years of pregnancy[16–20]. In addition, pregnant women with GDM consistently provide a high-glycemic environment to the fetus, which may increase the probability of neonatal obesity, metabolic syndrome, and other cardiometabolic disorders in the offspring[17–20]. Finding the suitable treatment strategy for GDM is critical.

Omega-3 fatty acids (ω-3 FAs) are essential for human health, and their deficiency can cause several chronic diseases[21]. ω-3 FAs, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and other family members, have been reported to has anti-inflammatory effects and can produce therapeutic effects on inflammatory diseases, such as diabetes, atherosclerosis, asthma, and arthritis. ω-3 FAs can inhibit the inflammatory effects of macrophages by binding to its receptor/sensor G protein-coupled receptor 120 (GPR120). Inflammation is the main factor that causes insulin resistance in diabetic patients. Feeding ω-3 FAs to diabetic mice can effectively inhibit inflammation and enhance systemic insulin sensitivity [22]. In addition, GPR120 is also highly expressed in hepatocytes, and supplementation mice with ω-3 FAs improved the accumulation of lipid in the live caused by a high-fat diet. In another study, the authors found that ω-3 FAs/GPR120 inhibited inflammation through the downstream scaffold protein β-arrestin-2 [23]. Then the anti-inflammatory effect of ω-3 FAs is finally demonstrated on the inhibition of the production of pro-inflammatory factor IL-1β[22].

Because pregnant women with GDM are often accompanied by ω-3 FAs deficiency in the blood, and ω-3 FAs has a role in regulating glucose and lipid metabolism, this study speculated that ω-3 FAs may alleviate the symptoms of GDM in pregnant women. We observed the therapeutic effect of ω-3 FAs through in vitro cell experiments and in vivo GDM mouse experiments. The results shown that ω-3 FAs could effectively inhibit the transformation of M0 macrophages into M1 pro-inflammatory phenotype, and further promote the lipid metabolism capacity of hepatocytes. Feeding ω-3 FAs to GDM mice can effectively alleviate the symptoms of glucose intolerance and insulin deficiency in mice, and reduce systemic inflammation and liver lipid accumulation in pregnant mice. In addition, ω-3 FAs supplementation also had a protective effect on offspring, reducing offspring body weight and stabilizing offspring blood sugar levels. These results suggest that ω-3 FAs have a protective effect on GDM pregnant mice and their progeny, which provides an alternative for clinical application.

THP1 cell culture

The macrophage cell line THP1 was maintained at 2 ~ 3*10⁵ cells/ml in RPMI 1640 medium supplemented with 10% FBS and 2 mmol/L L-glutamine. M0 phenotype macrophage was induced by addition of 200 nM phorbol 12-myristate 13-acetate (PMA, Sigma-Aldrich) in maintain medium for 3d. PMA treated cells was further stimulated to differentiation with 10 ng/ml ultra-pure LPS (Alexis Corporation) and without PMA for 8 h. After the induction, 20 µM DHA was added into the culture for another 20 h. Then the mRNA or supernatant were collected for further experiment. For coculture system, the macrophage was moved to HepG2 culture well at the ω-3 FAs addition step.

HepG2 cell culture

HepG2 cells were seeded and cultured in media consisting of EMEM (ATCC 30-2003) supplemented with 10% FBS (Gibco) and 1% Penn/Strep (Gibco) until specific treatments were applied. PA (Sigma-Aldrich) and OA (Sigma-Aldrich) were resolved in ethanol to a final concentration of 0.5 M respectively and then sonicated (200 W, 4 s on bursts, and 6 s interval) on ice, and then the emulsion was stocked. Before use, the emulsion stock solutions were dissolved in DMEM complete media at 60°C to concentration of 0.5 mM. After cooling to 37°C, the media was used to induce HepG2 cells to accumulate fatty acids.

GDM model establishment

C57BL/6J mice (8 weeks old) were fed at 25℃ with 12 hours light and 12 hours dark cycles. Female mice were supplied with high-fat diet (HFD; 60%kcal) for 4 weeks before mating and then maintained the HFD until they delivery. 2 female mice were mated with one male mouse overnight to cross. The presence of vaginal plugs was treated as the start time of pregnancy and is defined as gestational day 0. Form gestational day 1 to 4, 30 mg/kg streptozotocin (STZ, resolved in citrate buffer) was injected intraperitoneally each day. Normal pregnant mice fed with normal chow diet all the process were used as control (Ctrl group). The control group mice were injected with same volume of citrate buffer. 3 days later after last time STZ induction, random blood glucose was tested from the tail by glucometer (Roche, USA). Then mice with GDM were randomly divided into two groups: the GDM group and the GDM with ω-3 FAs treatment (ωGDM) group. The ωGDM group was given DHA 50 mg and EPA 100 mg each day by the oral administration. The GDM and Ctrl groups were administered intragastrically with the same volume of filled physiological saline. On gestational day 18, part of mice was sacrificed to collect the blood and liver. Other mice were maintained to give birth naturally to estimate the outcomes in offspring. All the animal experiments conformed to guidelines for the Care and Use of Animals published by Institutional Animal Ethical Committee.

GTT and ITT

Mice were firstly fasted for 16 hours, followed by intraperitoneal injection of 1.5 g/kg body weight of glucose dissolved in saline for the glucose tolerance test (GTT). Then the tail vein blood glucose levels were tested at 0, 15, 30, 60, 90, and 120 min after injection with a glucometer. Mice were firstly fasted for 6 hours, followed by intraperitoneal injection of 0.5 U/kg body weight of insulin for the insulin tolerance test (ITT). Then the tail vein blood glucose levels were tested at 0, 15, 30, 60, 90, and 120 min after injection with a glucometer.

Insulin, adiponectin, and inflammatory factor levels measurement

After fasting for 16 hours, 100–200 µL tail vein blood was collected at gestational day 18. The insulin, adiponectin, TNF-α, MCP-1, IL-1β and IL-8 levels of blood were tested by ELISA kits (CUSABIO, China) according to the manufacturer's guidance.

Statistical analysis

All data are presented as the mean ± standard error of the mean (SEM). The differences between two groups were analyzed using a two tailed Student’s t-test. The difference among groups 3 or more groups were analyzed using one-way ANOVAs for multiple comparisons. The data analysis was performed using GraphPad Prism. P-values < 0.05 were considered statistically significant.

ω-3 FAs promote the transformation of M0 macrophage into anti-inflammatory M2 phenotype.

Published data demonstrate that inflammation plays an important role in abnormal glucose and lipid metabolism. Among all immune cells, macrophages can effectively regulate lipid metabolism, and ω-3 FAs can influence the transformation of macrophages. Therefore, we first verified the effects of ω-3 FAs on macrophages at the cellular level. We used THP1 cells as model cells. After the induction of THP1 cells into M0 type, the medium containing LPS and IFN was used for short-term induction, and then the medium containing ω-3 FAs was replaced to further induce cell transformation. The experimental results showed that ω-3 FAs could effectively reduce the transformation of M0 cells into pro-inflammatory M1 macrophages (down-regulated expression of M1 macrophage markers IL-β1, TNF-α, MCP1, iNOS and IL-6 genes, Fig. 1A-E), and promote the transformation of M0 macrophages into anti-inflammatory M2 macrophages (M2 macrophage markers CD206, Arginase1, IL-10, MGL1 and CCL18 gene expression is up-regulated. Figure 1F-J). These results indicate that ω-3 FAs can effectively inhibit inflammation.

Macrophages induced by ω-3 FAs promote lipid metabolism in hepatocytes

Then, macrophages induced by ω-3 FAs were co-cultured with hepatocytes HepG2 (Fig. 2A) to observe the effects of inflammation on glycolipid metabolism in hepatocytes. We treated HepG2 with OA and PA to simulate the metabolic status of the liver in women with GDM. The experimental results showed that OA and PA could make a large amount of lipid droplets accumulate in HepG2 cells, but after co-culture with macrophages induced by ω-3 FAs, lipid droplets accumulation were effectively alleviated (Fig. 2B, C). The proliferative capacity of HepG2 is also affected by ω-3 FAs, demonstrating promoted cell proliferation (Fig. 2D). We then assessed the lipid metabolism capacity of cells at RNA levels and found that the expressions of lipid synthesis-related genes (ACLY, ACC1, GPAM, FASN) of HepG2 were down-regulated after co-culture with macrophages induced by ω-3 FAs (Fig. 2E-H). The expression of β-oxidation-related genes (ACC2, UCP3, Cs, CPT1) was up-regulated (Fig. 2I-L), which was consistent with the results of cell staining. Excessive accumulation of lipid can affect the function of hepatocyts, and if appropriate intervention is not available it may develop into cirrhosis or even liver cancer. Therefore, RNA levels of HGF and VEGF, which characterize the hepatic function, were detected, and it was found that both the expression levels were significantly increased (Fig. 2M, N), indicating that ω-3 FAs could protect the function of hepatocytes.

ω-3 FAs relieves GDM symptoms

After a series of in vitro cell experiments to confirm the function of ω-3 FAs, GDM pregnant mice were supplemented with ω-3 FAs. After 1 week of treatment, although blood glucose concentration showed a downward trend, it was not statistically significant (Fig. 3A). After 2 weeks of treatment, the blood glucose level was significantly downregulated (Fig. 3B), indicating that continuous ω-3 FAs treatment could effectively relieve the blood glucose level of pregnant mice with GDM. GTT and ITT tests were performed on pregnant mice after 2 weeks of treatment, and it was found that blood glucose levels after treatment with ω-3 FAs were lower than those of pregnant mice with GDM (Fig. 3C, D). Insulin is a direct factor in the regulation of blood glucose. Therefore, we detected the insulin in the blood of pregnant mice and found that ω-3 FAs could increase the serum insulin level, indicating that ω-3 FAs may regulate blood glucose level by regulating insulin (Fig. 3E). Glucose and lipid metabolism have dynamic balance and mutual influence, and adiponectin is an indirect indicator of blood lipid content. Therefore, we also detected adiponectin in blood, and the result was similar to that of insulin. ω-3 FAs can increase the levels of adiponectin in blood (Fig. 3F), indicating that ω-3 FAs also affect lipid metabolism in GDM pregnant mice.

Effects of ω-3 FAs on liver function in GDM pregnant mice

ω-3 FAs regulate the metabolism of glucose and lipids by regulating the immune response. Therefore, we tested the serum levels of inflammatory factors in GDM pregnant mice after 2 weeks of treatment with ω-3 FAs. The results showed that TNF-α, MCP-1, IL-8 and IL-1β with proinflammatory effects were significantly decreased compared with GDM pregnant mice, indicating that ω-3 FAs treatment reduced the systematic inflammatory response of GDM pregnant mice (Fig. 4A-D). After 2 weeks of treatment, the livers of pregnant mice were collected for further examination. HE staining showed that the treatment of ω-3 FAs could effectively alleviate liver damage (Fig. 4E). Then we made oil red staining on the liver sections, and found that the treatment of ω-3 FAs significantly reduced the accumulation of lipid droplets in the liver (Figure. 4F, G). Moreover, we conducted quantitative analysis on the triglycerides (TAG) and cholesterol (CHO) in the liver, and found that both of them significantly decreased (Figure. 4I, J). These results suggest that supplementation of ω-3 FAs can regulate liver lipid metabolism. If the fatty liver is not effectively controlled, it will further develop into liver fibrosis. Therefore, Sirus red staining was performed on the liver, and it was found that there was no large amount of collagen deposition in the livers of each group at the protein level (Figure. 4H). Compared with the GDM group, all the RNA levels of Collagen 1a1, ATAC2, TNF-β and PDGF in the ω-3 FAs treatment group showed significant decreas (Figure. 4K-N), indicating that the treatment of ω-3 FAs may effectively inhibit the occurrence of liver fibrosis.

Effects of supplementation of ω-3 FAs on offspring

Pregnant mice with GDM may influence on their offspring. We monitored the offspring in each group and found that there was no statistical difference in the number of newborns (Fig. 5A), but it effectively reduced neonatal mortality (Fig. 5B). One of the adverse consequences of GDM is the birth of giant fetuses. Therefore, we calculated the weight of newborn mice and found that ω-3 FAs treatment could reduce the giant newborn mice caused by GDM (Fig. 5C). In order to explore whether the treatment of ω-3 FAs can have lasting effects on offspring, we carried out 8-week weight measurements, and found that the weight of the offspring of pregnant mice treated with ω-3 FAs was lower than that of the offspring of GDM pregnant mice within 5 weeks after birth. However, from the 6th week, the weight of the offspring tended to be the same among the groups (Fig. 5D), indicating that the influence of GDM on the offspring could persist for a period of time, but not for a lifetime. We then tested the blood glucose level of the offspring before and after weaning. It was found that the blood glucose level of the offspring of pregnant mice with GDM was higher than that of the offspring treated with ω-3 FAs, but the blood glucose level was the lowest after weaning (Figure. 5E, F), indicating that breast milk would have an impact on the maintenance of blood glucose in the offspring. We then tested the GTT and ITT of the 3-week-old offspring and found that the glucose metabolism level of the pregnant offspring treated with ω-3 FAs was more similar to that of the pregnant offspring of the control group (Figure. 5G, H). These results indicate that ω-3 FAs treatment can not only relieve the symptoms of GDM in pregnant mice, but also protect on offspring.

The incidence of GDM in pregnant women is very high and serious complications may occur. If not properly treated, the disease can have serious consequences for both mother and fetus. Existing data show that the occurrence of GDM is related to a variety of factors, such as vitamin D deficiency, ω-3 FAs deficiency, etc. However, there are few reports on whether supplementation of ω-3 FAs can effectively relieve GDM symptoms in pregnant mice and reduce the adverse effects of hyperglycemic environment on the fetus. The effects of supplementation of ω-3 FAs on mothers and offspring of GDM were systematically investigated at the cellular and animal levels. We found that macrophages treated with ω-3 FAs could effectively promote the transformation of M0 macrophages into anti-inflammatory M2 macrophages. When the transformed M2 macrophages were co-cultured with hepatocyte cell line HepG2. Lipid droplet accumulation in HepG2 could be reduced. This effect is achieved by increasing β-oxidation and decreasing lipid synthesis of HepG2 cells. In addition, M2-type macrophages induced by ω-3 FAs also promoted the gene expression levels of HGF and VEGF, which represent liver function, suggesting that ω-3 FAs can reduce liver lipid accumulation and protect liver function by regulating immune response.

Then we tested the therapeutic effects of ω-3 FAs in GDM pregnant mice and their offspring We found that ω-3 FAs treatment could relieve the symptoms of GDM and reduce the blood glucose level in pregnant mice under starvation condition. Meanwhile, GTT and ITT also showed a decreased trend, and the blood insulin and adiponectin contents increased. These results suggest that ω-3 FAs have the ability to stabilize blood glucose levels through the regulation of insulin. Glucose metabolism in the body is directly related to lipid metabolism, and the increase of adiponectin content indicates that lipid metabolism is active. Therefore, we examined the lipid accumulation and lipid metabolism in the liver and found that the treatment of ω-3 FAs could effectively reduce the lipid accumulation in the liver of GDM pregnant mice and inhibit the occurrence of liver fibrosis. This protective effect may be achieved by reducing systemic inflammation in the body. We also observed the offspring of GDM pregnant mice treated with ω-3 FAs for 8 weeks, and found that the treatment of ω-3 FAs could reduce the birth mortality of the offspring of GDM pregnant mice and reduce the weight of newborn mice. The effects of GDM on the offspring persisted during lactation, but began to disappear at the 6th week after birth, indicating that the high glucose environment may affect the blood glucose homeostasis of the offspring, but after the removal of the harmful environment, the offspring have the ability to spontaneously recover.

In this study, we systematically analyzed the therapeutic effects of ω-3 FAs on glucose and lipid metabolism of GDM pregnant mice and their offspring, and briefly explored the mechanism, providing an alternative for translational medicine. It also provides some theoretical support for the clinical application of ω-3 FAs in the treatment of GDM. This study also has some shortcomings. The exploration of mechanism mainly focused on the detection of RNA level, without the confirmation of protein level. The target of ω-3 FAs has not yet been explored. Although the effects of ω-3 FAs on macrophages have been verified in vitro, the individual cell type level has not been explored in vivo. We will continue to improve these aspects in future studies. In conclusion, this study provides a data base for suggesting that ω-3 FAs can alleviate the symptoms of GDM.

Declaration of Competing Interest

The authors declare no financial interests and competing interests.

Author Contributions

Z.X, guided the design of the project and edited the manuscript, performed most of the experiment, wrote and edited the manuscript. L.F, performed part of the experiment and generated figures. Y.B, and Z.W, performed staining experiments.

Acknowledgement

We thank the support of the Animal Platform.

Ethics statement

The animal experiments were approved by the Animal Ethics Committee of Shijiazhuang Obstetrics and Gynecology Hospital.

Data Availability Statement

The data in this study are available from the corresponding author upon request.

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No competing interests reported.

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Version 1

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You are reading this latest preprint version

Omega-3 fatty acids prevent gestational diabetes mellitus via modulating lipid metabolism

Status:

Version 1

Abstract

Background

Methods

Results

Conclusion

Figures

Introduction

Methods

THP1 cell culture

HepG2 cell culture

GDM model establishment

GTT and ITT

Insulin, adiponectin, and inflammatory factor levels measurement

Statistical analysis

Results

Macrophages induced by ω-3 FAs promote lipid metabolism in hepatocytes

ω-3 FAs relieves GDM symptoms

Effects of ω-3 FAs on liver function in GDM pregnant mice

Effects of supplementation of ω-3 FAs on offspring

Discussion

Declarations

References

Additional Declarations

Status:

Version 1