Maternal fructose consumption down-regulates Lxra expression via miR-206-mediated regulation

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Abstract

Maternal fructose consumption affects the metabolic functions of offspring later in life. However, the molecular mechanism remains poorly understood. Differences of microRNA expression profile and DNA methylation status are a candidate mechanism to explain the developmental programming that contributes to the development of a metabolic disorder. This study examined the transgenerational effect of maternal fructose consumption from the perspective of epigenetic modification. To do this, we collected serum and liver tissues from male offspring rats that were exposed to maternal distilled water or 20% fructose water during gestation and lactation. A decreased serum high-density lipoprotein cholesterol (HDL-C) level was observed in the offspring of fructose-fed dams at postnatal day (PD) 160. Given research indicating a role of liver X receptor alpha (LXRA) in cholesterol metabolism, we analyzed Lxra expression. Real-time polymerase chain reaction analysis demonstrated that offspring that were delivered from fructose-fed dams exhibited decreased Lxra gene expression in their liver tissue. There is a well-established association between Lxra expression and the level of DNA methylation and miR-206 expression. Pyrosequencing assays revealed no differences in the level of DNA methylation in the Lxra promoter region, whereas miR-206 expression was increased in the liver at PD 60 and 160. Our data indicate that early-life exposure to maternal fructose results in changing of miR-206 expression level in the liver that suppresses the expression of Lxra. This phenomenon may be associated with the decreased serum HDL-C level in offspring.

Introduction

Fructose, a typical monosaccharide, is a natural sugar widely used in food and soft drinks. As it is inexpensive and has a strong sweet taste, consumption of fructose has increased sharply since the 1970s [1]. Recently, excessive fructose consumption has been identified as a major factor contributing to the development of metabolic disorders in developed countries [2,3]. Epidemiologic studies have suggested that excess fructose consumption is implicated in the development of metabolic abnormalities, including obesity, insulin resistance and dyslipidemia [4]. A meta-analysis of nine prospective cohort studies with 308,420 participants conducted in the United States, Japan, Sweden and Singapore found a greater risk of myocardial infarction and stroke with incremental increase in the soft drink consumption [5]. Therefore, the consumption of fructose has become a hot topic of global interest as metabolic diseases factor.

The developmental origins of health and disease (DOHaD) hypothesis states that the early-life environment can significantly impact the health of offspring later in life [6]. This hypothesis is based on epidemiological studies reporting that children born to pregnant women in the Netherlands and China who were suffering from food shortages due to wars and famines had a higher incidence of metabolic disease and mental illnesses during adulthood [6,7]. It is now known that not only undernourishment but also overnutrition during pregnancy can adversely affect children. Rooney and Ozanne have shown that maternal overnutrition predisposes offspring to obesity and type 2 diabetes [8]. This phenomenon has been reproduced in animal experiments. A maternal high-fat diet during gestation in rodents induces obesity and type 2 diabetes in offspring, indicating the importance of the maternal nutritional status for progeny.

Along with overall fructose consumption, the fructose intake of pregnant women appears to have increased in recent decades. Recent report clarified the adverse effect of maternal fructose in human. For example, maternal consumption of sugar-sweetened beverages, which contain relatively high amounts of fructose, is inversely associated with child cognitive ability [9]. Another study also showed that consumption of sugar-sweetened beverages during pregnancy is associated with obesity in children [10]. Collectively, the DOHaD phenomenon appears to be induced by excess maternal fructose consumption in humans. However, the underlying molecular mechanism remains unclear.

Several animal studies have investigated the effect of maternal fructose consumption on the physiology of offspring. We have shown that rats delivered from fructose-fed dams show impaired brain and endocrine system function, suggesting that maternal fructose consumption may affect multiple aspects of rat physiology [[11], [12], [13], [14], [15]]. In accordance with our observations, the Bocos research group has demonstrated the adverse effect of maternal fructose consumption [[16], [17], [18]]. Recently, they demonstrated that this may induce alterations in the high-density lipoprotein cholesterol (HDL-C) level in male offspring [19]. Furthermore, Toop et al. (2015) reported that maternal ingestion of high fructose corn syrup is associated with alterations in the plasma fatty acid level [20]. The overall conclusion from these studies is that maternal fructose consumption appears to affect lipid metabolism in offspring.

It has been demonstrated that maternal nutritional status affects lipid metabolism [19]. It is well known that liver X receptor alpha (LXRΑ) is a key molecule in lipid metabolism. Lxra gene expression appears to be sensitive to maternal nutrition such as maternal fructose consumption, and dysregulated expression of LXRA may affect liver lipid metabolism [19,21]. Recent studies have reported that Lxra gene expression is regulated by microRNA-206 (miR-206) and DNA methylation of its promoter region [[22], [23], [24]]. Therefore, in this study, we examined the molecular mechanism of Lxra expression change induced by maternal fructose consumption.

Our study aimed to clarify the long-term adverse effects of maternal fructose consumption on metabolic conditions in offspring, as well as the molecular mechanisms from the DOHaD perspective. As a measure of metabolic health, we longitudinally analyzed serum lipid parameters in offspring. Moreover, we explored whether offspring exhibit transcriptional abnormalities via the modifications of miR-206 expression level and DNA methylation status of Lxra promoter region.

Section snippets

Animals

This study was approved by the Fujita Health University's Animal Ethics Committee. Eight-week-old Sprague–Dawley (SD) female rats and 9-week-old SD male rats were obtained from Japan SLC (Hamamatsu, Japan) and kept in standard conditions on a 12-h light/dark cycle (lights on at 8:00 a.m.). Food and water were available ad libitum. After 1 week of acclimatization, the male and female rats were mated. The onset of pregnancy was detected by the presence of a vaginal plug. After confirmation of

Body weight and caloric intake

We first investigated the effect of fructose consumption on maternal body weight during gestation and lactation and found that there was no significant difference between the fructose and control groups (Fig. 1A). In addition, there were no significant differences in the total caloric intake among the dams within each group (Fig. 1B). The fructose consumption in fructose-fed dams accounted for approximately 30% of total caloric intake. On PD 21, offspring weights were not significantly

Discussion

In this study, we investigated the association between metabolic disorders caused by maternal fructose consumption and modifications of miRNA expression and DNA methylation status from the DOHaD perspective. Our findings indicate that maternal fructose consumption induced up-regulation of hepatic miR-206 expression. A higher expression level of miR-206 was maintained at PD 160. In addition, a decreased level of serum HDL-C was observed in conjunction with this increase in miR-206 expression.

Declaration of competing interest

All authors declare no conflicts of interest relevant to this article.

Acknowledgments

This work was supported by Japan Society for the Promotion of Science KAKENHI grant nos. 18K05493, 18K17987 and 17K07805.

Contribution statement

Y.M., E.M. and H.Y. participated in research design; Y.A., Y.N., I.K., A.T., G.M., R.F., Y.S., H.I., K.S. and S.H. carried out the experiments; and Y.M., H.Y. and K.O. wrote and reviewed the manuscript.

References (43)

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Funding: This work was supported by Japan Society for the Promotion of Science KAKENHI grant nos. 18K05493, 18K17987 and 17K07805.

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