Maternal fructose intake predisposes rat offspring to metabolic disorders via abnormal hepatic programming

Abstract

Given that fructose consumption has increased by more than 10‐fold in recent decades, it is possible that excess maternal fructose consumption causes harmful effects in the next generation. This study attempted to elucidate the mechanism of the harmful effects of excessive maternal fructose intake from the perspective of offspring liver function. Female rats during gestation and lactation were fed water containing fructose, and their offspring were fed normal water. We attempted to elucidate the mechanism of fructose‐induced transgenerational toxicity by conducting a longitudinal study focusing on hepatic programming prior to disease onset. Impaired Insulin resistance and decreased high‐density lipoprotein‐cholesterol levels were observed at 160 days of age. However, metabolic disorders were not observed in 60‐day‐old offspring. Microarray analysis of 60‐day‐old offspring livers showed the reduction of hepatic insulin‐like growth factor‐1 (Igf1) mRNA expression. This reduction continued until the rats were aged 160 days and attenuated Igf1 signaling. Hepatic microRNA‐29 (miR‐29a) and miR‐130a, which target Igf1 mRNA, were also found to be upregulated. Interestingly, these miRNAs were upregulated in the absence of metabolic disorder. In this study, we found that maternal fructose intake resulted in dysregulated expression of Igf1 and its target miRNAs in the offspring liver, and that these offspring were more likely to develop metabolic disorders. Abnormal hepatic programming induced by an imbalanced maternal nutritional environment is maintained throughout life, implying that it may contribute to metabolic disorders.

Effects of High-Fructose Corn Syrup Intake on Glucocorticoid Metabolism in Rats During Childhood, Adolescence and Adulthood

“…1.00 ± 0.09 1.20 ± 0.12* 1.00 ± 0.14 may be because of differences in the concentration of fructose administration and length of the intake period. According to our previous studies, exposure to fructose during early life stages such as fetal and lactation induces changes in miRNA expression and DNA methylation level in the liver [23,40]. These epigenetic modifications may be maintained at least until adulthood, altering mRNA expression of genes related to lipid metabolism.…”

Non-coding RNAs: The link between maternal malnutrition and offspring metabolism

“…Consistent with a previous study, Munetsuna et al found that maternal fructose intake resulted in an increase in miR-29a in the livers of the offspring at 160 days of age, which decreased Igf1 mRNA expression. Moreover, reduced IGF1 expression may induce IR and impair hepatic function ( 125 ). However, no impaired IR or decreased high-density lipoprotein cholesterol (HDL-C) levels were observed at 60 days of age, even with the increase in miR-29a ( 125 ).…”

“…Moreover, reduced IGF1 expression may induce IR and impair hepatic function ( 125 ). However, no impaired IR or decreased high-density lipoprotein cholesterol (HDL-C) levels were observed at 60 days of age, even with the increase in miR-29a ( 125 ). Therefore, it is possible to use the expression of miRNAs to predict the metabolic state later in life.…”

“…miR-130a/b can inhibit de novo lipogenesis, but enhance lipolysis ( 126 ) and regulate insulin sensitivity ( 127 ), thus being involved in metabolic diseases such as liver steatosis and T2D. Munetsuna et al ( 125 ) found that miR-130a was increased in the liver of offspring exposed to maternal fructose consumption at 60 days of age and persisted until 160 days of age, resulting in a decrease in its target Igf1 and thus affecting glucolipid metabolism. Conversely, Forness et al ( 79 ) found that miR-130 was decreased at Day 21 of gestation in the liver of male fetuses of GDM mothers while PPARγ levels were increased ( Figure 1 ).…”

Maternal High-Fructose Corn Syrup Intake Impairs Corticosterone Clearance by Reducing Renal 11β-Hsd2 Activity via miR-27a-Mediated Mechanism in Rat Offspring

“…The most common types of epigenetic modifications are DNA methylation and the effects of microRNAs (miRNAs), which can either activate or repress gene expression [19]. We previously reported that excess maternal fructose causes epigenetic abnormalities in offspring [20,21], which may explain the increase in circulating GC levels.…”