Early Life Exposure to Fructose Alters Maternal, Fetal and Neonatal Hepatic Gene Expression and Leads to Sex-Dependent Changes in Lipid Metabolism in Rat Offspring

Abstract

AimFructose consumption is associated with altered hepatic function and metabolic compromise and not surprisingly has become a focus for perinatal studies. We have previously shown that maternal fructose intake results in sex specific changes in fetal, placental and neonatal outcomes. In this follow-up study we investigated effects on maternal, fetal and neonatal hepatic fatty acid metabolism and immune modulation.MethodsPregnant rats were randomised to either control (CON) or high-fructose (FR) diets. Fructose was given in solution and comprised 20% of total caloric intake. Blood and liver samples were collected at embryonic day 21 (E21) and postnatal day (P)10. Maternal liver samples were also collected at E21 and P10. Liver triglyceride and glycogen content was measured with standard assays. Hepatic gene expression was measured with qPCR.ResultsMaternal fructose intake during pregnancy resulted in maternal hepatic ER stress, hepatocellular injury and increased levels of genes that favour lipogenesis. These changes were associated with a reduction in the NLRP3 inflammasome. Fetuses of mothers fed a high fructose diet displayed increased hepatic fructose transporter and reduced fructokinase mRNA levels and by 10 days of postnatal age, also have hepatic ER stress, and elevated IL1β mRNA levels. At P10, FR neonates demonstrated increased hepatic triglyceride content and particularly in males, associated changes in the expression of genes regulating beta oxidation and the NLRP3 inflammasome. Further, prenatal fructose results in sex-dependant changes in levels of key clock genes.ConclusionsMaternal fructose intake results in age and sex-specific alterations in maternal fetal and neonatal free fatty acid metabolism, which may be associated in disruptions in core clock gene machinery. How these changes are associated with hepatic inflammatory processes is still unclear, although suppression of the hepatic inflammasome, as least in mothers and male neonates may point to impaired immune sensing.

Rice Bran Oil Improves Insulin Resistance by Affecting the Expression of Antioxidants and Lipid‐Regulatory Genes

“…In the present study, HFD induced hepatic de novo lipogenesis through upregulating the expression level of lipid‐regulatory genes, Srebf1 and Ppara , in the HFD1 and HFD2 groups. The present data agree with the results of Clayton et al () who reported that fructose‐fed mother rats at postnatal day 10 demonstrated an increase in PPAR‐α. In contrast, Nagai et al () concluded that fructose or its metabolites downregulate the expression of Ppara in primary cultured hepatocytes.…”

“…Thus, induction of hepatic triacylglycerol synthesis observed in this study is mediated by SREBP that binds to the sterol regulatory elements of the lipogenic genes activating their transcription (Horton, Goldstein, & Brown, ). The current results are in harmony with those of Nagai et al (); Kanuri, Spruss, Wagnerberger, Bischoff, and Bergheim (); Spruss, Kanuri, Uebel, Bischoff, and Bergheim (); Nomura and Yamanouchi (); and Clayton, Vickers, Bernal, Yap, and Sloboda ().…”

Fructose during pregnancy provokes fetal oxidative stress: The key role of the placental heme oxygenase-1

“…Furthermore, in a long-term study [18], we reported that maternal fructose intake produced adverse effects (impaired insulin signal transduction, hyperinsulinemia, and hypoadiponectinemia), which could only have originated during intrauterine development since fructose administration was strictly confined to the pregnancy period. Recently, Clayton et al (2015) have confirmed that early life exposure to fructose alters maternal and perinatal hepatic gene expression [16].…”

“…Recently, Clayton et al. (2015) have confirmed that early life exposure to fructose alters maternal and perinatal hepatic gene expression .…”

Impact of perinatal exposure to sucrose or high fructose corn syrup (HFCS‐55) on adiposity and hepatic lipid composition in rat offspring

“…; Clayton et al . ), no studies have investigated the impact of sucrose or HFCS‐55 on hepatic fat content or fatty acid composition. This is significant, as the type of fatty acids stored in the liver, as well as the overall fat content, is known to influence hepatic metabolism and the risk of developing diseases including non‐alcoholic fatty liver disease (NAFLD) (Puri et al .…”