Abstract: The effects of early-life fructose consumption on hepatic signaling pathways and their

relation to the development of metabolic disorders in later life are not fully understood. To investigate

whether fructose overconsumption at a young age induces alterations in glucocorticoid signaling

that might contribute to development of metabolic disturbances, we analyzed glucocorticoid

receptor hormone-binding parameters and expression of its target genes involved in gluconeogenesis

(phosphoenolpyruvate carboxykinase and glucose-6-phosphatase) and lipid metabolism (lipin-1),

as well as redox and inflammatory status in the liver of female rats subjected to a fructose-rich

diet immediately after weaning. The fructose diet increased hepatic corticosterone concentration,

11-hydroxysteroid dehydrogenase type 1 level, glucocorticoid receptor protein level and

hormone-binding activity, as well as lipin-1 level. The expression of glucose-6-phosphatase was

reduced in fructose-fed rats, while phosphoenolpyruvate carboxykinase remained unaltered.

The fructose-rich diet increased the level of fructose transporter GLUT2, while the expression

of fructolytic enzymes fructokinase and aldolase B remained unaltered. The diet also affected

pro-inflammatory pathways, but had no effect on the antioxidant defence system. In conclusion,

a fructose-rich diet applied immediately after weaning promoted lipogenesis and enhanced hepatic

glucocorticoid signaling, possibly to protect against inflammatory damage, but without an effect on

gluconeogenesis and antioxidant enzymes. Yet, prolonged treatment might ultimately lead to more

pronounced metabolic disturbances.

Abstract

BACKGROUND: Increased fructose consumption correlateswith rising prevalence of variousmetabolic disorders, some of which

were linked to oxidative stress. The relationship between fructose consumption and oxidative stress is complex and effects of

a fructose-rich diet on the young population have not been fully elucidated. The aim of this study was to investigate whether

high-fructose diet applied in the period from weaning to adulthood induces oxidative stress in the liver, thus contributing to

induction or aggravation of metabolic disturbances in later adulthood. To that end we examined the effects of high-fructose

diet on expression and activity of antioxidant enzymes, markers of lipid peroxidation and protein damage in the liver as the

main fructose metabolizing tissue.

RESULTS: High-fructose diet increased only SOD2 (mitochondrial manganese superoxide dismutase) activity, with no effect on

other antioxidant enzymes, lipid peroxidation or accumulation of damaged proteins in the liver.

CONCLUSION: The results show that fructose-induced metabolic disturbances could not be attributed to oxidative stress, at

least not at young age. The absence of oxidative stress in the liver observed herein implies that young organisms are capable of

maintaining redox homeostasis when challenged by fructose-derived energy overload.

Increased fructose consumption is correlated with the rising prevalence of obesity, metabolic

syndrome, and type 2 diabetes. It is believed that reactive oxygen species contribute to the

development and progression of metabolic disturbances, especially those associated with

insulin resistance. Dietary fructose produces both pro-oxidative and antioxidative effects,

depending upon the experimental conditions, dosage, duration of treatment, and

pathophysiological milieu. The effects of fructose overconsumption on young populations,

which have an increased risk of developing metabolic disorders in adulthood, have not been

fully elucidated.Wehavepreviously shownthat rats subjected toa long-termfructose-enriched

diet immediately after weaning display impaired hepatic insulin sensitivity. In this study, we

tested the hypothesis that long-term fructose consumption induces alterations in the redox

setting of the liver. Starting fromthe 21st day after birth,maleWistar ratsweremaintained for 9

weeks on a standard diet (control) or a fructose-enriched diet that consisted of standard food

and 10%fructose solution instead of drinkingwater. The expression and activity of antioxidant

enzymes aswell as lipid peroxidation and protein damagemarkersweremeasured. The results

showed that a fructose-enriched diet led to an increased expression of mitochondrial

manganese superoxide dismutase but did not affect antioxidant enzymes activity, lipid

peroxidation, thiol content, and the level of protein oxidation. Therefore, our results suggest

that the decrease in hepatic insulin sensitivity that was previously observed in rats that were

kept on the same diet regimemight be attributed to molecular mechanisms other than redox

disbalance. A possible fructose-related micronutrient deficiency should be examined.

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