Short-term fructose feeding alters tissue metabolic pathways by modulating microRNAs expression both in young and adult rats

Abstract

Dietary high fructose (HFrD) is known as a metabolic disruptor contributing to the development of obesity, diabetes, and dyslipidemia. Children are more sensitive to sugar than adults due to the distinct metabolic profile, therefore it is especially relevant to study the metabolic alterations induced by HFrD and the mechanisms underlying such changes in animal models of different ages. Emerging research suggests the fundamental role of epigenetic factors such as microRNAs (miRNAs) in metabolic tissue injury. In this perspective, the aim of the present study was to investigate the involvement of miR-122-5p, miR-34a-5p, and miR-125b-5p examining the effects induced by fructose overconsumption and to evaluate whether a differential miRNA regulation exists between young and adult animals. We used young rats (30 days) and adult rats (90 days) fed on HFrD for a short period (2 weeks) as animal models. The results indicate that both young and adult rats fed on HFrD exhibit an increase in systemic oxidative stress, the establishment of an inflammatory state, and metabolic perturbations involving the relevant miRNAs and their axes. In the skeletal muscle of adult rats, HFrD impair insulin sensitivity and triglyceride accumulation affecting the miR-122-5p/PTP1B/P-IRS-1(Tyr612) axis. In liver and skeletal muscle, HFrD acts on miR-34a-5p/SIRT-1: AMPK pathway resulting in a decrease of fat oxidation and an increase in fat synthesis. In addition, liver and skeletal muscle of young and adult rats exhibit an imbalance in antioxidant enzyme. Finally, HFrD modulates miR-125b-5p expression levels in liver and white adipose tissue determining modifications in de novo lipogenesis. Therefore, miRNA modulation displays a specific tissue trend indicative of a regulatory network that contributes in targeting genes of various pathways, subsequently yielding extensive effects on cell metabolism.

Fructose Reduces Mitochondrial Metabolism and Increases Extracellular BCAA during Insulin Resistance in C2C12 Myotubes

“…In addition to observations linking fructose to reduced mitochondrial metabolism [20,21], David et al examined the effect of the fructose-induced model of insulin resistance S3b). Notes: Data were analyzed using two-way ANOVA followed by one-way ANOVA with Bonferroni's correction for multiple.…”

“…In fact, circulating levels of fructose in peripheral circulation tend to be substantially lower than glucose. In rats, fructose disproportionally increased lipid content and glucose intolerance to a greater extent in adult versus young animals [ 21 ]. Consistent with other observations, fructose reduced AMPK activation as well as Sirt1 expression yet resulted in a perplexing increase of PGC-1 mitofusin 2 and DRP1 in skeletal muscle [ 21 ].…”

Epigenetic modifications in obesity‐associated diseases

“…236 Excessive fructose consumption elevates the risk of developing T2D by impacting the regulatory network of miRNAs, thereby diminishing insulin sensitivity and promoting the accumulation of TG. 237 Consequently, it is crucial to restrict fructose consumption in our regular diet. Proper dietary interventions can mitigate the adverse effects of obesity and decrease the initiation and progress of associated complications.…”

“…Over‐consumption of fructose for an extended period might promote lipid accumulation and downregulated expression of LEP and miR‐192, which was also related to prostate cancer pathogenesis 236 . Excessive fructose consumption elevates the risk of developing T2D by impacting the regulatory network of miRNAs, thereby diminishing insulin sensitivity and promoting the accumulation of TG 237 . Consequently, it is crucial to restrict fructose consumption in our regular diet.…”

Mitochondrial Fission as a Therapeutic Target for Metabolic Diseases: Insights into Antioxidant Strategies

“…This elongation is regulated by Drp1 Ser637 dephosphorylation and a reduction in the fission proteins Drp1 and Fis1, as well as activation of the key mitochondrial biogenesis inductors PGC-1α and upregulation of the levels of the fusion proteins MFN1/2 and OPA1 [81][82][83][84]. Conversely, nutrient excess, such as high glucose/lipid levels, excess dietary fatty acids, or high fructose, can lead to increased mitochondrial ROS production and mitochondrial fragmentation in many cell types, including hepatocytes and skeletal muscle cells (Figure 3) [41,[85][86][87][88]. The activation of mitochondrial fission is regulated by several proteins, including Drp1 and its activators, such as receptor-interacting protein kinase 1 (RIPK1) and protein kinase Cδ (PKCδ).…”