The expression of microRNA-802 (miR-802) is known to be associated with insulin resistance (IR); however, the mechanism remains unclear. The present study investigated how miR-802 contributes to the development of IR using C57BL/6J mice fed a high-fat diet (HFD) to establish a model of IR. Adeno-associated virus overexpressing miR-802 was administered to the mice via tail vein injection. The effects of miR-802 on reactive oxygen species (ROS), lipid peroxidation (LPO) and the activities of multiple ROS-related enzymes were investigated. Western blot analysis was used to estimate the protein levels of extracellular signal regulated kinase (ERK), p38mitogen-activated protein kinases (p38MAPK), c-Jun N-terminal kinase (JNK), insulin receptor substrate 1 (IRS-1) and protein kinase B (AKT1). The results demonstrated that the levels of ROS and LPO production were increased in the livers of the miR-802-treated group compared with the control group. The activities of the ROS-related enzymes were reduced. Furthermore, the expression of phosphorylated (phosphor)-p38MAPK and phosphor-JNK were upregulated in the miR-802 overexpression group, whereas there was no difference in the expression levels of phosphor-ERK. The expression levels of phosphor-AKT1 were reduced in the miR-802-treated group and these effects were reversed by miR-802 knockdown. In conclusion, the results demonstrate that miR-802 may cause IR by activating the JNK and p38MAPK pathways to increase hepatic oxidative stress.

Nonalcoholic fatty liver disease (NAFLD) correlates with the high intake of fructoserich soft drinks. Both inflammation and dysregulated iron metabolism are pathogenic factors in the development of NAFLD. The present investigation assessed the effects of a high-fructose diet (HF diet) on inflammation and iron metabolism. In this study, rats were fed a control or HF diet for 4, 8, or 12 weeks, after which insulin resistance, transaminases levels, serum and liver lipid profiles, inflammatory factors, and iron metabolism-related molecules were evaluated. The activities of the hepatic inflammation-associated pathways, IKKβ/NF-κB, and JAK2/STAT3, were detected by western blot. Result showed that the HF diet-fed animals developed a time-dependent serum lipid increase and hepatic lipid accumulation as well as insulin resistance. Serum iron (SI), serum ferritin (SF), and transferrin saturation (TS) decreased while total iron-binding capacity (TIBC) and serum transferrin (s-TF) increased at 8 and 12 weeks in the HF diet group. The HF diet led to increased transaminases levels at 8 and 12 weeks, and iron deposition was observed in the liver, accompanied by an upregulation of ferritin light chain (FTL), hepcidin (HEPC), transferrin (TF), transferrin receptor 1 (TfR1), iron regulatory protein 1 (IRP1), hemojuvelin (HJV), and divalent metal transporter 1 (DMT1). Moreover, ferroportin (FPN1) levels were downregulated, as expected from the increased HEPC. A progressive inflammation phenotype was apparent, with increased inflammatory factors, MDA, IL-1β, IL-6, and TNF-α, in the serum and liver tissue. Concomitantly, the hepatic IKKβ/NF-κB and JAK2/STAT3 pathways were activated. In summary, we verified that HF diet induces systemic iron deficiency and hepatic iron accumulation, likely due to the activation of inflammation via the NF-κB and JAK2/STAT3 pathways. Practical applications As increasing numbers of individuals consume HF diets, the health implications of this type of over nutrition become globally relevant. Using a high-fructose diet rat model, our present study reveals inflammation as the link between a HF diet and dysregulated iron metabolism. Importantly, both inflammation and disrupted iron metabolism have been shown to be pathogenic factors in nonalcoholic fatty liver disease (NAFLD). The iron regulatory hormone, HEPC, is a link between the liver, How to cite this article: Wang C, Wang X, Song G, et al. A high-fructose diet in rats induces systemic iron deficiency and hepatic iron overload by an inflammation mechanism.

The development of type‑2 diabetes and its complications is associated with lipid metabolism disorder. Farnesoid X receptor (FXR) has an important role in regulating lipid and glucose metabolism. However, the underlying mechanism of this remains unclear. The present study investigated the role of fexaramine (Fex), an FXR agonist, on lipid metabolism. For this purpose, 6‑week‑old db/db mice were treated with Fex for 8 weeks via oral gavage and db/db mice treated with corn oil were used as controls. Body weight and food intake were monitored daily and bi‑weekly, respectively. A glucose tolerance test was performed during the final week of feeding. Blood samples were obtained for the analysis of lipids and enzymes related to hepatic function, and liver tissues were analyzed by histology and molecular examination. The results indicated that serum and liver triglyceride levels were decreased in db/db mice administered with Fex. Fewer small lipid droplets were observed in the liver. Small heterodimer partner (SHP), a downstream gene of FXR, was upregulated following Fex treatment. The mRNA and protein expression of genes associated with fatty acid oxidation [acetyl coenzyme A carboxylase (ACC), carnitine palmitoyl transferase 1α (CPT1‑α) and peroxisome proliferator‑activated receptor‑coactivator‑1α] was also increased. Additionally, the expression of AMP‑activated protein kinase (AMPK) was also increased. However, the expression of sterol‑regulatory element binding protein‑1c and fatty acid synthase, which are associated with fatty acid synthesis, was not significantly different. Taken together, the results of the present study suggested that activation of FXR and its downstream gene SHP may induce the AMPK‑ACC‑CPT1‑α signaling pathway, which promotes fatty acids oxidation, ultimately achieving its lipid‑lowering effect.

Background Studies have shown that the high incidence of type 2 diabetes in China is associated with low birth weight and excessive nutrition in adulthood, which occurred during the famine years of the 1950s and 1960s, though the specific molecular mechanisms are unclear. In this study, we proposed a severe maternal caloric restriction during late pregnancy, followed by a post weaning high-fat diet in mice. After weaning, normal and high-fat diets were provided to mice to simulate the dietary pattern of modern society. Methods The pregnant mice were divided into two groups: normal birth weight (NBW) group and low birth weight (LBW) group. After 3 weeks for weaning, the male offspring mice in the NBW and LBW groups were then randomly divided into four subgroups: NC, NH, LC and LC groups. The offspring mice in the NC, NH, LC and LC groups were respectively fed with normal diet, normal diet, high-fat diet and high-fat diet for 18 weeks. After 18 weeks of dietary intervention, detailed analyses of mRNA and protein expression patterns, signaling pathway activities, and promoter methylation states were conducted for all relevant genes. Results After dietary intervention for 18 weeks, the expressions of CD36, Fabp4, PPARγ, FAS, and ACC1 in the skeletal muscle tissue of the LH group were significantly increased compared with the LC and NH groups (P < 0.05). The level of p-AMPK/AMPK in the skeletal muscle tissue of the LH group was significantly decreased compared with the LC and NH groups (P < 0.05). CPT1 and PGC-1α protein expressions were up-regulated in the LH group (P < 0.05) compared to the LC group. Additionally, the DNA methylation levels of the PGC-1α and GLUT4 gene promoters in the skeletal muscle of the LH groups were higher than those of the LC and NH groups (P < 0.05). However, PPARγ DNA methylation level in the LH group was lower than those of the LC and NH groups (P < 0.05). Conclusions LBW combined with high-fat diets may increase insulin resistance and diabetes through regulating the CD36-related Fabp4-PPARγ and AMPK/ACC signaling pathways.

Diabetes mellitus is highly prevalent worldwide. High-fat-diet (HFD) consumption can lead to liver fat accumulation, impair hepatic glycometabolism, and cause insulin resistance and the development of diabetes. Resveratrol has been shown to improve the blood glucose concentration of diabetic mice, but its effect on the abnormal hepatic glycometabolism induced by HFD-feeding and the mechanism involved are unknown. In this study, we determined the effects of resveratrol on the insulin resistance of high-fat-diet-fed mice and a hepatocyte model by measuring serum biochemical indexes, key indicators of glycometabolism, glucose uptake, and glycogen synthesis in hepatocytes. We found that resveratrol treatment significantly ameliorated the HFD-induced abnormalities in glucose metabolism in mice, increased glucose absorption and glycogen synthesis, downregulated protein phosphatase 2A (PP2A) and activated Ca2+/CaM-dependent protein kinase kinase β (CaMKKβ), and increased the phosphorylation of AMP-activated protein kinase (AMPK). In insulin-resistant HepG2 cells, the administration of a PP2A activator or CaMKKβ inhibitor attenuated the effects of resveratrol, but the administration of an AMPK inhibitor abolished the effects of resveratrol. Resveratrol significantly ameliorates abnormalities in glycometabolism induced by HFD-feeding and increases glucose uptake and glycogen synthesis in hepatocytes. These effects are mediated through the activation of AMPK by PP2A and CaMKKβ.