Insulin-Sensitizing Effect of LXR Agonist T0901317 in High-Fat Fed Rats is Associated with Restored Muscle GLUT4 Expression and Insulin-Stimulated AS160 Phosphorylation

Abstract

Background/Aim: Liver X receptors (LXRs) are ligand-activated transcription factors that were shown to stimulate hepatic lipogenesis leading to liver steatosis and hypertriglyceridemia. Despite their pro-lipogenic action, LXR activators normalize glycemia and improve insulin sensitivity in rodent models of type 2 diabetes. Antidiabetic action of LXR agonists is thought to result from suppression of hepatic gluconeogenesis. However, it remains unclear whether LXR activation affects muscle insulin sensitivity. In the present study we attempted to answer this question. Methods: The experiments were performed on male Wistar rats fed for 5 weeks on either standard chow or high fat diet. The latter group was further divided into two subgroups receiving either selective LXR agonist - T0901317 (10mg/kg/d) or vehicle during the last week of the experiment. All animals were then anaesthetized and samples of the soleus as well as red and white sections of the gastrocnemius muscle were excised. Results: As expected, administration of T0901317 to high-fat fed rats augmented diet-induced hyperlipidemia. Nevertheless, it also normalized glucose tolerance and improved insulin-stimulated glucose uptake in isolated soleus muscle. In addition, LXR agonist completely restored glucose transporter 4 expression and insulin-stimulated Akt substrate of 160 kDa phosphorylation in all investigated muscles. Insulin-sensitizing effect of T0901317 was not related to changes in intramuscular level of lipid mediators of insulin resistance, since neither diacylglycerols nor ceramide content was affected by the treatment. Conclusion: We conclude that improvement in muscle insulin sensitivity is one of the mechanisms underlying the antidiabetic action of LXR activators.

Insulin Modulates Liver Function in a Type I Diabetes Rat Model

“…The results show that the concentrations of serum ALT, AST, and ALP did not change in non-diabetic rats after CLP or treatment with insulin. Conversely, insulin completely rescued liver enzymes in all CLP diabetic animals, probably by affecting hepatic glucose levels and lipid metabolism [22][23][24]. Another explanation for the dysfunction of organs located away from the focus of infection may be inappropriate neutrophil activation, the accumulation of neutrophils within the microcirculation next to certain organs, and neutrophil migration to regions other than the primary focus [25]; however, liver neutrophil infiltration was not observed in our study.…”

MiR-499-5p Contributes to Hepatic Insulin Resistance by Suppressing PTEN

“…The results showed that miR-499-5p negatively regulates AKT/GSK activation by targeting PTEN. It has been suggested that glucogenesis and lipogenesis are two major functions of livers [21]. In this study, we found that overexpression of miR-499-5p in NCTC cells significantly increased the glycogen content, while inhibition of miR-499-5p reduced the glycogen content.…”

Amino Acids Attenuate Insulin Action on Gluconeogenesis and Promote Fatty Acid Biosynthesis via mTORC1 Signaling Pathway in trout Hepatocytes

“…Insulin stimulates hepatic lipogenesis by increasing the mRNA and the processed nuclear form of sterol regulatory element-binding protein-1c (SREBP-1c), a transcription factor that activates all the genes needed to produce fatty acids and triglycerides in liver [5]. Insulin-dependent SREBP-1c transcriptional regulation also requires liver X receptor (LXR) activation [6,7].…”