Abstract
Skeletal muscle is perceived as a major tissue in glucose and lipid metabolism. High fat diet (HFD) lead to the accumulation of intramuscular lipids, including: long chain acyl-CoA, diacylglycerols, and ceramides. Ceramides are considered to be one of the most important lipid groups in the generation of skeletal muscle insulin resistance. So far, it has not been clearly established whether all ceramides adversely affect the functioning of the insulin pathway, or whether there are certain ceramide species that play a pivotal role in the induction of insulin resistance. Therefore, we designed a study in which the expression of CerS1 and CerS5 genes responsible for the synthesis of C18:0-Cer and C16:0-Cer, respectively, was locally silenced in the gastrocnemius muscle of HFD-fed mice through in vivo electroporation-mediated shRNA plasmids. Our study indicates that HFD feeding induced both, the systemic and skeletal muscle insulin resistance, which was accompanied by an increase in the intramuscular lipid levels, decreased activation of the insulin pathway and, consequently, a decrease in the skeletal muscle glucose uptake. CerS1 silencing leads to a reduction in C18:0-Cer content, with a subsequent increase in the activity of the insulin pathway, and an improvement in skeletal muscle glucose uptake. Such effects were not visible in case of CerS5 silencing, which indicates that the accumulation of C18:0-Cer plays a decisive role in the induction of skeletal muscle insulin resistance.
Highlights
Obesity is associated with a number of metabolic disorders, including cardiovascular disease, atherosclerosis, insulin resistance, and type 2 diabetes (T2D) [1,2]
CerS1 gene silencing in the muscle of animals fed High fat diet (HFD) caused a decrease in the content of its protein product by about 42% compared to HFD(+/+) animals (Figure 2B,D)
We noticed that HFD significantly increased the content of all the measured lipid classes, namely, LCACoA, DAG, and TAG, in the gastrocnemius muscle, but neither CerS1 nor CerS5 silencing resulted in statistically significant decrease in their content, except for ceramides
Summary
Obesity is associated with a number of metabolic disorders, including cardiovascular disease, atherosclerosis, insulin resistance, and type 2 diabetes (T2D) [1,2]. The increased FFA uptake and decreased β-oxidation rate contributes to the accumulation of intramyocellular lipids Among these lipids are biologically active ones such as ceramides (Cer), diacylglycerols (DAG), and LCACoA [8–12]. We showed that HFD leads to the highest increase in C18:0-Cer, which was accompanied by a weakening of the insulin signaling pathway, and the administration of myriocin causes a decrease in ceramide levels, with the largest decrease in C18:0-Cer, accompanied by an improvement in the function of the insulin signaling pathway in muscles [13] This discovery was confirmed by other researchers who showed that the deletion of CerS1 and, decrease in C18:0-Cer levels in skeletal muscles, improves systemic glucose metabolism in obesity [19]. The results do not overlap with another group of researchers who have shown that the use of a CerS1-specific inhibitor increases the rate of fatty acid oxidation in muscle, but does not protect against diet-induced insulin resistance [20]. We investigated the effect of local in vivo shRNA-mediated gene silencing of CerS1 and CerS5 on the bioactive lipid accumulation and insulin signaling pathway in gastrocnemius muscle of mice with diet-induced insulin resistance
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