Inhibition of CeramideDe NovoSynthesis Ameliorates Diet Induced Skeletal Muscles Insulin Resistance

Abstract

Nowadays wrong nutritional habits and lack of physical activity give a rich soil for the development of insulin resistance and obesity. Many researches indicate lipids, especially the one from the sphingolipids class, as the group of molecules heavily implicated in the progress of insulin resistance in skeletal muscle. Recently, scientists have focused their scrutiny on myriocin, a potent chemical compound that inhibits ceramide (i.e., central hub of sphingolipids signaling pathway) de novo synthesis. In the present research we evaluated the effects of myriocin application on type 2 diabetes mellitus in three different types of skeletal muscles: (1) slow-oxidative (red gastrocnemius), (2) oxidative-glycolytic (soleus), and (3) glycolytic (white gastrocnemius). For these reasons the animals were randomly divided into four groups: “control” (C), “myriocin” (M), “high fat diet” (HFD), “high fat diet” (HFD), and “high fat diet + myriocin” (HFD + M). Our in vivo study demonstrated that ceramide synthesis inhibition reduces intramuscular ceramide, its precursor sphinganine, and its derivatives sphingosine and sphingosine-1-phosphate concentrations. Moreover, FFA and TG contents were also decreased after myriocin treatment. Thus, myriocin presents potential therapeutic perspectives with respect to the treatment of insulin resistance and its serious consequences in obese patients.

Ceramide-Protein Interactions Modulate Ceramide-Associated Lipotoxic Cardiomyopathy

“…Our work presented here clearly demonstrates that genetic, pharmacological or dietary manipulation aimed at altering ceramide levels in the heart, likely acting via a number of CIPs, elicits cardiac defects associated with LCM. Inhibition of ceramide synthesis has been reported to have beneficial effects in several models related to metabolic syndrome and lipotoxicity, including obesity (Yang et al, 2009), diabetes and insulin resistance (Kurek et al, 2015; Ussher et al, 2010), non-alcoholic fatty liver disease (Kasumov et al, 2015; Kurek et al, 2015), and atherosclerotic plaques (Park et al, 2008b). …”

Pharmacologic activation of estrogen receptor α increases mitochondrial function, energy expenditure, and brown adipose tissue

“…6C). Sphingolipids have been attributed to, among others, insulin resistance, inflammation, and carcinogenesis (71)(72)(73). Detection of high levels of sphingolipids in the serum of obese animals could indicate the potential for susceptibility to many diseases.…”

Mechanism of increased risk of insulin resistance in aging skeletal muscle

“…As lipids accumulate, the levels of the CER and DAG increase, which impairs the insulin signaling pathway and promotes insulin resistance [96]. Studies have shown that increased CER levels in skeletal muscle in older individuals can promote insulin resistance [14], while reducing CER and DAG synthesis can improve skeletal muscle insulin sensitivity [61].…”