Inhibition of Ceramide De Novo Synthesis Affects Adipocytokine Secretion and Improves Systemic and Adipose Tissue Insulin Sensitivity

Abstract

Ceramide accumulation in muscle and in liver is implicated in the induction of insulin resistance. Much less in known about the role of ceramide in adipose tissue. The aim of the present study was to elucidate the role of ceramide in adipose tissue and to clarify whether lipids participate in the regulation of adipocytokine secretion. The experiments were performed on male Wistar rats divided into three groups: 1. Control, 2. fed high fat diet (HFD), and 3. fed HFD and treated with myriocin. Ceramide (Cer) and diacylglycerol (DAG) content were analyzed by LC/MS/MS. Hormone sensitive lipase (HSL) phosphorylation was analyzed by Western Blot. Plasma adiponectin and tumor necrosis factor alpha (TNF-α) concentration were measured by enzyme-linked immunosorbent assay. An oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) was also performed. In HFD group, total DAG and Cer content was elevated in both subcutaneous and visceral adipose tissue, which was accompanied by increased glucose, insulin, and HOMA-IR value. Myriocin treatment restored HOMA-IR as well as glucose and insulin concentration to control values. Moreover, myriocin decreased not only Cer, but also DAG levels in both fat depots. Furthermore, we observed a strong correlation between adiponectin (negative) and TNF-α (positive) and Cer in both fat tissues, which suggests that Cer is involved in the regulation of adipocytokine secretion.

GPAT Gene Silencing in Muscle Reduces Diacylglycerols Content and Improves Insulin Action in Diet-Induced Insulin Resistance

“…We found that HFD consumption led to insulin resistance, as evidenced by increased fasting glucose and insulin concentration, impaired glucose tolerance, reduced insulin responsiveness, an increase in HOMA-IR and decreased muscular glucose uptake compared to the control group. We have noticed a significant increase in plasma FFA concentration and a significant increase in all the studied lipid groups in nonsilenced muscle, which was in line with observations made by other research groups [ 1 , 2 , 3 , 4 , 5 , 7 , 19 , 26 ]. However, we wanted to find out how, under conditions of induced insulin resistance, reducing DAG content would affect the insulin pathway and whether it would improve muscle glucose uptake.…”

“…In obese and T2D subjects, plasma free fatty acid (FFA) concentration is often elevated compared to lean, healthy counterparts [ 1 ]. An increased concentration of FFA was observed in skeletal muscles in animals fed HFD [ 2 , 3 , 4 , 5 , 6 , 7 ], in obese people [ 8 , 9 ] and T2D patients [ 10 ]. Plasma FFAs enter muscle cells by diffusion or via protein transporters.…”

The Role of Ceramides in Diabetes and Cardiovascular Disease Regulation of Ceramides by Adipokines

“…Blocking ceramide production with SPT inhibitor myriocin in DIO mice led to increased levels of circulating high molecular weight adiponectin ( 59 ). This inverse relationship between adiponectin and ceramides has also been shown in rats ( 155 , 156 ) and dolphins.…”

Novel Insights and Mechanisms of Lipotoxicity-Driven Insulin Resistance

“…In another study, myriocin prevented the development of IR in young db/db mice and reduced liver mass, without changes in body weight, visceral fat mass, locomotor activity and oxygen consumption [ 76 ]. More recently, Blachnio-Zabielska et al also reported a protective effect of myriocin on insulin sensitivity in HFD-fed rats [ 77 ]. Surprisingly, the treatment also reduced DAG content in subcutaneous and visceral fat depots.…”