The sphingosine-1-phosphate analog FTY720 reduces muscle ceramide content and improves glucose tolerance in high fat-fed male mice.

FTY720 is a sphingosine-1-phosphate analog that has been shown to inhibit ceramide synthesis in vitro. Because ceramide accumulation in muscle is associated with insulin resistance, we aimed to examine whether FTY720 would prevent muscle ceramide accumulation in high fat-fed mice and subsequently improve glucose homeostasis. Male C57Bl/6 mice were fed either a chow or high fat-diet (HFD) for 6 wk, after which they were treated with vehicle or FTY720 (5 mg/kg) daily for a further 6 wk. The ceramide content of muscle was examined and insulin action was assessed. Whereas the HFD increased muscle ceramide, this was prevented by FTY720 treatment. This was not associated with alterations in the expression of genes involved in sphingolipid metabolism. Interestingly, the effects of FTY720 on lipid metabolism were not limited to ceramide because FTY720 also prevented the HFD-induced increase in diacylglycerol and triacylglycerol in muscle. Furthermore, the increase in CD36 mRNA expression induced by fat feeding was prevented in muscle of FTY720-treated mice. This was associated with an attenuation of the HFD-induced increase in palmitate uptake and esterification. In addition, FTY720 improved glucose homeostasis as demonstrated by a reduction in plasma insulin, an improvement in whole-body glucose tolerance, an increase in insulin-stimulated glucose uptake, and Akt phosphorylation in muscle. In conclusion, FTY720 exerts beneficial effects on muscle lipid metabolism that prevent lipid accumulation and improve glucose tolerance in high fat-fed mice. Thus, FTY720 and other compounds that target sphingosine-1-phosphate signaling may have therapeutic potential in treating insulin resistance.

Overexpression of sphingosine kinase 1 prevents ceramide accumulation and ameliorates muscle insulin resistance in high-fat diet-fed mice.

The sphingolipids sphingosine-1-phosphate (S1P) and ceramide are important bioactive lipids with many cellular effects. Intracellular ceramide accumulation causes insulin resistance, but sphingosine kinase 1 (SphK1) prevents ceramide accumulation, in part, by promoting its metabolism into S1P. Despite this, the role of SphK1 in regulating insulin action has been largely overlooked. Transgenic (Tg) mice that overexpress SphK1 were fed a standard chow or high-fat diet (HFD) for 6 weeks before undergoing several metabolic analyses. SphK1 Tg mice fed an HFD displayed increased SphK activity in skeletal muscle, which was associated with an attenuated intramuscular ceramide accumulation compared with wild-type (WT) littermates. This was associated with a concomitant reduction in the phosphorylation of c-jun amino-terminal kinase, a serine threonine kinase associated with insulin resistance. Accordingly, skeletal muscle and whole-body insulin sensitivity were improved in SphK1 Tg, compared with WT mice, when fed an HFD. We have identified that the enzyme SphK1 is an important regulator of lipid partitioning and insulin action in skeletal muscle under conditions of increased lipid supply.

The effect of cooking process on the total lipid and n-3 LC-PUFA contents of Australian Bass Strait scallops, Pecten fumatus.

A total of twenty-three Australian Bass Strait scallops, Pecten fumatus processed by three different cooking methods: steam, battered and deep-fry, and pan-fry were analysed to determine the total lipid and health-benefiting n-3 PUFA contents. Fry process resulted in a significantly higher lipid content (p<0.05) with 1.98g/100g being found in deep-fried and 1.78g/100g in pan-fried scallops while 1.31g/100g was recorded in the fresh control group (p<0.05). A higher concentration of alpha-linolenic acid (ALA, 18:3n-3), total n-6 PUFA and linoleic (LA, 18:2n-6) were also observed in fried scallops (p<0.05). The two main n-3 LC-PUFA were eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3) and their concentration also varied depending on the cooking methods. Pan-fried scallops showed a higher concentration of EPA, DHA and total n-3 PUFA while steamed scallops had a higher concentration of DHA only (p<0.05). The ratio of n-3/n-6 PUFA was markedly lower in both fried groups than in control and steamed scallops (p<0.0001). Three frozen samples were also examined and no significant variations in the lipid profiles have been observed after 22 days. The variation of lipid profiles reflects mainly the uptake of vegetable oil components and loss of water during cooking process. Scallops represent a good source of n-3 LC-PUFA with the concentration ranging from 312.4 mg/100g in fresh scallops to 522.1mg/100g in pan-fried scallops.