Cell-permeable ceramides increase basal glucose incorporation into triacylglycerols but decrease the stimulation by insulin in 3T3-L1 adipocytes

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Abstract
OBJECTIVE: To investigate mechanisms for the regulation of glucose incorporation into triacylgycerols in adipocytes by ceramides, which mediate some actions of tumour necrosis factor-alpha (TNFα). DESIGN: The effects of C2- and C6-ceramides (N-acetyl- and N-hexanoyl-sphingosines, respectively) on glucose uptake and incorporation into triacylglycerols and pathways of signal tansduction were measured in 3T3-L1 adipocytes. RESUTLS: C6-ceramide increased basal 2-deooxyglucose uptake but decreased insulin-stimulated uptake without changing the EC50 for insulin. Incubating 3T3-L1 adipocytes from 2 to 24 h with C2-ceramide progressively increased glucose incorporation into the fatty acid and especially the glycerol moieties of triacylglycerol. These effects were accompanied by increased GLUT1 synthesis resulting from ceramide-induced activation phosphatidylinositol 3-kinase, ribosomal S6 kinase and mitogen-activated protein kinase. C2-ceramide also increased p21-activated kinase and protein kinase B activities. However, C2-ceramide decreased the insulin-stimulated component of these signalling pathways and also glucose incorporation into triacylglycerol after 2 h. CONCLUSIONS: Cell-permeable ceramides can mimic some effects of TNFα in producing insulin resistance. However, ceramides also mediate long-term effects that enable 3T3 L1 adipocytes to take up glucose and store triacylglycerols in the absence of insulin. These observations help to explain part of the nature and consequence of TNFα-induced insulin resistance and the control of fat accumulation in adipocytes in insulin resistance and obesity.