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

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 (TNFa). DESIGN: The effects of C 2 -and C 6 -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: C 6 -ceramide increased basal 2-deooxyglucose uptake but decreased insulin-stimulated uptake without changing the EC 50 for insulin. Incubating 3T3-L1 adipocytes from 2 to 24 h with C 2 -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. C 2 -ceramide also increased p21-activated kinase and protein kinase B activities. However, C 2 -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 TNFa 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 TNFa-induced insulin resistance and the control of fat accumulation in adipocytes in insulin resistance and obesity.

Skeletal Muscle Lipogenic Protein Expression Is Not Different between Lean and Obese Individuals: A Potential Factor in Ceramide Accumulation

“…MUFA and PUFA are more readily oxidized than SFA (34,35), which can accumulate as ceramide and DAG (4). Research in cell lines demonstrates that the impaired insulinstimulated glucose transport that occurs after SFA exposure results from a ceramide-induced reduction in Akt activation (4,36). Thus, we speculate that ceramide accumulation plays a more significant role in human obesity, particularly as a consequence of a diet high in SFA.…”

Ceramide- and Oxidant-Induced Insulin Resistance Involve Loss of Insulin-Dependent Rac-Activation and Actin Remodeling in Muscle Cells

“…Such resistance is reversible by preincubation with antioxidants (20,31). Similarly, exposing adipose cells to 100 mol/l of the lipid metabolite analog C2-ceramide or long-chain ceramides leads to insulin resistance of glucose uptake and/or GLUT4 translocation (21)(22)(23)32). Glucose oxidase and C2-ceramide also elicit insulin resistance of glucose uptake in muscle cells (19,20,22,24).…”

Role of ceramide in diabetes mellitus: evidence and mechanisms

“…In agreement with this, overexpression of acid ceramidase as an alternative approach to reduce the ceramide level, negated the palmitate-induced ceramide accumulation and improved insulin signaling [93]. Similarly, acute application of ceramide analogue to 3 T3-adipocytes mimicked the palmitate induced insulin desensitizing effect [102]. …”