A Role for Ceramide, but Not Diacylglycerol, in the Antagonism of Insulin Signal Transduction by Saturated Fatty Acids

Abstract

Multiple studies suggest that lipid oversupply to skeletal muscle contributes to the development of insulin resistance, perhaps by promoting the accumulation of lipid metabolites capable of inhibiting signal transduction. Herein we demonstrate that exposing muscle cells to particular saturated free fatty acids (FFAs), but not mono-unsaturated FFAs, inhibits insulin stimulation of Akt/protein kinase B, a serine/threonine kinase that is a central mediator of insulin-stimulated anabolic metabolism. These saturated FFAs concomitantly induced the accumulation of ceramide and diacylglycerol, two products of fatty acyl-CoA that have been shown to accumulate in insulin-resistant tissues and to inhibit early steps in insulin signaling. Preventing de novo ceramide synthesis negated the antagonistic effect of saturated FFAs toward Akt/protein kinase B. Moreover, inducing ceramide buildup recapitulated and augmented the inhibitory effect of saturated FFAs. By contrast, diacylglycerol proved dispensable for these FFA effects. Collectively these results identify ceramide as a necessary and sufficient intermediate linking saturated fats to the inhibition of insulin signaling.The peptide hormone insulin stimulates the uptake and storage of glucose in skeletal muscle and adipose tissue while simultaneously inhibiting its efflux from the liver. In certain pathological conditions, including Type 2 diabetes mellitus (1) and metabolic syndrome X (2), these tissues become resistant to insulin such that a maximal dose of the hormone is unable to elicit these anabolic responses. Numerous studies suggest that the oversupply of lipid to peripheral tissues might contribute to the development of this insulin resistance. First, insulin-resistant subjects frequently display signs of abnormal lipid metabolism including obesity (3), increased circulating free fatty acid (FFA) 1 concentrations (4, 5), and elevated intramyocellular lipid levels (6). In fact, the size of the intramyocellular lipid depot correlates more tightly with the severity of insulin resistance than most known risk factors (6). Second, experimentally exposing peripheral tissues to lipids decreases their sensitivity to insulin. For example, (a) incubating isolated muscle strips or cultured muscle cells with FFAs (7-11), (b) infusing lipid emulsions into rodents or humans (12-15), or (c) expressing lipoprotein lipase in skeletal muscle of transgenic mice (16, 17) promotes intramyocellular lipid accumulation and compromises insulin-stimulated glucose uptake. These observations have prompted investigators to hypothesize that increased availability of lipids to peripheral tissues causes insulin resistance, perhaps by promoting the accumulation of one or more fat-derived metabolites capable of inhibiting insulin action (6, 18). The insulin receptor is a heterotetrameric tyrosine kinase receptor that mediates all of the anabolic effects of insulin (19). The activated receptor phosphorylates intracellular docking molecules (termed insulin receptor substrates, or IRS proteins) that r...

Natural Killer T Cells Are Involved in Adipose Tissues Inflammation and Glucose Intolerance in Diet-Induced Obese Mice

“…In fact, ceramide has been shown to be synthesized by long-chain fatty acids and to induce both inflammation and insulin resistance. 23 In agreement with our results, Rocha et al 5 reported that the HFD feeding increases a number of T cells and IFN-␥ gene expression in adipose tissue, suggesting T-cell priming toward the T H 1 slant. However, the HFD feeding has been shown to suppress T H 1 responses in B6 mice by inhibiting toll-like receptor-mediated maturation and proinflammatory cytokine production in dendritic cells.…”

Demographic and clinical variables affecting mid‐ to late‐life trajectories of plasma ceramide and dihydroceramide species

“…Ceramide blocks the translocation of Akt/protein kinase B (PKB) to the plasma membrane, thus inhibiting insulin signaling (Stratford et al ., 2001), and promotes the dephosphorylation of Akt/PKB by protein phosphatase 2A (Chavez et al ., 2003). In rodent models of type 2 diabetes, increases in islet ceramides precede beta‐cell dysfunction (Lee et al ., 1994).…”

Increased skeletal muscle ceramide level in men at risk of developing type 2 diabetes

“…So far, no data are available to compare with our results regarding the impact of family history of type 2 diabetes on ceramide metabolism in muscle. Experimental studies indicate that inhibition of ceramide degradation might have a profound effect on steady-state ceramide levels in tissues and might augment ceramide-associated insulin resistance [36].…”

“…Experimental studies revealed that even relatively small changes in the tissue ceramide level are sufficient to antagonise insulin action [36]. Data on the lean offspring of type 2 diabetic patients suggest that defective ceramide degradation is a primary abnormality, which leads to accumulation of ceramide in muscle and the subsequent development of insulin resistance.…”