The Path to Insulin Resistance: Paved with Ceramides?
2007; Cell Press; Volume: 5; Issue: 3 Linguagem: Inglês
10.1016/j.cmet.2007.02.005
ISSN1932-7420
Autores Tópico(s)Cholesterol and Lipid Metabolism
ResumoObesity-associated, system-wide elevations in free fatty acids, tumor necrosis factor α, and glucocorticoids increase intracellular lipid metabolites and promote insulin resistance. In this issue, Holland et al., 2007Holland W.L. Brozinick J.T. Wang L.-P. Hawkins E.D. Sargent K.M. Liu Y. Narra K. Hoehn K.L. Knotts T.A. Siesky A. et al.Cell Metab. 2007; 5 (this issue): 167-179Abstract Full Text Full Text PDF PubMed Scopus (825) Google Scholar provide pharmacological and genetic evidence that ceramide plays a key role in the development of insulin resistance induced by these factors. Obesity-associated, system-wide elevations in free fatty acids, tumor necrosis factor α, and glucocorticoids increase intracellular lipid metabolites and promote insulin resistance. In this issue, Holland et al., 2007Holland W.L. Brozinick J.T. Wang L.-P. Hawkins E.D. Sargent K.M. Liu Y. Narra K. Hoehn K.L. Knotts T.A. Siesky A. et al.Cell Metab. 2007; 5 (this issue): 167-179Abstract Full Text Full Text PDF PubMed Scopus (825) Google Scholar provide pharmacological and genetic evidence that ceramide plays a key role in the development of insulin resistance induced by these factors. The modern "super-size me" society offers an abundance of high-energy foods that are fueling the fires of obesity-induced insulin resistance. Obesity is now recognized as one of the predisposing factors for the development of insulin resistance in skeletal muscle and liver and a major contributor to the worldwide escalation in the incidence of non-insulin-dependent (type 2) diabetes mellitus. Cushing's syndrome is a rare disorder caused by systemic glucocorticoid excess that shares many metabolic and morphological similarities with obesity, including insulin resistance, visceral obesity, hypertension, and dyslipidemia. The overlapping phenotype between clinical profiles associated with obesity and Cushing's syndrome raises the possibility of a common molecular mechanism for disease onset. Given the disease burden and health costs associated with the rising prevalence of obesity and common morbidities such as type 2 diabetes, hypertension, cardiac failure, and atherosclerosis, efforts to identify and validate mechanisms for the cause and cure of metabolic disorders are warranted. Emerging evidence suggests that nutrient excess is associated with an increase in specific lipid-derived metabolites that inactivate signaling intermediates and cause insulin resistance. However, the mechanism by which specific lipid metabolites cause insulin resistance is incompletely resolved. In this issue of Cell Metabolism, Summers and colleagues (Holland et al., 2007Holland W.L. Brozinick J.T. Wang L.-P. Hawkins E.D. Sargent K.M. Liu Y. Narra K. Hoehn K.L. Knotts T.A. Siesky A. et al.Cell Metab. 2007; 5 (this issue): 167-179Abstract Full Text Full Text PDF PubMed Scopus (825) Google Scholar) identify the sphingolipid metabolite ceramide as a common molecular intermediate linking excess nutrients (i.e., saturated fatty acids, but not unsaturated fats) and glucocorticoids to the induction of insulin resistance. Several mechanisms have been proposed to explain how increased adipose mass affects whole-body insulin sensitivity. One theory is that adipose-tissue-derived cytokines induce a chronic inflammatory state that antagonizes insulin signaling and mitochondria function, thereby impairing glucose homeostasis (Hotamisligil, 2006Hotamisligil G.S. Nature. 2006; 444: 860-867Crossref PubMed Scopus (5614) Google Scholar). Another popular theory is based on evidence that excessive accumulation of lipid molecules in nonadipose tissues that are not suited for fat storage leads to the buildup of metabolites that stimulate negative feedback pathways to inhibit insulin signaling and metabolism (McGarry, 2002McGarry J.D. Diabetes. 2002; 51: 7-18Crossref PubMed Scopus (1162) Google Scholar). These mechanisms likely contribute to the downregulation of insulin signaling in peripheral tissues. Excessive levels of free fatty acids (FFAs), tumor necrosis factor α (TNFα), and glucocorticoids, through different mechanisms, stimulate the accumulation of the sphingolipid ceramide and various ceramide metabolites (Summers and Nelson, 2005Summers S.A. Nelson D.H. Diabetes. 2005; 54: 591-602Crossref PubMed Scopus (137) Google Scholar). Conversely, exercise training, which also improves insulin sensitivity, is associated with depletion of skeletal muscle ceramide (Dobrzyn and Gorski, 2002Dobrzyn A. Gorski J. Am. J. Physiol. Endocrinol. Metab. 2002; 282: E277-E285PubMed Google Scholar). Ceramide synthesis is dependent on the availability of long-chain saturated fats, which participate in the initial rate-limiting reaction involving the condensation of palmitoyl-CoA and serine, by a reaction catalyzed by serine palmitoyltransferase (SPT) to produce 3-oxosphinganine (Hannun, 1994Hannun Y.A. J. Biol. Chem. 1994; 269: 3125-3128Abstract Full Text PDF PubMed Google Scholar). The availability of palmitoyl-CoA and serine strongly influences the rate of this reaction. Subsequent reactions lead to the sequential synthesis of sphinganine, dihydroceramide, and ceramide, with the latter acting as a precursor of most active sphingolipids (Mathias et al., 1998Mathias S. Pena L.A. Kolesnick R.N. Biochem. J. 1998; 335: 465-480Crossref PubMed Scopus (605) Google Scholar). The synthesis of biologically active ceramide is completed by dihydroceramide desaturase (DES1). Although ceramides are one of the component lipids that make up sphingomyelin, a major lipid in the lipid bilayer, they also play an important role as an intracellular signaling molecule. Increased ceramide synthesis in response to excessive TNFα, saturated FFAs, or glucocorticoids is associated with an inhibition of insulin signal transduction by inhibiting Akt/PKB phosphorylation and activation (Figure 1). Ceramide promotes the dephosphorylation of Akt/PKB by protein phosphatase 2A (PP2A) (Dobrowsky et al., 1993Dobrowsky R.T. Kamibayashi C. Mumby M.C. Hannun Y.A. J. Biol. Chem. 1993; 268: 15523-15530Abstract Full Text PDF PubMed Google Scholar) and blocks the translocation of Akt/PKB from the cytoplasm to the plasma membrane (Stratford et al., 2004Stratford S. Hoehn K.L. Liu F. Summers S.A. J. Biol. Chem. 2004; 279: 36608-36615Crossref PubMed Scopus (287) Google Scholar). Holland et al., 2007Holland W.L. Brozinick J.T. Wang L.-P. Hawkins E.D. Sargent K.M. Liu Y. Narra K. Hoehn K.L. Knotts T.A. Siesky A. et al.Cell Metab. 2007; 5 (this issue): 167-179Abstract Full Text Full Text PDF PubMed Scopus (825) Google Scholar used pharmacological agents and genetically modified animals to test whether inhibition of ceramide synthesis improves glucose homeostasis in rodent models of insulin resistance, obesity, and diabetes. They report that myriocin, an antifungal compound that inhibits SPT, improves glucose tolerance in glucocorticoid-treated rats. Myriocin pretreatment partially maintained skeletal muscle insulin sensitivity and completely preserved hepatic insulin sensitivity in vivo, coincident with improved insulin action at the level of Akt/PKB. Treatment also lowered ceramide levels and prevented the progressive development of metabolic abnormalities in Zucker diabetic fatty rats. Myriocin failed to prevent lipid induction of inflammatory cytokines, indicating that the compound works independently or downstream of inflammatory modulators. From these pharmacological studies, the authors conclude that ceramide inactivation of Akt/PKB is a contributing mechanism by which the sphingolipid impairs insulin action. Future studies in which Akt/PKB signaling is genetically perturbed should be able to more definitely address its role in ceramide-mediated insulin resistance in skeletal muscle or liver. Using a more direct approach to target key enzymes in the ceramide synthesis pathway, the authors used DES1 knockout mice to address whether specifically targeting this enzyme, which converts metabolically inactive dihydroceramide into active ceramide in most peripheral tissues, modifies insulin sensitivity. Des1 null mice were runted and sickly, highlighting the importance of ceramides in normal physiology. Importantly, partial reduction of the DES1 enzyme in heterozygous knockout mice reduced the ratio of active ceramide to inactive dihydroceramide and lowered sphingolipid levels. The Des1 haploinsufficient mice exhibited enhanced insulin sensitivity and protection against dexamethasone-induced insulin resistance. Despite the caveats associated with the null phenotype, this work validates DES1 as a potential therapeutic target for the prevention of insulin resistance caused by nutrient excess or glucocorticoid therapy. While lipid metabolites are gaining recognition as signal transducers, there is a growing appreciation that not all fats are alike. Unsaturated fats, derived from plants, are considered "healthy," whereas saturated fats, derived from animal products, are considered "unhealthy." Consequently, the lipid metabolites derived from these different forms of fat may play specialized roles as signal transducers. Holland et al., 2007Holland W.L. Brozinick J.T. Wang L.-P. Hawkins E.D. Sargent K.M. Liu Y. Narra K. Hoehn K.L. Knotts T.A. Siesky A. et al.Cell Metab. 2007; 5 (this issue): 167-179Abstract Full Text Full Text PDF PubMed Scopus (825) Google Scholar highlight a dichotomy between the mechanisms by which saturated versus unsaturated fats cause insulin resistance. Saturated fats induce insulin resistance through a ceramide-dependent pathway; unsaturated fats do so through other lipid intermediates such as fatty acyl-CoAs and diacylglycerol. While ceramide-dependent mechanisms appear to contribute to the development of insulin resistance induced by saturated fats, the contribution of ceramide-independent metabolites to the insulin-resistance phenotype cannot be completely excluded. For example, diacylglycerides have been implicated in the development of insulin resistance (Turinsky et al., 1990Turinsky J. O'Sullivan D.M. Bayly B.P. J. Biol. Chem. 1990; 265: 16880-16885Abstract Full Text PDF PubMed Google Scholar) via activation of protein kinase C isoforms and negative feedback on the insulin signaling cascade (Itani et al., 2002Itani S.I. Ruderman N.B. Schmieder F. Boden G. Diabetes. 2002; 51: 2005-2011Crossref PubMed Scopus (1054) Google Scholar). These observations highlight diacylglycerol as an attractive candidate for peripheral insulin resistance since levels of this lipid metabolite are increased during lipid infusions and fat feeding. These findings warrant future studies to unravel the relative contribution of excessive ceramide versus diacylglyceride content to the insulin-resistance phenotype in humans. Part of the metabolic mystery of the deleterious effects of saturated fats and excessive glucocorticoids on insulin sensitivity may be explained by an accumulation of ceramide and impairments of insulin signaling. Future efforts to validate the role of ceramide-induced insulin resistance will require pharmacological approaches that offer greater specificity in modulating DES1 or other key regulators in the ceramide biosynthesis pathway, such as SP1 or dihydroceramide synthase. Genetic studies in humans to ascertain whether obesity-induced insulin resistance can be attributed to polymorphisms in the ceramide synthesis pathway may reveal the clinical importance of this pathway in human disease. For example, are functional single-nucleotide polymorphisms (SNPs) present in key enzymes of this pathway, and if so, do they render an individual more sensitive or resistant to the accumulation of ceramides and the ensuing effect of this lipid metabolite on insulin sensitivity? Finally, whether these results can be translated from bench to bedside to treat obesity- or glucocorticoid-induced insulin resistance in humans remains an open question. Nonetheless, Holland et al., 2007Holland W.L. Brozinick J.T. Wang L.-P. Hawkins E.D. Sargent K.M. Liu Y. Narra K. Hoehn K.L. Knotts T.A. Siesky A. et al.Cell Metab. 2007; 5 (this issue): 167-179Abstract Full Text Full Text PDF PubMed Scopus (825) Google Scholar have shown that targeting the ceramide biosynthesis pathway can dampen the flames of lipid-metabolite-induced insulin resistance. Inhibition of Ceramide Synthesis Ameliorates Glucocorticoid-, Saturated-Fat-, and Obesity-Induced Insulin ResistanceHolland et al.Cell MetabolismMarch 07, 2007In BriefInsulin resistance occurs in 20%–25% of the human population, and the condition is a chief component of type 2 diabetes mellitus and a risk factor for cardiovascular disease and certain forms of cancer. Herein, we demonstrate that the sphingolipid ceramide is a common molecular intermediate linking several different pathological metabolic stresses (i.e., glucocorticoids and saturated fats, but not unsaturated fats) to the induction of insulin resistance. Moreover, inhibition of ceramide synthesis markedly improves glucose tolerance and prevents the onset of frank diabetes in obese rodents. Full-Text PDF Open Archive
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