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A Role for Sphingolipids in Producing the Common Features of Type 2 Diabetes, Metabolic Syndrome X, and Cushing’s Syndrome
     Division of Endocrinology, Metabolism and Diabetes, University of Utah School of Medicine, Salt Lake City, Utah

    ABSTRACT

    Metabolic syndrome X and type 2 diabetes share many metabolic and morphological similarities with Cushing’s syndrome, a rare disorder caused by systemic glucocorticoid excess. Pathologies frequently associated with these diseases include insulin resistance, atherosclerosis, susceptibility to infection, poor wound healing, and hypertension. The similarity of the clinical profiles associated with these disorders suggests the influence of a common molecular mechanism for disease onset. Interestingly, numerous studies identify ceramides and other sphingolipids as potential contributors to these sequelae. Herein we review studies demonstrating that aberrant ceramide accumulation contributes to the development of the deleterious clinical manifestations associated with these diseases.

    Metabolic syndrome X (1), type 2 diabetes (2), and Cushing ’s syndrome (3) share a common set of pathogenic characteristics. A hallmark of these diseases is insulin resistance, i.e., when a maximal dose of the hormone is incapable of optimally eliciting its pleiotropic biological effects (e.g., stimulation of glucose uptake and glycogen, protein, and lipid synthesis in skeletal muscle). Other common disorders associated with these diseases include atherosclerosis, susceptibility to infection, poor wound healing, and hypertension. An enigma plaguing scientists has been to understand how these syndromes with markedly different etiologies share such a common clinical profile.

    Obesity predisposes individuals to both type 2 diabetes and metabolic syndrome X, but the mechanism by which increased adiposity induces defects in tissues other than adipose has remained elusive. A hypothesis gaining credibility is that increased deposition of lipid molecules in tissues not suited for fat storage, because of increased exposure to free fatty acids (4), induces these health complications (5,6). An alternative explanation is that fat-derived circulating factors initiate the various deleterious manifestations of these diseases (7eC9). For example, adipose tissue secretes factors that regulate insulin sensitivity in peripheral tissues (e.g., tumor necrosis factor [TNF-]-, interleukin 6, resistin, adiponectin, and leptin), produce an inflammatory response (e.g., TNF- and interleukin 6), induce vasoconstriction (i.e., angiotensinogen, the precursor for the vasoactive peptide angiotensin 2), and inhibit fibrinolysis (i.e., plasminogen activator inhibitor 1).

    Cushing’s syndrome results from excessive secretion of glucocorticoids that produce the sequelae listed above. While individuals with this disease generally display increased central adiposity and elevated circulating free fatty acid (FFA) levels, these conditions are likely to be a consequence of insulin resistance, rather than the primary cause. First, glucocorticoids induce insulin resistance within hours of administration and can do so independently of circulating FFAs (10,11). Second, dexamethasone directly antagonizes the effects of insulin when added to isolated cells or tissues (12eC15).

    Interestingly, FFAs, TNF-, and glucocorticoids, through different mechanisms, stimulate the accumulation of ceramide and various ceramide metabolites (16eC24), and these sphingolipids have been shown to amass in tissues from insulin-resistant rodents (25,26) and humans (27,28). Moreover, studies in isolated cells or tissues reveal putative roles for ceramide or its derivatives in either the onset or the progression of many of the pathologies associated with these diseases. Herein we review literature suggesting that aberrant sphingolipid accumulation accounts for some of the common clinical findings in type 2 diabetes, metabolic syndrome X, and Cushing’s syndrome.

    INCREASED SPHINGOLIPID PRODUCTION IN TYPE 2 DIABETES, METABOLIC SYNDROME X, AND CUSHING’S SYNDROME

    To understand how FFAs, TNF-, and glucorticoids regulate sphingolipid production, one needs to understand the biochemical pathways underlying ceramide synthesis and degradation. Although sphingolipids represent a significant dietary component, they are largely degraded in the mammalian intestine (29), and their production in animal tissues is primarily dependent on a widespread biosynthetic pathway (30). The initial, rate-limiting reaction is the condensation of palmitoyl CoA and serine, a reaction catalyzed by serine palmitoyltransferase (SPT), to produce 3-oxosphinganine (Fig. 1). The mechanisms underlying the regulation of this enzyme are largely unknown, but the availability of palmitoyl-CoA and serine strongly influences the rate of this reaction. Three reactions follow, resulting in sphinganine dihydroceramide ceramide production. Once generated, ceramide is a basic building block for numerous additional sphingolipid derivatives including sphingomyelin, sphingosine 1-phosphate (S1P), ceramide 1-phosphate, and a large family of glucosylceramides (Fig. 2).

    Saturated FFAs and ceramide synthesis.

    Intramyocellular lipid concentrations correlate more tightly with the severity of insulin resistance than other known risk factors, including BMI, percent body fat, waist-to-hip ratio, or age (6). In particular, numerous dietary and epidemiological studies in human populations indicate that saturated fats markedly decrease insulin responsiveness in peripheral tissues, while unsaturated fats have weaker or in some cases insulin-sensitizing effects (rev. in 31). These observations have prompted researchers to search for metabolites of saturated FFAs that inhibit insulin signaling or action. The most prevalent saturated FFA in both the circulation and in muscle is palmitate (32), which stimulates de novo ceramide synthesis by fueling the pathway with substrate (i.e., palmitoyl-CoA) (22eC24) and, in at least one cell type examined, by inducing expression of SPT (33). Using C2C12 myotubes, the saturated FFAs stearate (18:0), arachidate (20:0), and lignocerate (24:0), which all have hydrocarbon tails longer than that of palmitate, were also shown to induce ceramide accrual (24). By contrast, neither unsaturated FFAs nor saturated FFAs with hydrocarbon chains shorter than that of palmitate (i.e., laurate [12:0] and myristate [14:0]) stimulated ceramide accumulation. The mechanism by which longer FFAs might induce ceramide synthesis is unclear, as SPT has a great deal of specificity for FFAs with 16 ± 1 carbon atoms (30). We hypothesize that long-chain saturated FFAs selectively induce ceramide accumulation by increasing the intracellular pool of palmitoyl-CoA, either by being oxidized themselves to the shorter C16 form or by protecting the endogenous palmitoyl-CoA from further metabolism.

    TNF- and ceramide synthesis.

    The observation that ceramide plays a role in TNF- signaling initially derived from studies investigating the cytokine’s ability to regulate differentiation of HL60 promyelocytic leukemia cells. Briefly, the ability of TNF- to induce HL60 cell differentiation corresponded with its ability to hydrolyze sphingomyelin, and the addition of C2-ceramide, a short-chain ceramide analog, was sufficient to induce cell differentiation in the absence of exogenous TNF- (18). More recent studies have identified ceramide as a requisite intermediate for many of the cytokine’s biological effects (34,35). TNF- acutely produces ceramide by activating neutral and acidic forms of sphingomyelinase (19,36eC38). Moreover, TNF- also stimulates de novo ceramide synthesis, although the mechanism underlying this effect is unclear (20,21).

    Glucocorticoids and ceramide synthesis.

    The discovery that glucocorticoids have a large and specific effect on sphingolipids derived from studies addressing the theory that the broad scope of corticosteroid action was due to the ability of different hormones to directly modify membrane lipids (39). Specifically, the well-recognized importance of corticosteroids in protection against stress was considered to possibly relate to membrane fluidity, which is involved in the adaptation of bacteria, fish, and hibernating animals to extremes of heat and cold (40). To investigate this possibility, investigators quantified the fatty acid, phospholipid, and sphingolipid composition of membranes in various cell types incubated with dexamethasone. Notably, the glucocorticoid increased membrane sphingomyelin in rat epididymal fat cells (41). Dexamethasone was subsequently shown to increase sphingomyelin levels in HeLa cells (42) and human polymorphonuclear leukocytes (17), ceramide levels in a murine B lymphoma cell line (16), and sphingosine levels in 3T3-L1 preadipocytes (43). In vivo, epididymal fat cell ghosts isolated from adrenalectomized rats demonstrated decreased sphingomyelin levels, which could be restored by the administration of dexamethasone (44). By contrast, these researchers detected no change in either the levels or fatty acid composition of phospholipids, nor did they detect a change in cellular cholesterol levels.

    Recent studies have investigated the mechanism by which glucocorticoids regulate sphingolipid production. Dexamethasone increases the expression and/or activity of SPT (45) and neutral and acidic forms of sphingomyelinase (17,43,46,47). These observations are consistent with the established roles of glucocorticoid receptors as transcription factors whose entry into the nucleus is regulated by ligand binding. Interestingly, Cifone et al. (47) demonstrated that dexamethasone also acutely stimulates ceramide accumulation (i.e., within 15 min of dexamethasone addition) in thymocytes by activating acid sphingomyelinase.

    ROLE OF CERAMIDES IN INSULIN RESISTANCE

    Since the majority of glucose disposal occurs in skeletal muscle, insulin resistance in this tissue is generally thought to contribute most significantly to the glucose intolerance associated with nutrient or glucocorticoid oversupply. Thus far, ceramide has been shown to accumulate in insulin-resistant muscles in both rodents (25,26) and humans (27,28). Moreover, Straczkowski et al. (28) described a negative correlation between ceramide content of muscles and insulin sensitivity in 13 human subjects and further demonstrated that lipid infusion markedly elevated ceramide levels while decreasing insulin sensitivity. Exercise training, which improves insulin sensitivity, markedly decreases muscle ceramide levels in both rats and humans (48eC50). Although the increase in ceramide seen in these samples is modest, recent studies in cultured myotubes indicate that inducing a comparable increase (1.5- to 2-fold) in endogenous ceramide is sufficient to inhibit insulin signaling (23,24).

    Inhibition of insulin signaling and action by ceramides.

    Insulin accelerates glucose entry into skeletal muscle and adipose tissue by evoking the translocation of GLUT4 glucose transporters from intracellular stores to the plasma membrane. Simultaneously, the hormone regulates numerous metabolic enzymes (e.g., glycogen synthase or pp70 S6-kinase) to promote storage of the incoming glucose as glycogen, triglyceride, or protein. Insulin initiates these responses through its receptor, a tyrosine kinase, which subsequently phosphorylates a family of insulin receptor substrates (IRSs) (IRS-1, IRS-2, etc.). The phosphorylated IRS proteins activate a signaling pathway involving the sequential activation of phosphatidylinositol 3-kinase (PI3K) and Akt/protein kinase B (PKB), which are obligate intermediates in insulin’s metabolic, antiapoptotic, and mitogenic effects (51).

    Ceramide acutely inhibits insulin-stimulated glucose uptake, GLUT4 translocation, and/or glycogen synthesis in cultured adipocytes and/or muscle (52eC55). These effects appear to result from the sphingolipid’s ability to block activation of either IRS-1 or Akt/PKB (Fig. 3). Specifically, in 1996, two independent laboratories found that treating cultured cells with short-chain ceramide analogs or bacterial sphingomyelinases, which hydrolyze sphingomyelin to form choline and ceramide (Fig. 1), blocked insulin-stimulated tyrosine phosphorylation of IRS-1 and its subsequent recruitment and activation of PI3K (56,57). A third group found that ceramide directly inhibited PI3K isolated from serum-stimulated cells (58). However, the effect of ceramide on IRS and/or PI3K appears to be specific to certain cells or treatment conditions, as a number of different laboratories have shown that ceramide has no effect on PI3K or the production of its lipid products (23,53eC55,59eC60). In all cell types tested, however, ceramide has been shown to block activation of Akt/PKB "downstream" of PI3K by either inhibiting its translocation to the cell membranes (61eC63) and/or by promoting its dephosphorylation via protein phosphatase 2A (23,60,62,64eC66). While acute treatment with ceramides has these effects on insulin signaling, prolonged treatment of 3T3-L1 adipocytes with the sphingolipid was shown to downregulate GLUT4 expression (67).

    Role of ceramides in FFA-induced insulin resistance.

    Skeletal muscles exposed to excess lipid demonstrate decreased sensitivity to insulin. For example, incubating isolated muscle strips or cultured muscle cells with FFAs (22,68eC71), infusing lipid emulsions into rodents or humans (72eC75), or expressing lipoprotein lipase in skeletal muscle of transgenic mice (76,77) promotes intramyocellular lipid accumulation and compromises insulin-stimulated glucose uptake. To evaluate the role of ceramides in the insulin resistance associated with lipid oversupply, scientists have investigated the lipid’s role in FFA-induced insulin resistance using cultured myotubes. Schmitz-Pfeiffer et al. (22) first observed that treating C2C12 myotubes with concentrations of saturated FFAs within the physiological serum range increased the intracellular pool of ceramide, while simultaneously inhibiting activation of Akt/PKB, but not PI3K. In this cell type, short-chain ceramide analogs recapitulated this pattern of effects on insulin signal transduction. The authors thus speculated that ceramide was the primary intermediate linking saturated fats to the inhibition of insulin signaling. To definitively identify a role for ceramide as an intermediate in these effects of saturated FFAs in C2C12 myotubes, Chavez et al. (23) demonstrated that inhibitors of the biosynthetic enzymes SPT or dihydroceramide synthase prevented the effects of palmitate on both ceramide accumulation and Akt/PKB. Moreover, inhibitors of ceramide degradation (i.e., its glycosylation or deacylation) were shown to both mimic and exacerbate the palmitate effect on ceramide accrual and insulin signaling (23). Collectively these studies strongly indicate that ceramide is required for the inhibitory effects of saturated FFAs in cultured myotubes.

    Of note, researchers recently demonstrated that infusing a lipid mixture enriched in unsaturated fatty acids into rodents may induce insulin resistance through a ceramide-independent mechanism. Specifically, infusion of Liposyn II (Abbott, North Chicago, IL), a triglyceride emulsion that is predominantly comprised of the fatty acid linoleate (18:2), induced insulin resistance by inhibiting insulin signaling to IRS-1 and PI3K (78). This lipid cocktail did not affect Akt2/PKB- or glycogen synthase kinase 3- (79), nor did it induce ceramide accumulation (75,78). In a subsequent study, a lipid emulsion of comparable composition was shown to increase muscle ceramide levels in humans, and the authors speculated that different methods of muscle preparation may account for the opposite findings (28). Nonetheless, the relative absence of saturated fats in this cocktail makes it unlikely to markedly induce ceramide synthesis, which is dependent on the availability of palmitate. Quite possibly, different types of fat induce insulin resistance through distinct mechanisms, with saturated FFAs inducing insulin resistance through a ceramide-dependent pathway and unsaturated ones doing so through another lipid intermediate (e.g., diacylglycerol). Indeed, some evidence supports the hypothesis that diacylglycerol comprised of predominantly unsaturated FFAs is a potent activator of certain intracellular substrates (e.g., protein kinase C), while that composed of saturated fatty acids is a relatively poor agonist (80,81). An important future step will be to determine whether ameliorating ceramide accumulation, using either pharmacological or genetic manipulation strategies, quantitatively improves insulin sensitivity in intact organisms, such as insulin-resistant rodents.

    Role of ceramides in TNF-eCinduced insulin resistance.

    TNF- is a proinflammatory cytokine that inhibits insulin-stimulated glucose uptake and/or hepatic glucose production when administered to either cultured cells (82) or animals (83). Obesity increases expression of TNF- in white adipose tissue, prompting speculation that the cytokine induces insulin resistance in cases of increased adiposity. Although concentrations found in the circulation of obese patients are typically low, even in obese individuals, researchers have speculated that TNF- functions in an autocrine or paracrine manner and is secreted from fat cells pervading muscle tissue in obese animals (84) or directly from muscle (85). Neutralization of TNF- activity, either by infusing fa/fa Zucker rats with a soluble TNF receptor lgG fusion protein or by crossing insulin-resistant mice with knockout mice lacking either TNF- or TNF- receptors, was shown previously to increase peripheral insulin sensitivity (86,87). Although the systemic administration of a TNF-eCneutralizing antibody failed to improve insulin sensitivity in humans (88), the effectiveness of this strategy at negating TNF- activity could not be confirmed directly, and scientists speculate that increased TNF- levels could exacerbate the insulin-resistant condition.

    Under conditions whereby TNF- inhibits insulin signaling, the cytokine promotes ceramide accumulation in brown adipocytes (60), 3T3-L1 adipocytes, and C2C12 myotubes (A. Chavez, S.A.S., unpublished observation). Moreover, like ceramides, TNF- has been shown to block insulin signaling at the level of IRS-1 and Akt/PKB, depending on the cell type being examined (57,60,89,90), and to decrease the expression of IRS-1 and GLUT4 (91). Could ceramide mediate the inhibitory effects of TNF- on insulin signaling In myeloid 32D progenitor cells and 3T3-L1 adipocytes, the effects of TNF- on IRS-1 were recapitulated by the addition of exogenous bacterial sphingomyelinase or ceramides (57). In brown adipocytes, TNF- was shown to promote the dephosphorylation of Akt/PKB by activating PP2A (60). In this cell type, exogenous ceramides again recapitulated these TNF- effects, and the PP2A inhibitor okadaic acid prevented the effects of both antagonists. The authors concluded that ceramide was the principle mediator of the signaling pathway linking TNF- to the inhibition of insulin signaling.

    Role of ceramides in glucocorticoid-induced insulin resistance.

    When added to cultured cells or isolated tissues, glucocorticoids block glucose uptake (12eC15,92eC95) and glycogen and protein (96eC98) synthesis, but the mechanisms underlying these inhibitory effects remain unclear. Studies both in vitro and in vivo have demonstrated that dexamethasone decreases expression and/or activation of insulin receptors, IRS-1, or PI3K (99eC101), but others have failed to see inhibition by dexamethasone at these early signaling steps (102eC105). The inconsistencies between studies done in vivo may be explained by differing degrees of hyperinsulinemia under the different treatment regimes. When the compensatory increase in insulin levels was prevented, the effects on insulin receptor levels or binding affinity were abolished (106). Further downstream, corticosteroids have been shown to blunt the phosphorylation of Akt/PKB, 4E-BP1, p70S6K, and glycogen synthase (97,98,100,107eC109) and to inhibit the translocation and expression of GLUT4 (14,15). Elucidating the mechanisms underlying these antagonistic actions of glucocorticoids is not only important for comprehending the pathogenesis of Cushing’s syndrome, but is also extremely relevant for understanding the complications associated with exogenous glucocorticoid therapy.

    As described above, glucorticoids activate synthetic pathways promoting sphingolipid formation in a wide variety of tissues, including insulin-responsive ones. In adipocytes, for example, low doses of dexamethasone, which antagonize insulin-stimulated glucose uptake (110), selectively increase sphingolipid levels (41). By contrast, adrenalectomy, which increases insulin sensitivity in adipocytes (111), markedly decreases adipocyte sphingolipid levels (44). An important aspect of these studies is the remarkable size and specificity of the glucocorticoid effect. In 3T3-L1 preadipocytes, for example, glucocorticoids induce a 50% increase in membrane sphingomyelin levels within 3 h after their addition, without affecting phospholipids or cholesterol (112). Based on studies in cultured cells (23,24), one would predict that increasing ceramide levels by this amount would be likely to block insulin action.

    Though sphingolipids have been shown to be obligate intermediates in the pathways linking glucocorticoids to the regulation of various biological processes (e.g., thymocyte apoptosis [46]), researchers have yet to perform analogous studies determining whether ameliorating ceramide accumulation abates the glucocorticoid effect on insulin signaling or action. Nonetheless, two studies suggest that dexamethasone and ceramide inhibit insulin sig-naling and action using a common pathway. In L6 myoblasts, the effects of dexamethasone on distal constituents of the PI3K/Akt signaling pathway {i.e., ribosomal protein S6 kinase [p70(S6k)] and the cap-dependent translational repressor, eukaryotic initiation factor 4E (eIF4E)} were blocked by okadaic acid and calyculin A (109), which, as described above, have been shown to reverse the effects of ceramide on insulin signaling (24,60,66). Moreover, in 3T3-L1 cells, the inhibitory effects of sphingosine, sphinganine, or dexamethasone on glucose transport were not additive (113). Collectively, these studies suggest the involvement of redundant intracellular mechanisms linking both sphingolipids and glucocortiocids to the regulation of insulin signaling or action.

    ROLES OF SPHINGOLIPIDS IN OTHER FEATURES OF CUSHING’S SYNDROME, TYPE 2 DIABETES, AND THE METABOLIC SYNDROME

    In addition to having marked effects on insulin sensitivity, ceramide and its metabolites are implicated in a wide array of different biological processes. Interestingly, many of the complications evident in individuals with Cushing’s syndrome, type 2 diabetes, and metabolic syndrome X may be significantly influenced by increased sphingolipid deposition in other tissues. Herein we discuss evidence supporting a role for sphingolipids in the cardiovascular and immune systems.

    Atherosclerosis.

    Aggregation of LDLs within the arterial wall is a critical step in the initiation of atherosclerosis. These circulating entities consist of a core of cholesterol esters and triacylglycerols surrounded by a surface film containing apolipoprotein B-100, phosphtidylcholine, sphingomyelin, and cholesterol. LDLs extracted from atherosclerotic lesions are either aggregated or prone to aggregate (114,115). Interestingly, the ceramide content of these aggregated LDLs is 10- to 50-fold higher than that of plasma LDL (116). In fact, nonaggregated LDLs isolated from the same lesions are not enriched in ceramide, suggesting that ceramides could drive associations between LDLs. Support for this hypothesis derives from studies using isolated LDLs or artificial lipid vesicles, as exposing LDL particles to a small amount of bacterial sphingomyelinase was shown to promote LDL aggregation (116), and biophysical studies with artificial vesicles reveal that ceramides have a pronounced tendency for self-aggregation (117,118). Ceramide present in these plaques may be produced by secreted forms of neutral sphingomyelinase, which associate with the LDL particle but not with VLDLs or VHDLs (119).

    Scientists have also proposed roles for ceramide or its metabolites in other steps of atherogenesis (120,121). First, ceramide and sphingosine have been shown to induce apoptosis of certain cells lining the vascular wall, a process implicated in plaque erosion and thrombosis (122,123). In fact, increased myocardial levels of ceramide have been linked to cardiac myocyte apoptosis and the resulting cardiac dysfunction associated with obesity (124). Second, the ceramide metabolite S1P stimulates the proliferation of endothelial and smooth muscle cells in vascular walls (125,126), which would promote thickening and favor plaque stabilization. Third, ceramide, lactosyl ceramide, or S1P mediate an inflammatory response initiated by cytokines or oxidized LDL, which upregulates adhesion molecule expression and induces adhesion and migration of monocytes, important events in initiation and progression of atherogenesis (127). Fourth, various sphingolipids, by modulating platelet activation and aggregation (128eC130), may favor thrombosis.

    Hypertension.

    Hypertension results from increased peripheral resistance, which maintains elevated levels of arterial blood pressure. The increase in peripheral resistance results, in part, from abnormal constrictor and dilator responses and vascular remodeling. Though a clear picture has not yet emerged, accumulating evidence suggests that ceramide or its metabolites play important roles in regulating vascular tone (131).

    One mechanism by which sphingolipids might contribute to hypertension is by altering membrane fluidity, which has been shown to be decreased in hypertensive rats. Because of the extensive intermolecular hydrogen bonding between ceramides, they have been shown to markedly decrease membrane fluidity (132). Interestingly, Dorrance et al. (133) observed that membrane sphingomyelin levels were elevated in erythrocyte membranes isolated from stroke-prone, spontaneously hypertensive rats.

    Alternatively, several studies reveal potent vasoactive roles for various sphingolipid metabolites. For example, treating arterial rings with ceramide or sphingomyelinase has been shown to induce an endothelium-independent, sustained contraction (134). Moreover, sphingosine has been shown to impair endothelium-dependent relaxation (135), and S1P and sphingophosphorylcholine have been reported to induce contraction of mesenteric and intrarenal microvessels (136) and coronary arterial strips (137) and to inhibit renal blood flow when given to rats (138). Interestingly, Bolz et al. (139) found that overexpressing sphingosine kinase type 1 in vascular smooth muscle cells of resistance arteries increased both resting tone and myogenic responses, while overexpression of a dominant-negative sphingosine kinase mutant completely inhibited these processes. Paradoxically, TNF- has been shown to have strong vasodilatory powers, and ceramide has been shown to mediate its endothelium-independent vasodilatory effects on aortic segments (140) and its endothelium dependent effects in coronary arteries (141). Moreover, the lipid has been shown to attenuate the contractile responses of phenylephrine (142).

    The development of hypertension in individuals with the metabolic disorders discussed herein might relate to the regulation of nitric oxide (NO), which has strong vasodilatory functions. Corticosteroids have been shown to inhibit NO production in endothelial cells (143) by both inhibiting NO synthase (144) and increasing production of superoxides (145), which are NO scavengers. In diabetic patients, vascular superoxide production is similarly increased due to dysfunctional endothelial NO synthase (146). Ceramides have been shown to attenuate the vasodilatory effects of bradykinin in coronary arteries by increasing superoxide production and thus lowering NO accumulation (147). Moreover, the ability of TNF- to inhibit endothelium-dependent relaxation of coronary arteries is blocked by the addition of either superoxide scavengers or acid sphingomyelinase inhibitors (141). Further complexity in the vessel wall response, however, is due to the fact that whereas sphingolipids can induce NO production, NO can promote ceramide generation (148eC150).

    Sphingolipids, the immune response, and susceptibility to infection.

    Patients with either diabetes or Cushing’s syndrome are particularly susceptible to infection. Interestingly, certain sphingolipids have been speculated to render one susceptible to infection by either facilitating the entry of viruses or bacteria into host cells or by decreasing an individual’s resistance to these pathogens.

    Due to their long, largely saturated acyl chains, sphingolipids tend to pack together in microdomains that exclude phospholipids. In the presence of cholesterol, these sphingolipids organize themselves in raft structures that can be isolated from other membrane fractions due to their insolubility to some nonionic detergents. Ceramide, because of its tendency to self-associate, induces the coalescence of microscopic rafts into large-membrane macrodomains. Raft domains have been shown to recruit certain types of cellular proteins, while excluding others, and are important for processes such as signal transduction, sorting, and endocytosis. Interestingly, an abundance of evidence indicates that these raft structures facilitate entry of various pathogens (151eC155). The importance of ceramides in pathogen entry is underscored in studies investigating Neisseria gonorrhoeae, Pseudomonas aeruginosa, Staphylococcus aureus, and Sindbis virus, which have been shown to activate acid sphingomyelinase to rapidly induce ceramide formation (156eC159). A strength of these studies was the observation that inactivation of acid sphingomyelinase greatly hindered pathogen internalization. In addition, the protozoan, Leishmania donovani, was shown to induce ceramide generation through both de novo synthesis and activation of sphingomyelinase, and the elevated ceramide was shown to facilitate the survival of leishmanial parasites in the intramacrophageal milieu (160). Rafts, in addition to playing a potential role in pathogen entry, have been shown to serve as platforms for viral assembly or budding (154).

    The susceptibility to infection for individuals with these diseases additionally involves an altered immune response that renders them susceptible to opportunistic pathogens. For example, uncontrolled diabetes demonstrates defective migration of polymorphonuclear leukocytes, which ingest and destroy microbes, as well as impaired phagocytosis of the invading pathogen (161). Similarly, glucocorticoids have been shown to inhibit superoxide production, which is important for the destruction of the invading agent, both in vitro and in vivo (162,163). Interestingly, ceramides have been shown to mimic these effects as well. For example, increasing endogenous ceramide levels to a maximal level terminates functional responses in polymorphonuclear leukocytes, as ceramide inhibits phagocytosis and blocks superoxide release (164eC167). Diabetic individuals additionally exhibit an exaggerated inflammatory response to microbial products, which further compromises healing (161), and ceramides or sphingosine have been shown to augment the inflammatory response of TNF- or other proinflammatory cytokines (168eC170). In addition, ceramides and other sphingolipids have been shown to positively or negatively affect the function of mononuclear phagocytes, mast cells, dendritic cells, natural killer cells, cytotoxic T-cells, B-cells, and others (rev. in 171). While a complete understanding of the role of these sphingolipids in the immune response is beyond the scope of this article, one can easily envision how globally altering sphingolipid levels could interfere with the development of an appropriate defense against invading pathogens.

    THIAZOLIDINEDIONES, GLUCOSE TRANSPORT, CORTICOSTEROIDS, AND SPHINGOLIPIDS

    Thiazolidinediones (TZDs), which serve as ligands for the peroxisome proliferatoreCactivated receptor (PPAR)- transcription factors, have been shown to reduce insulin resistance induced by nutrient (172,173) or corticosteroid (174) oversupply. Additional studies demonstrate protective effects toward atherosclerosis and hypertension (175eC177). The mechanism by which PPAR- improves insulin sensitivity in skeletal muscles is unclear, although many models have been proposed. In adipose tissue, which has the highest expression of PPAR-, these drugs have been shown to inhibit expression or secretion of TNF-, resistin, and interleukin-6 and to stimulate expression of the insulin-sensitizing adiponectin (rev. in 178). Moreover, TZDs decrease circulating FFA levels by increasing the number of adipocytes and stimulating the expression of genes promoting the incorporation of FFAs into triglycerol. Lastly, TZDs have been shown to downregulate 11- hydroxysteroid dehydrogenase-1, an enzyme that generates the active cortisol from the inactive precursor cortisone, and thus could influence adipocyte secretion of glucocorticoids. Interestingly, studies also reveal a direct role in skeletal muscle, as rodents lacking the PPAR- in muscle demonstrate muscle and hepatic insulin resistance (179,180).

    By decreasing circulating TNF- and FFA levels, TZDs might be expected to lower tissue ceramide levels in insulin-resistant rodents. Indeed, TZDs have been shown to reduce ceramide levels in cardiac muscle of obese Zucker rats (124). However, additional studies imply a direct relationship between sphingolipids and the actions of PPAR-. TZDs prevent the inhibitory effects of TNF- (181eC183), glucocorticoids (13), and C2-ceramide (183) on insulin signaling when added to isolated cells or tissues. Conversely, sphingolipids have been shown to antagonize the effects of PPAR-. Specifically, sphingomyelin downregulates PPAR- gene expression in 3T3-F442 adipo-cytes and is an independent predictor of insulin resistance in obese women (184,185). Ceramide has similarly been shown to inhibit PPAR- expression (186). Could ceramides themselves serve as antagonists of PPAR-, whose agonists include other lipid moieties such as certain FFAs and prostaglandins Sphinganine, but not ceramide, has been shown to bind directly to PPAR- (187). However, to this author’s knowledge, no reports have shown a direct interaction between sphingolipids and PPAR-.

    OUTSTANDING QUESTIONS AND FUTURE DIRECTIONS

    Type 2 diabetes, metabolic syndrome X, and Cushing’s disease share a variety of common metabolic and hormonal abnormalities that likely contribute to the progression of the disease, creating a cyclical and amplifying process underlying these health abnormalities. In searching for common molecular events that account for the long list of clinical complications, we considered the possibility that aberrant sphingolipid accumulation in peripheral tissues could contribute to the pathogenesis of these diseases. Review of the literature reveals that elevated sphingolipid production in peripheral tissues could contribute to the development of insulin resistance, atherosclerosis, hypertension, and susceptibility to infection (Fig. 4). Important hurdles remain, however. An important future step will be to determine whether ameliorating ceramide accumulation in rodent models of these diseases, using either pharmacological or genetic manipulation strategies, improves insulin sensitivity and prevents the host of cardiovascular and immunological abnormalities that develop. Moreover, the existing literature investigating the mechanisms by which FFAs, TNF-, glucocorticoids, and ceramides induce their biological effects have shown considerable variability, with little consensus between groups. An explanation for these marked differences in effect is lacking and is clearly a major challenge for researchers. Lastly, although sphingoid bases and their related compounds are the subject of >5,000 publications in the past decade (188), the mechanisms underlying their effects have remained both elusive and controversial (189). In addition to defining a role for sphingolipids in the pathogenesis of disease, studies investigating the mechanism by which ceramides participate in this diverse array of biological responses have the opportunity to shed needed light on the role of this complicated family of molecules as regulators of basic cell function.

    NOTE ADDED IN PROOF

    After acceptance of this manuscript, Hojjati et al. (J Biol Chem; in press) reported that treating the apoE-deficient mouse, a well-known model of atherosclerosis, with an inhibitor of ceramide biosynthesis decreased the appearance of atherosclerotic lesions. These findings further support a role for the spingolipid or its metabolites in the formation of atherosclerotic plaques.

    ACKNOWLEDGMENTS

    Work from the authors’ laboratories described in this article was supported by National Institutes of Health Grant DK-58784, the American Diabetes Association, and the Ben and Iris Margolis Foundation.

    The authors thank the members of their laboratories, particularly Jose Antonio Chavez, William Holland, Trina Knotts, and Dallen Herzog, for assisting with the preparation of this manuscript.

    FFA, free fatty acid; IRS, insulin receptor substrate; PI3K, phosphatidylinositol 3-kinase; PKB, protein kinase B; PPAR, peroxisome proliferatoreCactivated receptor; S1P, sphingosine 1-phosphate; SPT, serine palmitoyltransferase; TNF, tumor necrosis factor; TZD, thiazolidinedione

    REFERENCES

    Hansen BC: The metabolic syndrome X. Ann N Y Acad Sci892 :1 eC24,1999

    Saltiel AR: New perspectives into the molecular pathogenesis and treatment of type 2 diabetes. Cell104 :517 eC529,2001

    Nelson DH: The adrenal cortex: physiologic function and disease. In Major Problems in Internal Medicine. Vol.18 . Smith LH, Ed. Toronto, Canada, Saunders, p.281 ,1980

    Reich H, Nelson DH, Zaffaroni A: Isolation of 17-hydroxycorticosterone from blood obtained from adrenal veins of dogs. J Biol Chem187 :411 eC417,1950

    Unger RH: Minireview: Weapons of lean body mass destruction: the role of ectopic lipids in the metabolic syndrome. Endocrinology144 :5159 eC5165,2003

    McGarry JD: Banting Lecture 2001: Dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes51 :7 eC18,2002

    Rajala MW, Scherer PE: Minireview: The adipocyte—at the crossroads of energy homeostasis, inflammation, and atherosclerosis. Endocrinology144 :3765 eC3773,2003

    Saltiel AR: You are what you secrete. Nat Med7 :887 eC888,2001

    Guerre-Millo M: Adipose tissue and adipokines: for better or worse. Diabetes Metab30 :13 eC19,2004

    Tappy L, Randin D, Vollenweider P, Vollenweider L, Paquot N, Scherrer U, Schneiter P, Nicod P, Jequier E: Mechanisms of dexamethasone-induced insulin resistance in healthy humans. J Clin Endocrinol Metab79 :1063 eC1069,1994

    Pellacani A, Fornengo P, Bruno A, Ceruti C, Mioletti S, Curto M, Rinaudo MT, Pagano G, Cavallo-Perin P: Acute methylprednisolone administration induces a transient alteration of glucose tolerance and pyruvate dehydrogenase in humans. Eur J Clin Invest29 :861 eC867,1999

    Sakoda H, Ogihara T, Anai M, Funaki M, Inukai K, Katagiri H, Fukushima Y, Onishi Y, Ono H, Fujishiro M, Kikuchi M, Oka Y, Asano T: Dexamethasone-induced insulin resistance in 3T3eCL1 adipocytes is due to inhibition of glucose transport rather than insulin signal transduction. Diabetes49 :1700 eC1708,2000

    Weinstein SP, Holand A, O’Boyle E, Haber RS: Effects of thiazolidinediones on glucocorticoid-induced insulin resistance and GLUT4 glucose transporter expression in rat skeletal muscle. Metabolism42 :1365 eC1369,1993

    Weinstein SP, Paquin T, Pritsker A, Haber RS: Glucocorticoid-induced insulin resistance: dexamethasone inhibits the activation of glucose transport in rat skeletal muscle by both insulin- and non-insulin-related stimuli. Diabetes44 :441 eC445,1995

    Weinstein SP, Wilson CM, Pritsker A, Cushman SW: Dexamethasone inhibits insulin-stimulated recruitment of GLUT4 to the cell surface in rat skeletal muscle. Metabolism47 :3 eC6,1998

    Quintans J, Kilkus J, McShan CL, Gottschalk AR, Dawson G: Ceramide mediates the apoptotic response of WEHI 231 cells to anti- immunoglobulin, corticosteroids and irradiation. Biochem Biophys Res Commun202 :710 eC714,1994

    Nelson DH, Murray DK, Brady RO: Dexamethasone-induced change in the sphingomyelin content of human polymorphonuclear leukocytes in vitro. J Clin Endocrinol Metab54 :292 eC295,1982

    Kim MY, Linardic C, Obeid L, Hannun Y: Identification of sphingomyelin turnover as an effector mechanism for the action of tumor necrosis factor alpha and gamma-interferon: specific role in cell differentiation. J Biol Chem266 :484 eC489,1991

    Wiegmann K, Schutze S, Machleidt T, Witte D, Kronke M: Functional dichotomy of neutral and acidic sphingomyelinases in tumor necrosis factor signaling. Cell78 :1005 eC1015,1994

    Xu J, Yeh CH, Chen S, He L, Sensi SL, Canzoniero LM, Choi DW, Hsu CY: Involvement of de novo ceramide biosynthesis in tumor necrosis factor-alpha/cycloheximide-induced cerebral endothelial cell death. J Biol Chem273 :16521 eC16526,1998

    Meyer SG, de Groot H: Cycloserine and threo-dihydrosphingosine inhibit TNF-alpha-induced cytotoxicity: evidence for the importance of de novo ceramide synthesis in TNF-alpha signaling. Biochim Biophys Acta1643 :1 eC4,2003

    Schmitz-Peiffer C, Craig DL, Bidn TJ: Ceramide generation is sufficient to account for the inhibition of the insulin-stimulated PKB pathway in C2C12 skeletal muscle cells pretreated with palmitate. J Biol Chem274 :24202 eC24210,1999

    Chavez JA, Knotts TA, Wang LP, Li G, Dobrowsky RT, Florant GL, Summers SA: A role for ceramide, but not diacylglycerol, in the antagonism of insulin signal transduction by saturated fatty acids. J Biol Chem13 :10297 eC10303,2003

    Chavez JA, Summers SA: Characterizing the effects of saturated fatty acids on insulin signaling and ceramide and diacylglycerol accumulation in 3T3eCL1 adipocytes and C2C12 myotubes. Arch Biochem Biophys419 :101 eC109,2003

    Turinsky J, O’Sullivan DM, Bayly BP: 1,2-Diacylglycerol and ceramide levels in insulin-resistant tissues of the rat in vivo. J Biol Chem265 :16880 eC16885,1990

    Gorska M, Dobrzyn A, Zendzian-Piotrowska M, Gorski J: Effect of streptozotocin-diabetes on the functioning of the sphingomyelin-signalling pathway in skeletal muscles of the rat. Horm Metab Res36 :14 eC21,2004

    Adams JM, 2nd, Pratipanawatr T, Berria R, Wang E, DeFronzo RA, Sullards MC, Mandarino LJ: Ceramide content is increased in skeletal muscle from obese insulin-resistant humans. Diabetes53 :25 eC31,2004

    Straczkowski M, Kowalska I, Nikolajuk A, Dzienis-Straczkowska S, Kinalska I, Baranowski M, Zendzian-Piotrowska M, Brzezinska Z, Gorski J: Relationship between insulin sensitivity and sphingomyelin signaling pathway in human skeletal muscle. Diabetes53 :1215 eC1221,2004

    Vesper H, Schmelz EM, Nikolova-Karakashian MN, Dillehay DL, Lynch DV, Merrill AH Jr: Sphingolipids in food and the emerging importance of sphingolipids to nutrition. J Nutr129 :1239 eC1250,1999

    Merrill AH Jr: De novo sphingolipid biosynthesis: a necessary, but dangerous, pathway. J Biol Chem277 :25843 eC25846,2002

    Rivellese AA, De Natale C, Lilli S: Type of dietary fat and insulin resistance. Ann N Y Acad Sci967 :329 eC335,2002

    Gorski J, Nawrocki A, Murthy M: Characterization of free and glyceride-esterified long chain fatty acids in different skeletal muscle types of the rat. Mol Cell Biochem178 :113 eC118,1998

    Shimabukuro M, Higa M, Zhou YT, Wang MY, Newgard CB, Unger RH: Lipoapoptosis in beta-cells of obese prediabetic fa/fa rats: role of serine palmitoyltransferase overexpression. J Biol Chem273 :32487 eC32490,1998

    Strelow A, Bernardo K, Adam-Klages S, Linke T, Sandhoff K, Kronke M, Adam D: Overexpression of acid ceramidase protects from tumor necrosis factor-induced cell death. J Exp Med192 :601 eC612,2000

    Saldeen J, Jaffrezou JP, Welsh N: The acid sphingomyelinase inhibitor SR33557 counteracts TNF-alpha-mediated potentiation of IL-1beta-induced NF-kappaB activation in the insulin-producing cell line Rinm5F. Autoimmunity32 :241 eC254,2000

    Andrieu-Abadie N, Levade T: Sphingomyelin hydrolysis during apoptosis. Biochim Biophys Acta1585 :126 eC134,2002

    Mathias S, Pena LA, Kolesnick RN: Signal transduction of stress via ceramide. Biochem J335 :465 eC480,1998

    Schutze S, Wiegmann K, Machleidt T, Kronke M: TNF-induced activation of NF-kappa B. Immunobiology193 :193 eC203,1995

    Nelson DH: Corticosteroid-induced changes in phospholipid membranes as mediators of their action. Endocr Rev1 :180 eC199,1980

    Nelson DH: The adrenal cortex: physiological function and disease. Major Probl Intern Med18 :iii-xii,1 eC281,1980

    Murray DK, Ruhmann-Wennhold A, Nelson DH: Dexamethasone effect on the phospholipid content of isolated fat cell ghosts from adrenalectomized rats. Endocrinology105 :774 eC777,1979

    Johnston D, Matthews ER, Melnykovych G: Glucocorticoid effects on lipid metabolism in HeLa cells: inhibition of cholesterol synthesis and increased sphingomyelin synthesis. Endocrinology107 :1482 eC1488,1980

    Ramachandran CK, Murray DK, Nelson DH: Dexamethasone increases neutral sphingomyelinase activity and sphingosine levels in 3T3eCL1 fibroblasts. Biochem Biophys Res Commun167 :607 eC613,1990

    Murray DK, Ruhmann-Wennhold A, Nelson DH: Adrenalectomy decreases the sphingomyelin and cholesterol content of fat cell ghosts. Endocrinology111 :452 eC455,1982

    Linn SC, Kim HS, Keane EM, Andras LM, Wang E, Merrill AH Jr: Regulation of de novo sphingolipid biosynthesis and the toxic consequences of its disruption. Biochem Soc Trans29 :831 eC835,2001

    Lepine S, Lakatos B, Maziere P, Courageot MP, Sulpice JC, Giraud F: Involvement of sphingosine in dexamethasone-induced thymocyte apoptosis. Ann N Y Acad Sci973 :190 eC193,2002

    Cifone MG, Migliorati G, Parroni R, Marchetti C, Millimaggi D, Santoni A, Riccardi C: Dexamethasone-induced thymocyte apoptosis: apoptotic signal involves the sequential activation of phosphoinositide-specific phospholipase C, acidic sphingomyelinase, and caspases. Blood93 :2282 eC2296,1999

    Dobrzyn A, Knapp M, Gorski J: Effect of acute exercise and training on metabolism of ceramide in the heart muscle of the rat. Acta Physiol Scand181 :313 eC319,2004

    Dobrzyn A, Zendzian-Piotrowska M, Gorski J: Effect of endurance training on the sphingomyelin-signalling pathway activity in the skeletal muscles of the rat. J Physiol Pharmacol55 :305 eC313,2004

    Helge JW, Dobrzyn A, Saltin B, Gorski J: Exercise and training effects on ceramide metabolism in human skeletal muscle. Exp Physiol89 :119 eC127,2004

    Whiteman EL, Cho H, Birnbaum MJ: Role of Akt/protein kinase B in metabolism. Trends Endocrinol Metab13 :444 eC451,2002

    Nelson DH, Murray DK: Sphingolipids inhibit insulin and phorbol ester stimulated uptake of 2-deoxyglucose. Biochem Biophys Res Commun138 :463 eC467,1986

    Hajduch E, Balendran A, Batty IH, Litherland GJ, Blair AS, Downes CP, Hundal HS: Ceramide impairs the insulin-dependent membrane recruitment of protein kinase B leading to a loss in downstream signalling in L6 skeletal muscle cells. Diabetologia44 :173 eC183,2001

    Wang C-N, O’Brien L, Brindley DN: Effects of cell-permeable ceramides and tumor necrosis factor- on insulin signaling and glucose uptake in 3T3eCL1 adipocytes. Diabetes47 :24 eC31,1998

    Summers SA, Garza LA, Zhou H, Birnbaum MJ: Regulation of insulin-stimulated glucose transporter GLUT4 translocation and Akt kinase activity by ceramide. Mol Cell Biol18 :5457 eC5464,1998

    Kanety H, Hemi R, Papa MZ, Karasik A: Sphingomyelinase and ceramide suppress insulin-induced tyrosine phosphorylation of the insulin receptor substrate-1. J Biol Chem271 :9895 eC9897,1996

    Peraldi P, Hotamisligil GS, Buurman WA, White MF, Spiegelman BM: Tumor necrosis factor (TNF-)-alpha inhibits insulin signaling through stimulation of the p55 TNF-receptor and activation of sphingomyelinase. J Biol Chem271 :13018 eC13022,1996

    Zundel W, Giaccia A: Inhibition of the anti-apoptotic PI(3)K/Akt/Bad pathway by stress. Genes Dev12 :1941 eC1946,1998

    Kralik SF, Liu P, Leffler BJ, Elmendorf JS: Ceramide and glucosamine antagonism of alternate signaling pathways regulating insulin-and osmotic shock-induced glucose transporter 4 translocation. Endocrinology143 :37 eC46,2002

    Teruel T, Hernandez R, Lorenzo M: Ceramide mediates insulin resistance by tumor necrosis factor- in brown adipocytes by maintaining Akt in an inactive dephosphorylated state. Diabetes50 :2563 eC2571,2001

    Stratford S, DeWald DB, Summers SA: Ceramide dissociates 3'-phosphoinositide production from pleckstrin homology domain translocation. Biochem J354 :359 eC368,2001

    Stratford S, Hoehn KL, Liu F, Summers SA: Regulation of insulin action by ceramide: dual mechanisms linking ceramide accumulation to the inhibition of Akt/protein kinase B. J Biol Chem279 :36608 eC36615,2004

    Powell DJ, Hajduch E, Kular G, Hundal HS: Ceramide disables 3-phosphoinositide binding to the pleckstrin homology domain of protein kinase B (PKB)/Akt by a PKCzeta-dependent mechanism. Mol Cell Biol23 :7794 eC7808,2003

    Salinas M, Lopez-Valdaliso R, Martin D, Alvarez A, Cuadrado A: Inhibition of PKB/Akt1 by C2-ceramide involves activation of ceramide-activated protein phosphatase in PC12 cells. Mol Cell Neurosci15 :156 eC169,2000

    Zinda MJ, Vlahos CJ, Lai MT: Ceramide induces the dephosphorylation and inhibition of constitutively activated Akt in PTEN negative U87mg cells. Biochem Biophys Res Commun280 :1107 eC1115,2001

    Cazzolli R, Carpenter L, Biden TJ, Schmitz-Peiffer C: A role for protein phosphatase 2AeClike activity, but not atypical protein kinase C, in the inhibition of protein kinase B/Akt and glycogen synthesis by palmitate. Diabetes50 :2210 eC2218,2001

    Long SD, Pekala PH: Lipid mediators of insulin resistance: ceramide signalling down regulates GLUT4 gene transcription in 3T3eCL1 adipocytes. Biochem J319 :179 eC184,1996

    Hunnicutt JW, Hardy RW, Williford J, McDonald JM: Saturated fatty acid-induced insulin resistance in rat adipocytes. Diabetes43 :540 eC545,1994

    Montell E, Turini M, Marotta M, Roberts M, Noe V, Ciudad CJ, Mace K, Gomez-Foix AM: DAG accumulation from saturated fatty acids desensitizes insulin stimulation of glucose uptake in muscle cells. Am J Physiol Endocrinol Metab280 :E229 eCE237,2001

    Storz P, Doppler H, Wernig A, Pfizenmaier K, Muller G: Cross-talk mechanisms in the development of insulin resistance of skeletal muscle cells palmitate rather than tumour necrosis factor inhibits insulin-dependent protein kinase B (PKB)/Akt stimulation and glucose uptake. Eur J Biochem266 :17 eC25,1999

    Thompson AL, Lim-Fraser MY, Kraegen EW, Cooney GJ: Effects of individual fatty acids on glucose uptake and glycogen synthesis in soleus muscle in vitro. Am J Physiol Endocrinol Metab279 :E577 eCE584,2000

    Bachmann OP, Dahl DB, Brechtel K, Machann J, Haap M, Maier T, Loviscach M, Stumvoll M, Claussen CD, Schick F, Haring HU, Jacob S: Effects of intravenous and dietary lipid challenge on intramyocellular lipid content and the relation with insulin sensitivity in humans. Diabetes50 :2579 eC2584,2001

    Sinha R, Dufour S, Petersen KF, LeBon V, Enoksson S, Ma YZ, Savoye M, Rothman DL, Shulman GI, Caprio S: Assessment of skeletal muscle triglyceride content by 1H nuclear magnetic resonance spectroscopy in lean and obese adolescents: relationships to insulin sensitivity, total body fat, and central adiposity. Diabetes51 :1022 eC1027,2002

    Neschen S, Moore I, Regittnig W, Yu CL, Wang Y, Pypaert M, Petersen KF, Shulman GI: Contrasting effects of fish oil and safflower oil on hepatic peroxisomal and tissue lipid content. Am J Physiol Endocrinol Metab282 :E395 eCE401,2002

    Itani SI, Ruderman NB, Schmieder F, Boden G: Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IB-. Diabetes51 :2005 eC2011,2002

    Kim JK, Fillmore JJ, Chen Y, Yu C, Moore IK, Pypaert M, Lutz EP, Kako Y, Velez-Carrasco W, Goldberg IJ, Breslow JL, Shulman GI: Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. Proc Natl Acad Sci U S A98 :7522 eC7527,2001

    Ferreira LD, Pulawa LK, Jensen DR, Eckel RH: Overexpressing human lipoprotein lipase in mouse skeletal muscle is associated with insulin resistance. Diabetes50 :1064 eC1068,2001

    Yu C, Chen Y, Cline GW, Zhang D, Zong H, Wang Y, Bergeron R, Kim JK, Cushman SW, Cooney GJ, Atcheson B, White MF, Kraegen EW, Shulman GI: Mechanism by which fatty acids inhibit insulin activation of IRS-1 associated phosphatidylinositol 3-kinase activity in muscle. J Biol Chem277 :50230 eC50236,2002

    Kim YB, Shulman GI, Kahn BB: Fatty acid infusion selectively impairs insulin action on Akt1 and protein kinase C lambda/zeta but not on glycogen synthase kinase-3. J Biol Chem277 :32915 eC32922,2002

    Hodgkin MN, Pettitt TR, Martin A, Michell RH, Pemberton AJ, Wakelam MJ: Diacylglycerols and phosphatidates: which molecular species are intracellular messengers Trends Biochem Sci23 :200 eC204,1998

    Wakelam MJ: Diacylglycerol: when is it an intracellular messenger Biochim Biophys Acta1436 :117 eC126,1998

    Kern PA, Saghizadeh M, Ong JM, Bosch RJ, Deem R, Simsolo RB: The expression of tumor necrosis factor in human adipose tissue: regulation by obesity, weight loss, and relationship to lipoprotein lipase. J Clin Invest95 :2111 eC2119,1995

    Lang CH, Dobrescu C, Bagby GJ: Tumor necrosis factor impairs insulin action on peripheral glucose disposal and hepatic glucose output. Endocrinology130 :43 eC52,1992

    Hotamisligil GS, Shargill NS, Spiegelman BM: Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science259 :87 eC91,1993

    Saghizadeh M, Ong JM, Garvey WT, Henry RR, Kern PA: The expression of TNF-alpha by human muscle: relationship to insulin resistance. J Clin Invest97 :1111 eC1116,1996

    Uysal KT, Wiesbrock SM, Marino WM, Hotamisligil GS: Protection from obesity-induced insulin resistance in mice lacking TNF-a function. Nature389 :610 eC614,1997

    Uysal KT, Wiesbrock SM, Hotamisligil GS: Functional analysis of tumor necrosis factor (TNF-) receptors in TNF-alpha-mediated insulin resistance in genetic obesity. Endocrinology139 :4832 eC4838,1998

    Ofei F, Hurel S, Newkirk J, Sopwith M, Taylor R: Effects of an engineered human anti-TNF-alpha antibody (CDP571) on insulin sensitivity and glycemic control in patients with NIDDM. Diabetes45 :881 eC885,1996

    Hotamisligil GS, Murray DL, Choy LN, Spiegelman BM: Tumor necrosis factor alpha inhibits signaling from the insulin receptor. Proc Natl Acad Sci U S A91 :4854 eC4858,1994

    Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM: IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science271 :665 eC668,1996

    Stephens JM, Lee J, Pilch PF: Tumor necosis factor--induced insulin resistance in 3T3eCL1 adipocytes is accompanied by a loss of insulin receptor substrate-1 and GLUT4 expression without a loss of insulin receptor-mediated signal transduction. J Biol Chem272 :971 eC976,1997

    Carter-Su C, Okamoto K: Effect of glucocorticoids on hexose transport in rat adipocytes: evidence for decreased transporters in the plasma membrane. J Biol Chem260 :11091 eC11098,1985

    Carter-Su C, Okamoto K: Inhibition of hexose transport in adipocytes by dexamethasone: role of protein synthesis. Am J Physiol248 :E215 eCE223,1985

    Carter-Su C, Okamoto K: Effect of insulin and glucocorticoids on glucose transporters in rat adipocytes. Am J Physiol252 :E441 eCE453,1987

    Oda N, Nakai A, Mokuno T, Sawai Y, Nishida Y, Mano T, Asano K, Itoh Y, Kotake M, Kato S, et al: Dexamethasone-induced changes in glucose transporter 4 in rat heart muscle, skeletal muscle and adipocytes. Eur J Endocrinol133 :121 eC126,1995

    Guillaume-Gentil C, Assimacopoulos-Jeannet F, Jeanrenaud B: Involvement of non-esterified fatty acid oxidation in glucocorticoid-induced peripheral insulin resistance in vivo in rats. Diabetologia36 :899 eC906,1993

    Coderre L, Srivastava AK, Chiasson JL: Effect of hypercorticism on regulation of skeletal muscle glycogen metabolism by insulin. Am J Physiol262 :E427 eCE433,1992

    Daw JC, Lefer AM, Berne RM: Influences of corticosteroids on cardiac glycogen concentration in the rat. Circ Res22 :639 eC647,1968

    Turnbow M, Keller S, Rice K, Garner C: Dexamethasone down-regulation of insulin receptor substrate-1 in 3T3eCL1 adipocytes. J Biol Chem269 :2516 eC2520,1994

    Buren J, Liu HX, Jensen J, Eriksson JW: Dexamethasone impairs insulin signalling and glucose transport by depletion of insulin receptor substrate-1, phosphatidylinositol 3-kinase and protein kinase B in primary cultured rat adipocytes. Eur J Endocrinol146 :419 eC429,2002

    Saad MJ, Folli F, Kahn JA, Kahn CR: Modulation of insulin receptor, insulin receptor substrate-1, and phosphatidylinositol 3-kinase in liver and muscle of dexamethasone-treated rats. J Clin Invest92 :2065 eC2072,1993

    Pagano G, Cavallo-Perin P, Cassader M, Bruno A, Ozzello A, Masciola P, Dall’omo AM, Imbimbo B: An in vivo and in vitro study of the mechanism of prednisone-induced insulin resistance in healthy subjects. J Clin Invest72 :1814 eC1820,1983

    Beck-Nielsen H, De Pirro R, Pedersen O: Prednisone increases the number of insulin receptors on monocytes from normal subjects. J Clin Endocrinol Metab50 :1 eC4,1980

    Saad MJ, Folli F, Araki E, Hashimoto N, Csermely P, Kahn CR: Regulation of insulin receptor, insulin receptor substrate-1, and phosphatidylinositol 3-kinase in 3T3eCF442A adipocytes: effects of differentiation, insulin, and dexamethasone. Mol Endocrinol8 :545 eC557,1994

    Saad MJ, Folli F, Kahn CR: Insulin and dexamethasone regulate insulin receptors, insulin receptor substrate-1, and phosphatidylinositol 3-kinase in Fao hepatoma cells. Endocrinology136 :1579 eC1588,1995

    Giorgino F, Almahfouz A, Goodyear LJ, Smith RJ: Glucocorticoid regulation of insulin receptor and substrate IRS-1 tyrosine phosphorylation in rat skeletal muscle in vivo. J Clin Invest91 :2020 eC2030,1993

    Long W, Barrett EJ, Wei L, Liu Z: Adrenalectomy enhances the insulin sensitivity of muscle protein synthesis. Am J Physiol Endocrinol Metab284 :E102 eCE109,2003

    Shah OJ, Anthony JC, Kimball SR, Jefferson LS: Glucocorticoids oppose translational control by leucine in skeletal muscle. Am J Physiol Endocrinol Metab279 :E1185 eCE1190,2000

    Shah OJ, Kimball SR, Jefferson LS: Glucocorticoids abate p70(S6k) and eIF4E function in L6 skeletal myoblasts. Am J Physiol Endocrinol Metab279 :E74 eCE82,2000

    Olefsky JM: Effect of dexamethasone on insulin binding, glucose transport, and glucose oxidation of isolated rat adipocytes. J Clin Invest56 :1499 eC1508,1975

    Fernandez BM, Saggerson ED: Alterations in response of rat white adipocytes to insulin, noradrenaline, corticotropin and glucagon after adrenalectomy: correction of these changes by adenosine deaminase. Biochem J174 :111 eC118,1978

    Nelson DH, Murray DK: Dexamethasone increases the synthesis of sphingomyelin in 3T3eCL1 cell membranes. Proc Natl Acad Sci U S A79 :6690 eC6692,1982

    Murray DK, Hill ME, Nelson DH: Inhibitory action of sphingosine, sphinganine and dexamethasone on glucose uptake: studies with hydrogen peroxide and phorbol ester. Life Sci46 :1843 eC1849,1990

    Hoff HF, Morton RE: Lipoproteins containing apo B extracted from human aortas: structure and function. Ann N Y Acad Sci454 :183 eC194,1985

    Guyton JR, Klemp KF: Development of the lipid-rich core in human atherosclerosis. Arterioscler Thromb Vasc Biol16 :4 eC11,1996

    Schissel SL, Tweedie-Hardman J, Rapp JH, Graham G, Williams KJ, Tabas I: Rabbit aorta and human atherosclerotic lesions hydrolyze the sphingomyelin of retained low-density lipoprotein: proposed role for arterial-wall sphingomyelinase in subendothelial retention and aggregation of atherogenic lipoproteins. J Clin Invest98 :1455 eC1464,1996

    Holopainen JM, Lehtonen JY, Kinnunen PK: Lipid microdomains in dimyristoylphosphatidylcholine-ceramide liposomes. Chem Phys Lipids88 :1 eC13,1997

    Holopainen JM, Lemmich J, Richter F, Mouritsen OG, Rapp G, Kinnunen PK: Dimyristoylphosphatidylcholine/C16:0-ceramide binary liposomes studied by differential scanning calorimetry and wide- and small-angle x-ray scattering. Biophys J78 :2459 eC2469,2000

    Kinnunen PK, Holopainen JM: Sphingomyelinase activity of LDL: a link between atherosclerosis, ceramide, and apoptosis Trends Cardiovasc Med12 :37 eC42,2002

    Auge N, Negre-Salvayre A, Salvayre R, Levade T: Sphingomyelin metabolites in vascular cell signaling and atherogenesis. Prog Lipid Res39 :207 eC229,2000

    Levade T, Auge N, Veldman RJ, Cuvillier O, Negre-Salvayre A, Salvayre R: Sphingolipid mediators in cardiovascular cell biology and pathology. Circ Res89 :957 eC968,2001

    Mallat Z, Tedgui A: Apoptosis in the vasculature: mechanisms and functional importance. Br J Pharmacol130 :947 eC962,2000

    Mallat Z, Tedgui A: Current perspective on the role of apoptosis in atherothrombotic disease. Circ Res88 :998 eC1003,2001

    Zhou YT, Grayburn P, Karim A, Shimabukuro M, Higa M, Baetens D, Orci L, Unger RH: Lipotoxic heart disease in obese rats: implications for human obesity. Proc Natl Acad Sci U S A97 :1784 eC1789,2000

    Yatomi Y, Ohmori T, Rile G, Kazama F, Okamoto H, Sano T, Satoh K, Kume S, Tigyi G, Igarashi Y, Ozaki Y: Sphingosine 1-phosphate as a major bioactive lysophospholipid that is released from platelets and interacts with endothelial cells. Blood96 :3431 eC3438,2000

    Auge N, Nikolova-Karakashian M, Carpentier S, Parthasarathy S, Negre-Salvayre A, Salvayre R, Merrill AH Jr, Levade T: Role of sphingosine 1-phosphate in the mitogenesis induced by oxidized low density lipoprotein in smooth muscle cells via activation of sphingomyelinase, ceramidase, and sphingosine kinase. J Biol Chem274 :21533 eC21538,1999

    Chatterjee S: Sphingolipids in atherosclerosis and vascular biology. Arterioscler Thromb Vasc Biol18 :1523 eC1533,1998

    Bhatia R, Matsushita K, Yamakuchi M, Morrell CN, Cao W, Lowenstein CJ: Ceramide triggers Weibel-Palade body exocytosis. Circ Res95 :319 eC324,2004

    Soeda S, Honda O, Shimeno H, Nagamatsu A: Sphingomyelinase and cell-permeable ceramide analogs increase the release of plasminogen activator inhibitor-1 from cultured endothelial cells. Thromb Res80 :509 eC518,1995

    Hirokawa M, Kitabayashi A, Kuroki J, Miura AB: Induction of tissue factor production but not the upregulation of adhesion molecule expression by ceramide in human vascular endothelial cells. Tohoku J Exp Med191 :167 eC176,2000

    Constable PD, Smith GW, Rottinghaus GE, Tumbleson ME, Haschek WM: Fumonisin-induced blockade of ceramide synthase in sphingolipid biosynthetic pathway alters aortic input impedance spectrum of pigs. Am J Physiol Heart Circ Physiol284 :H2034 eCE2044,2003

    Kronke M: Biophysics of ceramide signaling: interaction with proteins and phase transition of membranes. Chem Phys Lipids101 :109 eC121,1999

    Dorrance AM, Graham D, Webb RC, Fraser R, Dominiczak A: Increased membrane sphingomyelin and arachidonic acid in stroke-prone spontaneously hypertensive rats. Am J Hypertens14 :1149 eC1153,2001

    Zheng T, Li W, Wang J, Altura BT, Altura BM: Sphingomyelinase and ceramide analogs induce contraction and rises in [Ca(2+)](i) in canine cerebral vascular muscle. Am J Physiol Heart Circ Physiol278 :H1421 eCH1428,2000

    Murohara T, Kugiyama K, Ohgushi M, Sugiyama S, Ohta Y, Yasue H: Effects of sphingomyelinase and sphingosine on arterial vasomotor regulation. J Lipid Res37 :1601 eC1608,1996

    Bischoff A, Czyborra P, Fetscher C, Meyer Zu Heringdorf D, Jakobs KH, Michel MC: Sphingosine-1-phosphate and sphingosylphosphorylcholine constrict renal and mesenteric microvessels in vitro. Br J Pharmacol130 :1871 eC1877,2000

    Todoroki-Ikeda N, Mizukami Y, Mogami K, Kusuda T, Yamamoto K, Miyake T, Sato M, Suzuki S, Yamagata H, Hokazono Y, Kobayashi S: Sphingosylphosphorylcholine induces Ca(2+)-sensitization of vascular smooth muscle contraction: possible involvement of rho-kinase. FEBS Lett482 :85 eC90,2000

    Bischoff A, Czyborra P, Meyer Zu Heringdorf D, Jakobs KH, Michel MC: Sphingosine-1-phosphate reduces rat renal and mesenteric blood flow in vivo in a pertussis toxin-sensitive manner. Br J Pharmacol130 :1878 eC1883,2000

    Bolz SS, Vogel L, Sollinger D, Derwand R, Boer C, Pitson SM, Spiegel S, Pohl U: Sphingosine kinase modulates microvascular tone and myogenic responses through activation of RhoA/Rho kinase. Circulation108 :342 eC347,2003

    Johns DG, Webb RC: TNF-alpha-induced endothelium-independent vasodilation: a role for phospholipase A2-dependent ceramide signaling. Am J Physiol275 :H1592 eCH1598,1998

    Zhang DX, Yi FX, Zou AP, Li PL: Role of ceramide in TNF-alpha-induced impairment of endothelium-dependent vasorelaxation in coronary arteries. Am J Physiol Heart Circ Physiol283 :H1785 eCH1794,2002

    Zheng T, Li W, Wang J, Altura BT, Altura BM: C2-ceramide attenuates phenylephrine-induced vasoconstriction and elevation in [Ca2+]i in rat aortic smooth muscle. Lipids34 :689 eC695,1999

    Yang S, Zhang L: Glucocorticoids and vascular reactivity. Curr Vasc Pharmacol2 :1 eC12,2004

    Mitchell BM, Webb RC: Impaired vasodilation and nitric oxide synthase activity in glucocorticoid-induced hypertension. Biol Res Nurs4 :16 eC21,2002

    Iuchi T, Akaike M, Mitsui T, Ohshima Y, Shintani Y, Azuma H, Matsumoto T: Glucocorticoid excess induces superoxide production in vascular endothelial cells and elicits vascular endothelial dysfunction. Circ Res92 :81 eC87,2003

    Guzik TJ, Mussa S, Gastaldi D, Sadowski J, Ratnatunga C, Pillai R, Channon KM: Mechanisms of increased vascular superoxide production in human diabetes mellitus: role of NAD(P)H oxidase and endothelial nitric oxide synthase. Circulation105 :1656 eC1662,2002

    Zhang DX, Zou AP, Li PL: Ceramide reduces endothelium-dependent vasodilation by increasing superoxide production in small bovine coronary arteries. Circ Res88 :824 eC831,2001

    Franzen R, Fabbro D, Aschrafi A, Pfeilschifter J, Huwiler A: Nitric oxide induces degradation of the neutral ceramidase in rat renal mesangial cells and is counterregulated by protein kinase C. J Biol Chem277 :46184 eC46190,2002

    Huwiler A, Dorsch S, Briner VA, van den Bosch H, Pfeilschifter J: Nitric oxide stimulates chronic ceramide formation in glomerular endothelial cells. Biochem Biophys Res Commun258 :60 eC65,1999

    Pautz A, Franzen R, Dorsch S, Boddinghaus B, Briner VA, Pfeilschifter J, Huwiler A: Cross-talk between nitric oxide and superoxide determines ceramide formation and apoptosis in glomerular cells. Kidney Int61 :790 eC796,2002

    Gulbins E, Kolesnick R: Raft ceramide in molecular medicine. Oncogene22 :7070 eC7077,2003

    Manes S, del Real G, Martinez AC: Pathogens: raft hijackers. Nat Rev Immunol3 :557 eC568,2003

    Simons K, Ehehalt R: Cholesterol, lipid rafts, and disease. J Clin Invest110 :597 eC603,2002

    Chazal N, Gerlier D: Virus entry, assembly, budding, and membrane rafts. Microbiol Mol Biol Rev67 :226 eC237,2003

    Gulbins E, Dreschers S, Wilker B, Grassme H: Ceramide, membrane rafts and infections. J Mol Med82 :357 eC363,2004

    Grassme H, Gulbins E, Brenner B, Ferlinz K, Sandhoff K, Harzer K, Lang F, Meyer TF: Acidic sphingomyelinase mediates entry of N. gonorrhoeae into nonphagocytic cells. Cell91 :605 eC615,1997

    Hauck CR, Grassme H, Bock J, Jendrossek V, Ferlinz K, Meyer TF, Gulbins E: Acid sphingomyelinase is involved in CEACAM receptor-mediated phagocytosis of Neisseria gonorrhoeae. FEBS Lett478 :260 eC266,2000

    Esen M, Schreiner B, Jendrossek V, Lang F, Fassbender K, Grassme H, Gulbins E: Mechanisms of Staphylococcus aureus induced apoptosis of human endothelial cells. Apoptosis6 :431 eC439,2001

    Jan JT, Chatterjee S, Griffin DE: Sindbis virus entry into cells triggers apoptosis by activating sphingomyelinase, leading to the release of ceramide. J Virol74 :6425 eC6432,2000

    Ghosh S, Bhattacharyya S, Das S, Raha S, Maulik N, Das DK, Roy S, Majumdar S: Generation of ceramide in murine macrophages infected with Leishmania donovani alters macrophage signaling events and aids intracellular parasitic survival. Mol Cell Biochem223 :47 eC60,2001

    Soory M: Hormone mediation of immune responses in the progression of diabetes, rheumatoid arthritis and periodontal diseases. Curr Drug Targets Immune Endocr Metabol Disord2 :13 eC25,2002

    Mandell GL, Rubin W, Hook EW: The effect of an NADH oxidase inhibitor (hydrocortisone) on polymorphonuclear leukocyte bactericidal activity. J Clin Invest49 :1381 eC1388,1970

    Nelson DH, Meikle AW, Benowitz B, Murray DK, Ruhmann-Wennhold A: Cortisol and dexamethasone suppression of superoxide anion production by leukocytes from normal subjects. Trans Assoc Am Physicians91 :381 eC387,1978

    Mansfield PJ, Hinkovska-Galcheva V, Carey SS, Shayman JA, Boxer LA: Regulation of polymorphonuclear leukocyte degranulation and oxidant production by ceramide through inhibition of phospholipase D. Blood99 :1434 eC1441,2002

    Suchard SJ, Hinkovska-Galcheva V, Mansfield PJ, Boxer LA, Shayman JA: Ceramide inhibits IgG-dependent phagocytosis in human polymorphonuclear leukocytes. Blood89 :2139 eC2147,1997

    Hinkovska-Galcheva V, Kjeldsen L, Mansfield PJ, Boxer LA, Shayman JA, Suchard SJ: Activation of a plasma membrane-associated neutral sphingomyelinase and concomitant ceramide accumulation during IgG-dependent phagocytosis in human polymorphonuclear leukocytes. Blood91 :4761 eC4769,1998

    Nakamura T, Abe A, Balazovich KJ, Wu D, Suchard SJ, Boxer LA, Shayman JA: Ceramide regulates oxidant release in adherent human neutrophils. J Biol Chem269 :18384 eC18389,1994

    Ballou LR, Chao CP, Holness MA, Barker SC, Raghow R: Interleukin-1-mediated PGE2 production and sphingomyelin metabolism: evidence for the regulation of cyclooxygenase gene expression by sphingosine and ceramide. J Biol Chem267 :20044 eC20050,1992

    Ballou LR, Laulederkind SJ, Rosloniec EF, Raghow R: Ceramide signalling and the immune response. Biochim Biophys Acta1301 :273 eC287,1996

    Candela M, Barker SC, Ballou LR: Sphingosine synergistically stimulates tumor necrosis factor alpha-induced prostaglandin E2 production in human fibroblasts. J Exp Med174 :1363 eC1369,1991

    Cinque B, Di Marzio L, Centi C, Di Rocco C, Riccardi C, Grazia Cifone M: Sphingolipids and the immune system. Pharmacol Res47 :421 eC437,2003

    Hevener AL, Reichart D, Janez A, Olefsky J: Thiazolidinedione treatment prevents free fatty acideCinduced insulin resistance in male wistar rats. Diabetes50 :2316 eC2322,2001

    Chang AY, Wyse BM, Gilchrist BJ, Peterson T, Diani AR: Ciglitazone, a new hypoglycemic agent. I. Studies in ob/ob and db/db mice, diabetic Chinese hamsters, and normal and streptozotocin-diabetic rats. Diabetes32 :830 eC838,1983

    Yen TT, Gill AM, Powell JG, Sampson BM: Ciglitazone prevents and reverses dexamethasone-induced hyperglycemia in female viable yellow mice. Int J Obes Relat Metab Disord16 :923 eC933,1992

    Dandona P, Aljada A: Endothelial dysfunction in patients with type 2 diabetes and the effects of thiazolidinedione antidiabetic agents. J Diabetes Complications18 :91 eC102,2004

    Dandona P, Aljada A, Chaudhuri A: Vascular reactivity and thiazolidinediones. Am J Med115 (Suppl. 8A) :81S eC86S,2003

    Hsueh WA, Bruemmer D: Peroxisome proliferator-activated receptor gamma: implications for cardiovascular disease. Hypertension43 :297 eC305,2004

    Rangwala SM, Lazar MA: Peroxisome proliferator-activated receptor gamma in diabetes and metabolism. Trends Pharmacol Sci25 :331 eC336,2004

    Hevener AL, He W, Barak Y, Le J, Bandyopadhyay G, Olson P, Wilkes J, Evans RM, Olefsky J: Muscle-specific PPAR-g deletion causes insulin resistance. Nat Med9 :1491 eC1497,2003

    Norris AW, Chen L, Fisher SJ, Szanto I, Ristow M, Jozsi AC, Hirshman MF, Rosen ED, Goodyear LJ, Gonzalez FJ, Spiegelman BM, Kahn CR: Muscle-specific PPAR-gamma-deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones. J Clin Invest112 :608 eC618,2003

    Szalkowski D, White-Carrington S, Berger J, Zhang B: Antidiabetic thiazolidinediones block the inhibitory effect of tumor necrosis factor-alpha on differentiation, insulin-stimulated glucose uptake, and gene expression in 3T3eCL1 cells. Endocrinology136 :1474 eC1481,1995

    Peraldi P, Xu M, Spiegelman BM: Thiazolidinediones block tumor necrosis factor-alpha-induced inhibition of insulin signaling. J Clin Invest100 :1863 eC1869,1997

    Solomon SS, Usdan LS, Palazzolo MR: Mechanisms involved in tumor necrosis factor-alpha induction of insulin resistance and its reversal by thiazolidinedione(s). Am J Med Sci322 :75 eC78,2001

    Zeghari N, Vidal H, Younsi M, Ziegler O, Drouin P, Donner M: Adipocyte membrane phospholipids and PPAR-gamma expression in obese women: relationship to hyperinsulinemia. Am J Physiol Endocrinol Metab279 :E736 eCE743,2000

    Al-Makdissy N, Bianchi A, Younsi M, Picard E, Valet P, Martinet N, Dauca M, Donner M: Down-regulation of peroxisome proliferator-activated receptor-gamma gene expression by sphingomyelins. FEBS Lett493 :75 eC79,2001

    Sprott KM, Chumley MJ, Hanson JM, Dobrowsky RT: Decreased activity and enhanced nuclear export of CCAAT-enhancer-binding protein beta during inhibition of adipogenesis by ceramide. Biochem J365 :181 eC191,2002

    Van Veldhoven PP, Mannaerts GP, Declercq P, Baes M: Do sphingoid bases interact with the peroxisome proliferator activated receptor alpha (PPAR-alpha) Cell Signal12 :475 eC479,2000

    Hannun YA, Obeid LM: The Ceramide-centric universe of lipid-mediated cell regulation: stress encounters of the lipid kind. J Biol Chem277 :25847 eC25850,2002

    Van Blitterswijk WJ, Van Der Luit AH, Veldman RJ, Verheij M, Borst J: Ceramide: second messenger or modulator of membrane structure and dynamics Biochem J369 :199 eC211,2003(Scott A. Summers, and Don)