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CrossTalk proposal: Intramyocellular ceramide accumulation does modulate insulin resistance

2016; Wiley; Volume: 594; Issue: 12 Linguagem: Inglês

10.1113/jp271676

1469-7793

Scott A. Summers, Bret H. Goodpaster,

Circadian rhythm and melatonin

The oversupply of nutrients to skeletal muscle produces metabolic by-products that drive insulin resistance, predisposing people to diabetes, atherosclerosis and heart disease. Ceramides, reactive oxygen species, diacylglycerols, branched chain amino acids, acylcarnitines, citric acid cycle intermediates and other metabolites have all been implicated as antagonists of insulin action, but their relative importance is a source of contention. Here we advance the position that ceramides are both sufficient and necessary for obesity-induced insulin resistance. Ceramides antagonize insulin signalling by blocking activation of the anabolic enzyme Akt/PKB, inhibiting glucose uptake and impairing storage of nutrients as glycogen or triglyceride (Chaurasia & Summers, 2015) (Fig. 1). These sphingolipids also disrupt lipid metabolism, particularly in the liver, by inhibiting oxidation and stimulating fatty acid uptake (Chaurasia & Summers, 2015). Three lines of evidence support roles in insulin resistance in vivo. First, ceramide reduction interventions invariably improve insulin sensitivity in mice, rats and hamsters. Second, lipidomic profiling studies reveal strong relationships between tissue ceramides and insulin resistance in humans, non-human primates and rodents. Third, glucocorticoids, inflammatory agonists and adiponectin modulate insulin sensitivity by positively or negatively altering ceramide synthesis or metabolism. Here we highlight a subset of prominent studies conducted in model systems and humans revealing roles for the sphingolipid in muscle insulin resistance and metabolic disorders. Studies in isolated muscle or cultured myotubes reveal that the effects can be tissue-autonomous. Exogenous ceramides antagonize insulin signalling or action in cultured myocytes or isolated fibres. Moreover, inhibition of ceramide synthesis (i.e. myriocin, fumonisin B1, or siRNA-mediated knockdown of Spt subunits or Des-1) or stimulation of ceramide degradation (e.g. acid ceramidase overexpression) negates lipid-antagonism of insulin signalling in these systems (Chaurasia & Summers, 2015). A provocative hypothesis that is gaining traction is that muscle ceramides may also be also delivered through the circulation. Infusion of ceramide-enriched low density lipoproteins reduced whole-body glucose owing to a reduction in glucose disposal in skeletal muscle (Boon et al. 2013). Depletion of ceramides from these lipoproteins rendered them ineffectual as insulin antagonists. These data may explain why tissue-specific reduction of sphingolipid synthesis in adipose tissue or the liver reduces serum ceramides and markedly improves whole body and/or muscle insulin sensitivity (Turpin et al. 2014; Xia et al. 2015). The preponderance of lipid profiling studies in humans demonstrate relationships between ceramides and insulin resistance. For example, elevations in muscle ceramides were reported in individuals with general or abdominal obesity (Amati et al. 2011; Coen et al. 2013; de la Maza et al. 2015) in association with muscle insulin resistance (Adams et al. 2004; Coen et al. 2010; Amati et al. 2011). These cross-sectional observations are not universal (Skovbro et al. 2008), and this discordance is the source of the existing controversy. Associations between liver ceramides and hepatic insulin resistance (Longato et al. 2012) and between adipose ceramides and fatty liver disease (Kolak et al. 2007) are also reported. Insulin-sensitizing treatments (metformin, pioglitazone, exercise, bariatric surgery, etc.) reduce ceramides. Both diet-induced weight loss (Dube et al. 2011) and exercise training (Dube et al. 2008, 2011; Amati et al. 2011) lower muscle ceramide levels and enhance muscle insulin sensitivity. Profound weight loss caused by bariatric surgery also reduced muscle ceramides in conjunction with improved insulin sensitivity (Coen et al. 2015). Superimposing exercise after this surgery-induced weight loss further reduced specific ceramide species (Coen et al. 2015). In contrast, levels of diacylglycerols in skeletal muscle were not altered with bariatric surgery-induced weight loss (Coen et al. 2015), nor were they decreased by chronic exercise training (Amati et al. 2011). To the contrary, muscle diacylglcyerol levels were actually higher in endurance-trained athletes who have markedly high insulin sensitivity in skeletal muscle (Amati et al. 2011). Infusion of a lipid emulsion into humans induces insulin resistance. The intervention increases muscle diacylglycerols, but not ceramides (Itani, 2002; Nowotny et al. 2013; Szendroedi et al. 2014). This triglyceride emulsion is comprised primarily of unsaturated lipids, which could explain the lack of observed increases in ceramides. Indeed, rodent studies using lipid infusion cocktails reveal that saturated fats induce insulin resistance via ceramide-dependent mechanisms, while unsaturated fats antagonize insulin action through a different mechanism (Holland et al. 2007). Highly trained athletes exposed to this unsaturated lipid emulsion also become insulin resistant, but their insulin resistance (and associated decreased glucose oxidation) is compensated by an increase in fatty acid oxidation, i.e. their greater metabolic flexibility (Dube et al. 2014). Thus we argue that this lipid infusion model induces a physiological insulin resistance that does not resemble pathobiology. Circulating sphingolipids are also associated with insulin resistance and type 2 diabetes in humans. Plasma ceramides are higher in obese children (Lopez et al. 2013) and diabetic adults (Haus et al. 2009) and correlate with the severity of insulin resistance (Haus et al. 2009). Plasma ceramides also correlate with characteristics of the metabolic syndrome in non-human primates fed a Western diet (Brozinick et al. 2013). Studies exploring the effects of insulin-sensitizing pioglitazone treatment on plasma ceramides also demonstrate a correlation between the decrease in plasma ceramides and improved insulin sensitivity (Warshauer et al. 2015). Bergman and colleagues reported that an acute bout of exercise decreased plasma ceramide levels during recovery consistent with the insulin-sensitizing effects of exercise (Bergman et al. 2015). Taken together, the majority of human studies demonstrate a consistent role for tissue and circulating ceramides in insulin resistance, obesity and type 2 diabetes. The Scherer group recently attributed the broad spectrum of anti-diabetic and cardioprotective actions of adiponectin to the activation of a ceramidase (Holland et al. 2011). Adiponectin receptors contain a domain with high homology to ceramidase enzymes, and substitution for residues predicted to be important for ceramidase activity negates adiponectin action. Moreover, increasing circulating adiponectin levels in mice selectively depletes ceramides in various tissues, while genetic ablation of adiponectin receptors exacerbates sphingolipid-dependent toxicity. These findings suggest that ceramide depletion could be a unifying mechanism to explain the pleiotropic actions of the adipokine. Subsequent studies revealed that FGF21, a member of the fibroblast growth factor superfamily, enhances insulin sensitivity through a mechanism involving adiponectin-dependent reductions in tissue ceramide levels (Holland et al. 2013). A panoply of interventional studies in rodents and profiling studies in humans reveal likely roles for sphingolipids in insulin resistance in skeletal muscle, as well as liver and adipose tissue. These data clearly reveal the promise of ceramide reduction therapies to treat metabolic disorders resulting from obesity and dyslipidaemia. Readers are invited to give their views on this and the accompanying CrossTalk articles in this issue by submitting a brief (250 word) comment. Comments may be submitted up to 6 weeks after publication of the article, at which point the discussion will close and the CrossTalk authors will be invited to submit a 'Last Word'. Please email your comment, including a title and a declaration of interest, to jphysiol@physoc.org. Comments will be moderated and accepted comments will be published online only as 'supporting information' to the original debate articles once discussion has closed. Scott Summers directs the Translational Metabolic Health laboratory and Bioenergetics Core at the Baker IDI Heart and Diabetes Institute. His lab endeavours to elucidate the metabolic basis of diabetes and heart disease, with recent emphasis on the role of ceramides modulators of nutrient homeostasis. He is also the co-founder and scientific advisor of Centaurus Therapeutics Inc., a USA-based biotechnology company developing new therapeutics to combat the metabolic underpinnings of chronic diseases. Bret Goodpaster conducts clinical translational 'bench to bedside' investigations of skeletal muscle and its role in human health, ageing and disease. He reported the Athlete's Paradox in 2001, demonstrating that endurance athletes have markedly high insulin sensitivity despite having high levels of muscle triglycerides. This helped move the field towards a better understanding of lipotoxicity within skeletal muscle, including the potential role for ceramides in insulin resistance. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Professor Summers is a shareholder with Centaurus Therapeutics, Inc. Both authors have approved the final version of the manuscript and agree to be accountable for all aspects of the work. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. This work is supported by NIH grants R01AG20128 and R01DK078192 to B.G., an NHMRC research fellowship APP1112502 (to S.A.S.), and by the Victorian State Government OIS scheme. The authors thank the members of their laboratories for helpful discussion. The figure in this article was partially adapted from Servier Medical Art.