Rebuttal from Max C. Petersen and Michael J. Jurczak.
Rebuttal from Max C. Petersen and Michael J. Jurczak.
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Max C. Petersen 和 Michael J. Jurczak 的反驳。
DOI：
10.1113/jp272137
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Jurczak,MichaelJ
中科院分区：
文献类型：
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作者：
Petersen,MaxC;Jurczak,MichaelJ
Summers&Goodpaster(2016)使用了三条论据来支持神经酰胺介导骨骼肌胰岛素抵抗的假设。在这里，我们注意到对这些论点的警告，我们认为这些论点削弱了他们的提议。我们的同事对神经酰胺生物合成的药物或遗传抑制报告进行了分类，这些报告证明了对肥胖相关的胰岛素抵抗的保护作用。然而，抑制剂myriocin的胰岛素增敏作用与体重、能量消耗和异位脂质的大体变化有关，这可以解释独立于对神经酰胺的影响的胰岛素增敏表型(Yang等人)。2009年)。类似的与能量平衡有关的警告适用于所引用的其他模型：丝氨酸棕榈酰转移酶单倍体不足小鼠、鞘磷脂合成酶缺失小鼠、果糖喂养的仓鼠和神经酰胺合成酶6缺失小鼠(Li等人。2011年；Dekker等人。2013年；特平等人。2014年)。从这些模型中可以得出结论，抑制神经酰胺的合成可以预防饮食诱导的胰岛素抵抗。然而，由于上述混杂因素，仅将这些表型归因于神经酰胺对胰岛素信号的抑制需要更多的还原模型。其次，我们的同事回顾了考察神经酰胺和胰岛素敏感性之间关系的人体研究，我们也回顾了这些研究(Petersen等人。2016)。如上所述，这些数据是模棱两可的，并不能得出一致的结论。尽管在一些研究中有几种胰岛素增敏干预措施--抗糖尿病药物、减肥和锻炼--减少了肌肉神经酰胺，但这些干预措施通过多种机制发挥作用，因此不能提供对神经酰胺具体作用的因果洞察。最后，我们的同事描述了一个有趣的假设，即脂联素的胰岛素增敏作用是通过神经酰胺酶激活来调节的。虽然这一假说引人入胜，并得到了优雅的实验证据的支持，但它主要与肝脏和脂肪组织有关(Holland等人。2011年；夏等人。2015年)，与目前关于神经酰胺在骨骼肌胰岛素抵抗中的作用的辩论无关。正如我们的相声文章(Petersen&Jurczak，2016)中指出的那样，骨骼肌胰岛素信号中与肥胖相关的缺陷是在神经酰胺作用部位的上游检测到的，因此神经酰胺不是解释胰岛素抵抗所必需的。我们还反对神经酰胺足以解释胰岛素抵抗的结论；尽管试图特别干扰体内神经酰胺的水平，但这些遗传和药物干预往往会造成多发性、混杂的影响。我们同意萨默斯和古德巴斯特的观点，即由营养过剩产生的肌肉胰岛素抵抗很难明确地归因于一个或多个特定的介体。尽管我们认识到，大量报告得出结论认为神经酰胺调节骨骼肌胰岛素抵抗，但我们坚持认为，对主要数据的仔细检查揭示了引起健康的科学怀疑的警告和弱点。
Summers & Goodpaster (2016) employ three lines of argument to support the hypothesis that ceramides mediate skeletal muscle insulin resistance. Here, we note caveats to these arguments that we believe weaken their proposal. Our colleagues catalogue reports of pharmacological or genetic inhibition of ceramide biosynthesis that demonstrate protection from obesity-associated insulin resistance. However, the insulin-sensitizing effects of the inhibitor myriocin are associated with gross changes in body weight, energy expenditure and ectopic lipid that could account for the insulin-sensitizing phenotype independent of effects on ceramides (Yang et al. 2009). Similar energy balance-related caveats apply for the other models cited: serine palmitoyltransferase-haploinsufficient mice, sphingomyelin synthase-null mice, fructose-fed hamsters and ceramide synthase-6-null mice (Li et al. 2011; Dekker et al. 2013; Turpin et al. 2014). It is valid to conclude from these models that inhibiting ceramide synthesis prevents diet-induced insulin resistance. However, owing to the aforementioned confounders, attributing these phenotypes solely to ceramide inhibition of insulin signalling requires more reductive models. Second, our colleagues review human studies examining the relationship between ceramides and insulin sensitivity, which we also review (Petersen et al. 2016). As noted, these data are equivocal and do not converge on a conclusion. Although several insulin-sensitizing interventions–antidiabetic agents, weight loss, and exercise–reduce muscle ceramides in some studies, these interventions work by multiple, well-described mechanisms and thus do not provide causal insight into the specific role of ceramides.Finally, our colleagues describe the intriguing hypothesis that the insulin-sensitizing effects of adiponectin are mediated by ceramidase activation. While fascinating and supported by elegant experimental evidence, this hypothesis primarily concerns liver and adipose tissue (Holland et al. 2011; Xiaet al. 2015) and is unrelated to the present debate on the role of ceramides in skeletal muscle insulin resistance. As noted in our CrossTalk article (Petersen & Jurczak, 2016), obesity-associated defects in skeletal muscle insulin signalling are detected upstream of the putative site of ceramide action, such that ceramides are not necessary to explain insulin resistance. We also argue against the conclusion that ceramides are sufficient to account for insulin resistance; despite attempts to specifically perturb ceramide levels in vivo, these genetic and pharmacological interventions often cause pleotropic, confounding effects. We agree with Summers and Goodpaster that muscle insulin resistance produced by nutrient oversupply has been difficult to unequivocally attribute to one or more specific mediators. Although we recognize that a large number of reports conclude that ceramides modulate skeletal muscle insulin resistance, we maintain that close examination of the primary data reveals caveats and weaknesses that engender a healthy scientific skepticism.