Madsen Søren, Cutler Harry B, Cooke Kristen C, Potter Meg, Khor Jasmine, Rau Christoph D, Masson Stewart Wc, Howell Anna, Modrusan Zora, Don Anthony S, Stöckli Jacqueline, Vegas Alexis Diaz, James David E
School of Life and Environmental Sciences, University of Sydney, Camperdown, New South Wales, Australia; Charles Perkins Centre, University of Sydney, Camperdown, New South Wales, Australia.
School of Life and Environmental Sciences, University of Sydney, Camperdown, New South Wales, Australia; Charles Perkins Centre, University of Sydney, Camperdown, New South Wales, Australia.
Mol Metab. 2025 Jul 11;99:102212. doi: 10.1016/j.molmet.2025.102212.
Lipids, in particular ceramides and diacylglycerols (DAGs), are implicated in insulin resistance (IR), however their precise roles remain unclear. Here, we leverage natural genetic variation to examine muscle lipids and systemic IR in 399 Diversity Outbred Australia mice fed either chow or a high-fat diet. Adipose tissue mass was significantly associated with 55% of muscle lipid features and whole-body insulin sensitivity, with DAGs as the only lipid class enriched in this association. To disentangle the contribution of adiposity and muscle lipids to whole-body insulin sensitivity, we employed two independent approaches: (1) a linear model correcting muscle lipid features for adipose tissue mass to assess their relationship with insulin sensitivity, and (2) stratifying mice into insulin sensitivity quartiles within adiposity bins. Both revealed that very long-chain ceramides, but not DAGs, were linked to IR. RNA sequencing and proteomics from the same muscles further associated these very long-chain ceramides with cellular stress, mitochondrial dysfunction, and protein synthesis. Meanwhile, DAGs correlated with leptin gene expression in skeletal muscle, suggesting they originate from contaminating adipocytes rather than myocytes per se. We propose that many muscle lipids, including DAGs, associate with muscle and systemic IR due to accumulation of adipose tissue rather than directly influencing muscle insulin sensitivity. By addressing the relationship between adiposity and metabolic state, we identified very long-chain muscle ceramides as being highly associated with IR independently of adiposity.
脂质，特别是神经酰胺和二酰基甘油（DAGs），与胰岛素抵抗（IR）有关，但其确切作用仍不清楚。在此，我们利用自然遗传变异，对399只喂食普通饲料或高脂饮食的澳大利亚多样性远交系小鼠的肌肉脂质和全身IR进行研究。脂肪组织质量与55%的肌肉脂质特征和全身胰岛素敏感性显著相关，DAGs是该关联中唯一富集的脂质类别。为了厘清肥胖和肌肉脂质对全身胰岛素敏感性的贡献，我们采用了两种独立的方法：（1）一种线性模型，校正脂肪组织质量对肌肉脂质特征的影响，以评估它们与胰岛素敏感性的关系；（2）将小鼠按肥胖程度分层为胰岛素敏感性四分位数。两者均显示，超长链神经酰胺而非DAGs与IR相关。来自相同肌肉的RNA测序和蛋白质组学进一步将这些超长链神经酰胺与细胞应激、线粒体功能障碍和蛋白质合成联系起来。同时，DAGs与骨骼肌中的瘦素基因表达相关，表明它们源自污染的脂肪细胞而非肌细胞本身。我们提出，包括DAGs在内的许多肌肉脂质与肌肉和全身IR相关，是由于脂肪组织的积累，而非直接影响肌肉胰岛素敏感性。通过研究肥胖与代谢状态之间的关系，我们确定超长链肌肉神经酰胺与IR高度相关，且独立于肥胖因素。
