Metabolic Remodeling of Human Skeletal Myocytes by Cocultured Adipocytes Depends on the Lipolytic State of the System
Metabolic Remodeling of Human Skeletal Myocytes by Cocultured Adipocytes Depends on the Lipolytic State of the System
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DOI：
10.2337/db10-0427
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发表时间：
2011-07-01
期刊：
影响因子：
7.7
通讯作者：
Muoio, Deborah M.
中科院分区：
文献类型：
--
作者：
Kovalik, Jean-Paul;Slentz, Dorothy;Muoio, Deborah M.
目的：脂肪细胞浸润肌肉骨骼系统是公认的衰老、肥胖和2型糖尿病的标志。肌间脂肪细胞可能是多余脂肪的良性储存场所，也可能由于脂肪分解或促炎细胞因子分泌失调而破坏能量稳态。本研究旨在了解局部脂肪细胞对骨骼肌细胞代谢的净影响。研究设计和方法：使用由原代人脂肪细胞和来源于瘦肉或肥胖供体的人骨骼肌管组成的共培养系统模拟这两种组织之间的相互作用。在与脂溶性沉默或激活的脂肪细胞共培养后，对肌细胞进行代谢分析，包括转录物和代谢物分析，以及底物选择和胰岛素作用的评估。结果：共培养的脂肪细胞增加了参与氧化代谢基因的肌管mRNA表达，与供体和脂溶活性程度无关。处于基础状态的脂肪细胞会隔离游离脂肪酸，从而迫使邻近的肌管更多地依赖葡萄糖燃料。在这种情况下，来自瘦弱而非肥胖供体的肌管中的胰岛素作用增强。相反，当暴露于具有脂溶活性的脂肪细胞时，共培养的肌管改变了底物的使用，有利于脂肪酸，这伴随着细胞内甘油三酯和连链酰基肉碱的积累，葡萄糖氧化减少，胰岛素信号的适度衰减。结论共培养脂肪细胞对肌细胞底物选择和胰岛素作用的影响取决于系统的代谢状态。这些发现有助于理解肌间脂肪形成的代谢后果。糖尿病60:1882-1893,2011
OBJECTIVE-Adipocyte infiltration of the musculoskeletal system is well recognized as a hallmark of aging, obesity, and type 2 diabetes. Intermuscular adipocytes might serve as a benign storage site for surplus lipid or play a role in disrupting energy homeostasis as a result of dysregulated lipolysis or secretion of proinflammatory cytokines. This investigation sought to understand the net impact of local adipocytes on skeletal myocyte metabolism.RESEARCH DESIGN AND METHODS-Interactions between these two tissues were modeled using a coculture system composed of primary human adipocytes and human skeletal myotubes derived from lean or obese donors. Metabolic analysis of myocytes was performed after coculture with lipolytically silent or activated adipocytes and included transcript and metabolite profiling along with assessment of substrate selection and insulin action.RESULTS-Cocultured atlipocytes increased myotube mRNA expression of genes involved in oxidative metabolism, regardless of the donor and degree of lipolytic activity. Adipocytes in the basal state sequestered free fatty acids, thereby forcing neighboring myotubes to rely more heavily on glucose fuel. Under this condition, insulin action was enhanced in myotubes from lean but not obese donors. In contrast, when exposed to lipolytically active adipocytes, cocultured myotubes shifted substrate use in favor of fatty acids, which was accompanied by intracellular accumulation of triacylglycerol and even-chain acylcarnitines, decreased glucose oxidation, and modest attenuation of insulin signaling.CONCLUSIONS-The effects of cocultured adipocytes on myocyte substrate selection and insulin action depended on the metabolic state of the system. These findings are relevant to understanding the metabolic consequences of intermuscular adipogenesis. Diabetes 60:1882-1893, 2011