Muscle ectopic fat deposition contributes to anabolic resistance in obese sarcopenic old rats through eIF2α activation.
Muscle ectopic fat deposition contributes to anabolic resistance in obese sarcopenic old rats through eIF2α activation.
复制标题
DOI：
10.1111/acel.12263
复制
发表时间：
2014-12
期刊：
影响因子：
7.8
通讯作者：
Walrand S
中科院分区：
文献类型：
--
作者：
Tardif N;Salles J;Guillet C;Tordjman J;Reggio S;Landrier JF;Giraudet C;Patrac V;Bertrand-Michel J;Migne C;Collin ML;Chardigny JM;Boirie Y;Walrand S
肥胖和衰老的特点是胰岛素敏感性（IS）和肌肉蛋白质合成下降。肌肉内神经酰胺的积累与肥胖期间的胰岛素抵抗有关。我们的目的是测量接受低脂饮食 (LFD) 或高脂饮食 (HFD) 10 周的雄性 Wistar 幼鼠（YR，6 个月）和老年（OR，25 个月）大鼠的 IS、肌肉神经酰胺水平、蛋白质合成和参与翻译起始的细胞内信号通路的激活。采用相应的细胞方法，使用棕榈酸酯处理的 C2C12 肌管诱导细胞内神经酰胺沉积。 HFD 后，在手术室中观察到脂肪组织储存脂质的能力下降，脂肪细胞直径减小，并出现纤维化。因此，饲喂 HFD 的 OR 具有胰岛素抵抗性，显示肌内神经酰胺水平大幅增加，并且与 eIF2α 磷酸化增加相关的肌肉蛋白质合成减少。肌内脂质的积累给线粒体带来了脂质负担，并造成 OR 骨骼肌代谢和调节途径之间的脱节。在 C2C12 细胞中，棕榈酸诱导的神经酰胺积累与蛋白质合成减少以及 eIF2α 磷酸化上调相关。总之，手术室中发现脂肪组织扩张能力降低，反映出脂质缓冲能力较低。肌肉线粒体活性在 OR 中受到影响，导致氧化进入肌肉细胞的脂肪酸的能力降低。因此，OR 比 YR 更容易发生异位肌肉脂质积累，导致肌肉蛋白质合成代谢下降。这种代谢变化是对抗肌肉减少性肥胖的潜在治疗靶点。
Obesity and aging are characterized by decreased insulin sensitivity (IS) and muscle protein synthesis. Intramuscular ceramide accumulation has been implicated in insulin resistance during obesity. We aimed to measure IS, muscle ceramide level, protein synthesis, and activation of intracellular signaling pathways involved in translation initiation in male Wistar young (YR, 6-month) and old (OR, 25-month) rats receiving a low- (LFD) or a high-fat diet (HFD) for 10 weeks. A corresponding cellular approach using C2C12 myotubes treated with palmitate to induce intracellular ceramide deposition was taken. A decreased ability of adipose tissue to store lipids together with a reduced adipocyte diameter and a development of fibrosis were observed in OR after the HFD. Consequently, OR fed the HFD were insulin resistant, showed a strong increase in intramuscular ceramide level and a decrease in muscle protein synthesis associated with increased eIF2α phosphorylation. The accumulation of intramuscular lipids placed a lipid burden on mitochondria and created a disconnect between metabolic and regulating pathways in skeletal muscles of OR. In C2C12 cells, palmitate-induced ceramide accumulation was associated with a decreased protein synthesis together with upregulated eIF2α phosphorylation. In conclusion, a reduced ability to expand adipose tissues was found in OR, reflecting a lower lipid buffering capacity. Muscle mitochondrial activity was affected in OR conferring a reduced ability to oxidize fatty acids entering the muscle cell. Hence, OR were more prone to ectopic muscle lipid accumulation than YR, leading to decreased muscle protein anabolism. This metabolic change is a potential therapeutic target to counter sarcopenic obesity.
登录
查看更多内容
DOI：
10.1152/ajpendo.00038.2010
发表时间：
2010-11-01
影响因子：
5.1
作者：
Deldicque, Louise;Cani, Patrice D.;Baar, Keith
通讯作者：
Baar, Keith
DOI：
10.1152/ajpregu.2001.280.6.r1772
发表时间：
2001-06-01
影响因子：
2.8
作者：
Karagiannides, I;Tchkonia, T;Kirkland, JL
通讯作者：
Kirkland, JL
DOI：
10.1073/pnas.0600821103
发表时间：
2006-03-28
影响因子：
11.1
作者：
Karagiannides, L;Kokkotou, E;Pothoulakis, C
通讯作者：
Pothoulakis, C
影响因子：
7.8
作者：
Kaeberlein M;Kennedy BK
通讯作者：
Kennedy BK
影响因子：
5.8
作者：
Goodpaster, BH;He, J;Kelley, DE
通讯作者：
Kelley, DE