Adipose triglyceride lipase deletion from adipocytes, but not skeletal myocytes, impairs acute exercise performance in mice
Adipose triglyceride lipase deletion from adipocytes, but not skeletal myocytes, impairs acute exercise performance in mice
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DOI：
10.1152/ajpendo.00530.2014
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发表时间：
2015-05-15
影响因子：
5.1
通讯作者：
Kershaw, Erin E.
中科院分区：
文献类型：
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作者：
Dube, John J.;Sitnick, Mitch T.;Kershaw, Erin E.
脂肪甘油三酯脂肪酶（ATGL）是几乎所有细胞（包括脂肪细胞和骨骼肌细胞）中介导甘油三酯水解的限速酶，因此在动员脂肪酸方面起着关键作用。全身性ATGL缺乏会促进小鼠和人类的骨骼肌病和运动不耐受，但这些表型中组织特异性的作用仍不清楚。本研究的目的是确定脂肪细胞与骨骼肌细胞中ATGL介导的甘油三酯水解对急性运动表现的相对贡献。为了实现这一目标，我们构建了脂肪细胞和骨骼肌细胞特异性靶向缺失ATGL的小鼠模型。然后我们让未经训练的小鼠接受急性峰值和次最大运动干预，并评估运动表现和能量底物代谢。脂肪细胞内ATGL介导的脂解受损会降低峰值和次最大运动表现，降低外周能量底物的可利用性，使能量底物偏好转向碳水化合物氧化，并降低骨骼肌内激素敏感脂肪酶（HSL）丝氨酸660位点的磷酸化和线粒体呼吸。相比之下，骨骼肌细胞内ATGL介导的脂解受损并不足以降低峰值和次最大运动表现或外周能量底物的可利用性，反而在峰值运动期间倾向于增强代谢灵活性。此外，这些小鼠中扩大的肌内甘油三酯池在运动后减少，同时HSL磷酸化得以保留，这表明HSL可能在运动期间补偿骨骼肌中ATGL功能的受损。这些数据表明，在急性运动期间，脂肪细胞而非骨骼肌细胞中ATGL介导的脂解起更重要的作用，部分原因是当ATGL缺失时，存在维持肌肉（而非脂肪组织）中脂解的代偿机制。
Adipose triglyceride lipase (ATGL) is the rate-limiting enzyme mediating triacylglycerol hydrolysis in virtually all cells, including adipocytes and skeletal myocytes, and hence, plays a critical role in mobilizing fatty acids. Global ATGL deficiency promotes skeletal myopathy and exercise intolerance in mice and humans, and yet the tissue-specific contributions to these phenotypes remain unknown. The goal of this study was to determine the relative contribution of ATGL-mediated triacylglycerol hydrolysis in adipocytes vs. skeletal myocytes to acute exercise performance. To achieve this goal, we generated murine models with adipocyte-and skeletal myocyte-specific targeted deletion of ATGL. We then subjected untrained mice to acute peak and submaximal exercise interventions and assessed exercise performance and energy substrate metabolism. Impaired ATGL-mediated lipolysis within adipocytes reduced peak and submaximal exercise performance, reduced peripheral energy substrate availability, shifted energy substrate preference toward carbohydrate oxidation, and decreased HSL Ser(660) phosphorylation and mitochondrial respiration within skeletal muscle. In contrast, impaired ATGL-mediated lipolysis within skeletal myocytes was not sufficient to reduce peak and submaximal exercise performance or peripheral energy substrate availability and instead tended to enhance metabolic flexibility during peak exercise. Furthermore, the expanded intramyocellular triacylglycerol pool in these mice was reduced following exercise in association with preserved HSL phosphorylation, suggesting that HSL may compensate for impaired ATGL action in skeletal muscle during exercise. These data suggest that adipocyte rather than skeletal myocyte ATGL-mediated lipolysis plays a greater role during acute exercise in part because of compensatory mechanisms that maintain lipolysis in muscle, but not adipose tissue, when ATGL is absent.