Department of Medicine, Preventive Medicine and Nutrition, Columbia University, New York, New York, USA.
Diabetes. 2009 Nov;58(11):2516-24. doi: 10.2337/db08-1096. Epub 2009 Aug 12.
Transgenic expression of diacylglycerol acyltransferase-1 (DGAT1) in skeletal muscle leads to protection against fat-induced insulin resistance despite accumulation of intramuscular triglyceride, a phenomenon similar to what is known as the "athlete paradox." The primary objective of this study is to determine how DGAT1 affects muscle fatty acid oxidation in relation to whole-body energy metabolism and insulin sensitivity.
We first quantified insulin sensitivity and the relative tissue contributions to the improved whole-body insulin sensitivity in muscle creatine kisase (MCK)-DGAT1 transgenic mice by hyperinsulinemic-euglycemic clamps. Metabolic consequences of DGAT1 overexpression in skeletal muscles were determined by quantifying triglyceride synthesis/storage (anabolic) and fatty acid oxidation (catabolic), in conjunction with gene expression levels of representative marker genes in fatty acid metabolism. Whole-body energy metabolism including food consumption, body weights, oxygen consumption, locomotor activity, and respiration exchange ratios were determined at steady states.
MCK-DGAT1 mice were protected against muscle lipoptoxicity, although they remain susceptible to hepatic lipotoxicity. While augmenting triglyceride synthesis, DGAT1 overexpression also led to increased muscle mitochondrial fatty acid oxidation efficiency, as compared with wild-type muscles. On a high-fat diet, MCK-DGAT1 mice displayed higher basal metabolic rates and 5-10% lower body weights compared with wild-type littermates, whereas food consumption was not different.
DGAT1 overexpression in skeletal muscle led to parallel increases in triglyceride synthesis and fatty acid oxidation. Seemingly paradoxical, this phenomenon is characteristic of insulin-sensitive myofibers and suggests that DGAT1 plays an active role in metabolic "remodeling" of skeletal muscle coupled with insulin sensitization.
在骨骼肌中过表达二酰基甘油酰基转移酶-1（DGAT1）会导致对脂肪诱导的胰岛素抵抗的保护，尽管肌内甘油三酯积累，这一现象类似于所谓的“运动员悖论”。本研究的主要目的是确定 DGAT1 如何影响肌肉脂肪酸氧化与全身能量代谢和胰岛素敏感性的关系。
我们首先通过高胰岛素-正常血糖钳夹技术来量化胰岛素敏感性以及肌肉肌酸激酶（MCK）-DGAT1 转基因小鼠中改善的全身胰岛素敏感性的相对组织贡献。通过定量甘油三酯合成/储存（合成代谢）和脂肪酸氧化（分解代谢），以及脂肪酸代谢代表性标记基因的表达水平，确定骨骼肌中 DGAT1 过表达的代谢后果。在稳态下，测定包括食物消耗、体重、耗氧量、运动活动和呼吸交换比在内的全身能量代谢。
MCK-DGAT1 小鼠虽然仍易发生肝脂肪毒性，但对肌肉脂肪毒性有保护作用。虽然增加了甘油三酯的合成，但与野生型肌肉相比，DGAT1 过表达也导致肌肉线粒体脂肪酸氧化效率增加。在高脂肪饮食中，MCK-DGAT1 小鼠的基础代谢率比野生型同窝仔鼠高 5-10%，而体重则没有差异。
骨骼肌中 DGAT1 的过表达导致甘油三酯合成和脂肪酸氧化的平行增加。这种看似矛盾的现象是胰岛素敏感肌纤维的特征，表明 DGAT1 在与胰岛素敏化相关的骨骼肌代谢“重塑”中发挥积极作用。
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