Virginia Polytechnic Institute and State University, Department of Human Nutrition, Foods, and Exercise, Blacksburg, VA 24061, USA.
Am J Physiol Endocrinol Metab. 2010 May;298(5):E988-98. doi: 10.1152/ajpendo.00307.2009. Epub 2010 Feb 23.
Toll-like receptor 4 (TLR4), a protein integral to innate immunity, is elevated in skeletal muscle of obese and type 2 diabetic humans and has been implicated in the development of lipid-induced insulin resistance. The purpose of this study was to examine the role of TLR4 as a modulator of basal (non-insulin-stimulated) substrate metabolism in skeletal muscle with the hypothesis that its activation would result in reduced fatty acid oxidation and increased partitioning of fatty acids toward neutral lipid storage. Human skeletal muscle, rodent skeletal muscle, and skeletal muscle cell cultures were employed to study the functional consequences of TLR4 activation on glucose and fatty acid metabolism. Herein, we demonstrate that activation of TLR4 with low (metabolic endotoxemia) and high (septic conditions) doses of LPS results in increased glucose utilization and reduced fatty acid oxidation in skeletal muscle and that these changes in metabolism in vivo occur in concert with increased circulating triglycerides. Moreover, animals with a loss of TLR4 function possess increased oxidative capacity in skeletal muscle and present with lower fasting levels of triglycerides and nonesterified free fatty acids. Evidence is also presented to suggest that these changes in substrate metabolism under metabolic endotoxemic conditions are independent of skeletal muscle-derived proinflammatory cytokine production. This report illustrates that skeletal muscle is a target for circulating endotoxin and may provide critical insight into the link between a proinflammatory state and dysregulated metabolism as observed with obesity, type 2 diabetes, and metabolic syndrome.
Toll 样受体 4（TLR4）是先天免疫的重要组成部分，在肥胖和 2 型糖尿病患者的骨骼肌中升高，并与脂质诱导的胰岛素抵抗的发展有关。本研究的目的是研究 TLR4 作为骨骼肌基础（非胰岛素刺激）底物代谢调节剂的作用，假设其激活会导致脂肪酸氧化减少和脂肪酸向中性脂质储存的分配增加。本研究采用人类骨骼肌、啮齿动物骨骼肌和骨骼肌细胞培养物来研究 TLR4 激活对葡萄糖和脂肪酸代谢的功能后果。在此，我们证明 TLR4 的激活（低剂量（代谢性内毒素血症）和高剂量（脓毒症条件）的 LPS）导致骨骼肌葡萄糖利用率增加和脂肪酸氧化减少，而这些代谢变化在体内与循环甘油三酯增加同时发生。此外，TLR4 功能丧失的动物具有增加的骨骼肌氧化能力，表现出较低的空腹甘油三酯和非酯化游离脂肪酸水平。还有证据表明，在代谢性内毒素血症条件下，这些底物代谢的变化独立于骨骼肌源性促炎细胞因子的产生。本报告表明，骨骼肌是循环内毒素的靶标，并可能为炎症状态与失调代谢之间的联系提供重要见解，这种联系在肥胖、2 型糖尿病和代谢综合征中观察到。
