Department of Pediatrics, University of California, San Diego, CA 92093-0673, USA.
Gastroenterol Res Pract. 2010;2010. doi: 10.1155/2010/212563. Epub 2010 Aug 10.
Chronic inflammation is a key feature of insulin resistance and obesity. Toll-Like Receptor 4 (TLR4), involved in modulating innate immunity, is an important mediator of insulin resistance and its comorbidities. TLR4 contributes to the development of insulin resistance and inflammation through its activation by elevated exogenous ligands (e.g., dietary fatty acids and enteric lipopolysaccharide) and endogenous ligands (e.g., free fatty acids) which are elevated in obese states. TLR4, expressed in insulin target tissues, activates proinflammatory kinases JNK, IKK, and p38 that impair insulin signal transduction directly through inhibitory phosphorylation of insulin receptor substrate (IRS) on serine residues. TLR4 activation also leads to increased transcription of pro-inflammatory genes, resulting in elevation of cytokine, chemokine, reactive oxygen species, and eicosanoid levels that promote further insulin-desensitization within the target cell itself and in other cells via paracrine and systemic effects. Increased understanding of cell type-specific TLR4-mediated effects on insulin action present the opportunity and challenge of developing related therapeutic approaches for improving insulin sensitivity while preserving innate immunity.
慢性炎症是胰岛素抵抗和肥胖的一个关键特征。 Toll 样受体 4（TLR4）参与调节先天免疫，是胰岛素抵抗及其合并症的重要介质。TLR4 通过其被升高的外源性配体（例如，膳食脂肪酸和肠内脂多糖）和内源性配体（例如，游离脂肪酸）激活，促进胰岛素抵抗和炎症的发展，这些配体在肥胖状态下升高。TLR4 在胰岛素靶组织中表达，激活促炎激酶 JNK、IKK 和 p38，通过丝氨酸残基上胰岛素受体底物（IRS）的抑制性磷酸化直接损害胰岛素信号转导。TLR4 的激活还导致促炎基因的转录增加，导致细胞因子、趋化因子、活性氧和类二十烷酸水平升高，从而促进靶细胞本身和通过旁分泌和全身作用的其他细胞中进一步的胰岛素脱敏。对 TLR4 介导的细胞类型特异性对胰岛素作用的理解增加了提供相关治疗方法的机会和挑战，这些方法可以改善胰岛素敏感性，同时保留先天免疫。
