Faculty of Pharmacy, Department of Toxicology, Gazi University, Hipodrom, Ankara, Turkey.
Adv Exp Med Biol. 2024;1460:273-295. doi: 10.1007/978-3-031-63657-8_9.
Obesity is characterized by the chronic low-grade activation of the innate immune system. In this respect, macrophage-elicited metabolic inflammation and adipocyte-macrophage interaction have primary importance in obesity. Large quantity of macrophages is accumulated by different mechanisms in obese adipose tissue. Hypertrophic adipocyte-derived chemotactic monocyte chemoattractant protein-1 (MCP-1)/C-C chemokine receptor 2 (CCR2) pathway promotes more macrophage accumulation into the obese adipose tissue. However, obesity-induced changes in adipose tissue macrophage density are mainly dependent on increases in the triple-positive cluster of differentiation (CD)11b+ F4/80+ CD11c+ adipose tissue macrophage subpopulation. As epigenetic regulators, microRNAs (miRNAs) are one of the most important mediators of obesity. miRNAs are expressed by adipocytes as well as macrophages and regulate inflammation with the expression of target genes. A paracrine loop involving free fatty acids and tumor necrosis factor-alpha (TNF-α) between adipocytes and macrophages establishes a vicious cycle that aggravates inflammatory changes in the adipose tissue. Adipocyte-specific caspase-1 and production of interleukin-1beta (IL-1β) by macrophages; both adipocyte and macrophage induction by toll-like receptor-4 (TLR4) through nuclear factor-kappaB (NF-κB) activation; free fatty acid-induced and TLR-mediated activation of c-Jun N-terminal kinase (JNK)-related pro-inflammatory pathways in CD11c+ immune cells; are effective in mutual message transmission between adipocyte and macrophage and in the development of adipose tissue inflammation. Thus, the metabolic status of adipocytes and their released exosomes are important determinants of macrophage inflammatory output. However, old adipocytes are removed by macrophages through trogocytosis or sending an "eat me" signal. As a single miRNA can be able to regulate a variety of target genes and signaling pathways, reciprocal transfer of miRNAs between adipocytes and macrophages via miRNA-loaded exosomes reorganizes the different stages of obesity. Changes in the expression of circulating miRNAs because of obesity progression or anti-obesity treatment indicate that miRNAs could be used as potential biomarkers. Therefore, it is believed that targeting macrophage-associated miRNAs with anti-obesity miRNA-loaded nano-carriers may be successful in the attenuation of both obesity and adipose tissue inflammation in clinical practice. Moreover, miRNA-containing exosomes and transferable mitochondria between the adipocyte and macrophage are investigated as new therapeutic targets for obesity-related metabolic disorders.
肥胖症的特征是固有免疫系统的慢性低度激活。在这方面，巨噬细胞引起的代谢炎症和脂肪细胞-巨噬细胞相互作用在肥胖中具有主要意义。大量巨噬细胞通过不同的机制在肥胖脂肪组织中积累。肥大脂肪细胞衍生的趋化单核细胞趋化蛋白-1（MCP-1）/C-C 趋化因子受体 2（CCR2）途径促进更多的巨噬细胞进入肥胖脂肪组织。然而，肥胖引起的脂肪组织中巨噬细胞密度的变化主要取决于三阳性簇分化（CD）11b+ F4/80+ CD11c+脂肪组织巨噬细胞亚群的增加。作为表观遗传调节剂，microRNAs（miRNAs）是肥胖的最重要调节因子之一。miRNAs 由脂肪细胞和巨噬细胞表达，并通过靶基因的表达来调节炎症。脂肪细胞和巨噬细胞之间涉及游离脂肪酸和肿瘤坏死因子-α（TNF-α）的旁分泌环建立了一个恶性循环，加剧了脂肪组织的炎症变化。脂肪细胞特异性半胱氨酸天冬氨酸蛋白酶-1（caspase-1）和巨噬细胞产生白细胞介素-1β（IL-1β）；脂肪细胞和巨噬细胞通过核因子-κB（NF-κB）激活诱导 Toll 样受体-4（TLR4）；游离脂肪酸诱导和 TLR 介导的 c-Jun N 末端激酶（JNK）相关促炎途径在 CD11c+免疫细胞中；在脂肪细胞和巨噬细胞之间的相互信息传递以及脂肪组织炎症的发展中都有效。因此，脂肪细胞的代谢状态及其释放的外泌体是巨噬细胞炎症输出的重要决定因素。然而，衰老的脂肪细胞通过胞饮作用或发出“吃我”信号被巨噬细胞清除。由于单个 miRNA 可以调节多种靶基因和信号通路，脂肪细胞和巨噬细胞之间通过负载 miRNA 的外泌体的 miRNA 相互转移重新组织了肥胖的不同阶段。由于肥胖进展或抗肥胖治疗而导致的循环 miRNA 表达的变化表明，miRNA 可作为潜在的生物标志物。因此，用抗肥胖 miRNA 负载的纳米载体靶向与巨噬细胞相关的 miRNA 可能在临床上成功减轻肥胖和脂肪组织炎症。此外，脂肪细胞和巨噬细胞之间的含 miRNA 的外泌体和可转移的线粒体被作为肥胖相关代谢紊乱的新治疗靶点进行研究。
