这篇叙述性综述探讨了肥胖的病理生理学,细胞衰老,和外来体释放。当暴露于过量的营养时,脂肪细胞发生线粒体功能障碍并产生活性氧,DNA损伤。这会引发脂肪细胞肥大和缺氧,抑制脂联素分泌和脂肪生成,增加的内质网应激和适应不良的未折叠蛋白反应,metaflammation,和巨噬细胞的极化。这种前馈循环不能通过抗氧化剂系统解决,热休克反应途径,或DNA修复机制,通过自分泌导致可传播的细胞衰老,旁分泌,和内分泌信号。因此,衰老可以影响前脂肪细胞,成熟脂肪细胞,组织巨噬细胞和淋巴细胞,肝细胞,血管内皮,胰腺β细胞,肌细胞,下丘脑核,和肾足细胞.衰老相关分泌表型与内脏脂肪组织扩张和代谢密切相关;抑制SIRT-1、脂联素、和自噬;外泌体释放增加,外泌体微小RNA,促炎脂肪因子,和饱和游离脂肪酸.由此产生的股骨高度畸形,胰岛素抵抗,脂肪酸β-氧化减少导致脂毒性和进行性肥胖,代谢综合征,以及身体和认知功能下降。体重循环与持续的免疫衰老和暴露于棕榈酸酯有关。细胞衰老,外泌体释放,可传播的衰老相关分泌表型导致肥胖和代谢综合征。靶向治疗对细胞衰老具有相互关联和协同作用,肥胖,和过早衰老。
This narrative review explores the pathophysiology of obesity, cellular senescence, and exosome release. When exposed to excessive nutrients, adipocytes develop mitochondrial dysfunction and generate reactive oxygen species with DNA damage. This triggers adipocyte hypertrophy and hypoxia, inhibition of adiponectin secretion and adipogenesis, increased endoplasmic reticulum stress and maladaptive unfolded protein response, metaflammation, and polarization of macrophages. Such feed-forward cycles are not resolved by antioxidant systems, heat shock response pathways, or DNA repair mechanisms, resulting in transmissible cellular senescence via autocrine, paracrine, and endocrine signaling. Senescence can thus affect preadipocytes, mature adipocytes, tissue macrophages and lymphocytes, hepatocytes, vascular endothelium, pancreatic β cells, myocytes, hypothalamic nuclei, and renal podocytes. The senescence-associated secretory phenotype is closely related to visceral adipose tissue expansion and metaflammation; inhibition of SIRT-1, adiponectin, and autophagy; and increased release of exosomes, exosomal micro-RNAs, pro-inflammatory adipokines, and saturated free fatty acids. The resulting hypernefemia, insulin resistance, and diminished fatty acid β-oxidation lead to lipotoxicity and progressive obesity, metabolic syndrome, and physical and cognitive functional decline. Weight cycling is related to continuing immunosenescence and exposure to palmitate. Cellular senescence, exosome release, and the transmissible senescence-associated secretory phenotype contribute to obesity and metabolic syndrome. Targeted therapies have interrelated and synergistic effects on cellular senescence, obesity, and premature aging.