aSchool of Biomedical Sciences, Curtin Health Innovation Research Institute (CHIRI), Curtin University, Perth, Western Australia, Australia bLaboratory of Cellular Physiology, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre cNational Institute of Hormones and Women's Health, Porto Alegre, RS, Brazil.
Curr Opin Clin Nutr Metab Care. 2014 Jul;17(4):295-305. doi: 10.1097/MCO.0000000000000077.
Obesity is a chronic inflammatory disease in which the physiological resolution of inflammation is attenuated, leading to low-grade inflammation throughout the body. However, the heat shock response, which is a key component of the physiological response to resolve inflammation, is seriously hampered in adipose tissue and other metabolic organs (e.g. skeletal muscle, liver, pancreatic β-cells) in metabolic diseases. In this review, we hypothesize that adipocyte metabolic stress triggers the onset of fat cell senescence, and companion senescence-associated secretory phenotype (SASP), and that such a scenario is responsible for attenuating the resolution of inflammation.
We shall discuss the role of the heat shock response in the context of the resolution of inflammation and the relevance of heat shock response blockade in chronic inflammatory diseases. Sirtuin-1 is responsible for the induction of heat shock transcription factor-1 mRNA expression and for the stabilization of heat shock transcription factor-1 in a high-profile activity state. However, adipose tissue-emanated SASP depress sirtuin-1 expression, leading adipocytes to a perpetual state of unresolved inflammation, due to a dampening of the heat shock response.
The advance of inflammasome-mediated SASP from adipose to other tissues promotes cellular senescence in many other cells of the organism, aggravating obesity-dependent chronic inflammation. Inducers of heat shock response (e.g. heat shock itself, physical exercise and calorie restriction) may efficiently interrupt this vicious cycle and are envisaged as the best and also the most economical treatment for obesity-related chronic diseases.
肥胖是一种慢性炎症性疾病，其炎症的生理消退过程减弱，导致全身低度炎症。然而，在代谢疾病中，热休克反应（一种解决炎症的生理反应的关键组成部分）在脂肪组织和其他代谢器官（如骨骼肌、肝脏、胰岛β细胞）中受到严重阻碍。在这篇综述中，我们假设脂肪细胞代谢应激引发脂肪细胞衰老，以及伴随的衰老相关分泌表型（SASP），这种情况导致炎症消退减弱。
我们将讨论热休克反应在炎症消退中的作用以及热休克反应阻断在慢性炎症性疾病中的相关性。Sirtuin-1 负责诱导热休克转录因子-1 mRNA 的表达，并使热休克转录因子-1稳定在高活性状态。然而，脂肪组织分泌的 SASP 抑制了 Sirtuin-1 的表达，导致脂肪细胞处于未解决的炎症持续状态，因为热休克反应受到抑制。
炎症小体介导的 SASP 从脂肪组织向其他组织的转移，促进了机体许多其他细胞的衰老，加剧了肥胖相关的慢性炎症。热休克反应的诱导剂（如热休克本身、体育锻炼和热量限制）可以有效地打断这种恶性循环，被认为是肥胖相关慢性疾病的最佳治疗方法，也是最经济的方法。
