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.
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
Correspondence to Philip Newsholme, School of Biomedical Sciences, Curtin Health Innovation Research Institute (CHIRI), Curtin University, GPO Box U1987, Perth, Western Australia, Australia. Tel: +61 8 9266 7425; fax: +61 8 9266 7424; e-mail: firstname.lastname@example.org