title: The fat cell senescence hypothesis: a mechanism responsible for abrogating the resolution of inflammation in chronic disease.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Philip
authors.initials: P
authors.lastname: Newsholme
authors.forename: Paulo I Homem
authors.initials: PI
authors.lastname: de Bittencourt
mesh_terms: D017667:Adipocytes / Q000166:cytology*; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000097:blood; D016922:Cellular Senescence; D002908:Chronic Disease; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018840:HSP70 Heat-Shock Proteins / Q000097:blood; D000076249:Heat Shock Transcription Factors; D018869:Heat-Shock Response; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D008099:Liver / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009765:Obesity / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D012333:RNA, Messenger; D014157:Transcription Factors; D056564:Sirtuin 1