title: A crucial role for adipose tissue p53 in the regulation of insulin resistance.
abstract: Various stimuli, such as telomere dysfunction and oxidative stress, can induce irreversible cell growth arrest, which is termed 'cellular senescence'. This response is controlled by tumor suppressor proteins such as p53 and pRb. There is also evidence that senescent cells promote changes related to aging or age-related diseases. Here we show that p53 expression in adipose tissue is crucially involved in the development of insulin resistance, which underlies age-related cardiovascular and metabolic disorders. We found that excessive calorie intake led to the accumulation of oxidative stress in the adipose tissue of mice with type 2 diabetes-like disease and promoted senescence-like changes, such as increased activity of senescence-associated beta-galactosidase, increased expression of p53 and increased production of proinflammatory cytokines. Inhibition of p53 activity in adipose tissue markedly ameliorated these senescence-like changes, decreased the expression of proinflammatory cytokines and improved insulin resistance in mice with type 2 diabetes-like disease. Conversely, upregulation of p53 in adipose tissue caused an inflammatory response that led to insulin resistance. Adipose tissue from individuals with diabetes also showed senescence-like features. Our results show a previously unappreciated role of adipose tissue p53 expression in the regulation of insulin resistance and suggest that cellular aging signals in adipose tissue could be a new target for the treatment of diabetes (pages 996-967).
authors.affiliation: Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chuo-ku, Chiba, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Minamino
authors.forename: Masayuki
authors.initials: M
authors.lastname: Orimo
authors.forename: Ippei
authors.initials: I
authors.lastname: Shimizu
authors.forename: Takeshige
authors.initials: T
authors.lastname: Kunieda
authors.forename: Masataka
authors.initials: M
authors.lastname: Yokoyama
authors.forename: Takashi
authors.initials: T
authors.lastname: Ito
authors.forename: Aika
authors.initials: A
authors.lastname: Nojima
authors.forename: Akira
authors.initials: A
authors.lastname: Nabetani
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Oike
authors.forename: Hisahiro
authors.initials: H
authors.lastname: Matsubara
authors.forename: Fuyuki
authors.initials: F
authors.lastname: Ishikawa
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000375:Aging / Q000235:genetics / Q000378:metabolism; D000818:Animals; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D002149:Energy Intake; D016158:Genes, p53; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53