Various stimuli, such as telomere dysfunction and oxidative stress, can induce irreversible cell growth arrest, which is termed 'cellular senescence'1,2. 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 diseases3,4,5,6. 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 β-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).
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We thank H. Karagiri for discussion, W.C. Greene (University of California) and T. Fujita (The Tokyo Metropolitan Institute of Medical Science) for expression vector encoding constitutively active IκB and p55-A2-Luc (luciferase reporter vector containing the κB binding sites), respectively, A. Berns (The Netherlands Cancer Institute) for floxed Trp53 mice, and E. Fujita, Y. Ishiyama, R. Kobayashi and Y. Ishikawa for their excellent technical assistance. This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture and Health and Labor Sciences Research Grants (to I.K.); a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan; and grants from the Suzuken Memorial Foundation, the Japan Diabetes Foundation, the Ichiro Kanehara Foundation, the Tokyo Biochemical Research Foundation, the Takeda Science Foundation, the Cell Science Research Foundation and the Japan Foundation of Applied Enzymology (to T.M.).
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Minamino, T., Orimo, M., Shimizu, I. et al. A crucial role for adipose tissue p53 in the regulation of insulin resistance. Nat Med 15, 1082–1087 (2009). https://doi.org/10.1038/nm.2014
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