title: Oxidative stress accumulates in adipose tissue during aging and inhibits adipogenesis.
abstract: Aging constitutes a major independent risk factor for the development of type 2 diabetes and is accompanied by insulin resistance and adipose tissue dysfunction. One of the most important factors implicitly linked to aging and age-related chronic diseases is the accumulation of oxidative stress. However, the effect of increased oxidative stress on adipose tissue biology remains elusive. In this study, we demonstrate that aging in mice results in a loss of fat mass and the accumulation of oxidative stress in adipose tissue. In vitro, increased oxidative stress through glutathione depletion inhibits preadipocyte differentiation. This inhibition of adipogenesis is at least in part the result of reduced cell proliferation and an inhibition of G(1)→S-phase transition during the initial mitotic clonal expansion of the adipocyte differentiation process. While phosphorylation of the retinoblastoma protein (Rb) by cyclin/cdk complexes remains unaffected, oxidative stress decreases the expression of S-phase genes downstream of Rb. This silencing of S phase gene expression by increased oxidative stress is mediated through a transcriptional mechanism involving the inhibition of E2F recruitment and transactivation of its target promoters. Collectively, these data demonstrate a previously unrecognized role of oxidative stress in the regulation of adipogenesis which may contribute to age-associated adipose tissue dysfunction.
authors.affiliation: Saha Cardiovascular Research Center, University of Kentucky College of Medicine, Lexington, Kentucky, United States of America.
authors.forename: Hannes M
authors.initials: HM
authors.lastname: Findeisen
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Pearson
authors.forename: Florence
authors.initials: F
authors.lastname: Gizard
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhao
authors.forename: Hua
authors.initials: H
authors.lastname: Qing
authors.forename: Karrie L
authors.initials: KL
authors.lastname: Jones
authors.forename: Dianne
authors.initials: D
authors.lastname: Cohn
authors.forename: Elizabeth B
authors.initials: EB
authors.lastname: Heywood
authors.forename: Rafael
authors.initials: R
authors.lastname: de Cabo
authors.forename: Dennis
authors.initials: D
authors.lastname: Bruemmer
mesh_terms: D041721:3T3-L1 Cells; D000273:Adipose Tissue / Q000254:growth & development / Q000378:metabolism*; D000375:Aging / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D001823:Body Composition; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D005978:Glutathione / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D005978:Glutathione