title: Increased CUG triplet repeat-binding protein-1 predisposes to impaired adipogenesis with aging.
abstract: Preadipocyte differentiation capacity declines between middle and old age. Expression of the adipogenic transcription factors, CCAAT/enhancer-binding protein (C/EBP) alpha and peroxisome proliferator-activated receptor gamma (PPARgamma), is lower in differentiating preadipocytes from old than young animals, although no age-related changes occur in C/EBPbeta mRNA, which is upstream of C/EBPalpha and PPARgamma. C/EBPbeta-liver-enriched inhibitory protein (C/EBPbeta-LIP), a truncated C/EBPbeta isoform that is a dominant inhibitor of differentiation, increases with aging in rat fat tissue and preadipocytes. CUG triplet repeat-binding protein-1 (CUGBP1) binds to C/EBPbeta mRNA, increasing C/EBPbeta-LIP translation. Abundance and nucleotide binding activity of CUGBP1 increased with aging in preadipocytes. CUGBP1 overexpression in preadipocytes from young animals increased C/EBPbeta-LIP and impaired adipogenesis. Decreasing CUGBP1 in preadipocytes from old rats by RNA interference reduced C/EBPbeta-LIP abundance and promoted adipogenesis. Tumor necrosis factor-alpha, levels of which are elevated in fat tissue with aging, increased CUGBP1 protein, CUGBP1 binding activity, and C/EBPbeta-LIP in preadipocytes from young rats. Thus, CUGBP1 contributes to regulation of adipogenesis in primary preadipocytes and is responsive to tumor necrosis factor-alpha. With aging, preadipocyte CUGBP1 abundance and activity increases, resulting in enhanced translation of the C/EBPbeta-LIP isoform, thereby blocking effects of adipogenic transcription factors, predisposing preadipocytes from old animals to resist adipogenesis. Altered translational processing, possibly related to changes in cytokine milieu and activation of stress responses, may contribute to changes in progenitor differentiation and tissue function with aging.
authors.affiliation: Medicine and Biochemistry, Boston University, Boston, Massachusetts 02118, USA.
authors.forename: Iordanes
authors.initials: I
authors.lastname: Karagiannides
authors.forename: Thomas
authors.initials: T
authors.lastname: Thomou
authors.forename: Tamara
authors.initials: T
authors.lastname: Tchkonia
authors.forename: Tamar
authors.initials: T
authors.lastname: Pirtskhalava
authors.forename: Kyriakos E
authors.initials: KE
authors.lastname: Kypreos
authors.forename: Andrew
authors.initials: A
authors.lastname: Cartwright
authors.forename: Georgia
authors.initials: G
authors.lastname: Dalagiorgou
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Lash
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Farmer
authors.forename: Nikolai A
authors.initials: NA
authors.lastname: Timchenko
authors.forename: James L
authors.initials: JL
authors.lastname: Kirkland
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D050156:Adipogenesis; D000375:Aging; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D000067879:CELF1 Protein; D002454:Cell Differentiation; D005786:Gene Expression Regulation; D009711:Nucleotides / Q000737:chemistry*; D047495:PPAR gamma / Q000378:metabolism*; D011485:Protein Binding; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D000067879:CELF1 Protein; C000594460:Celf1 protein, rat; D009711:Nucleotides; D047495:PPAR gamma; D016601:RNA-Binding Proteins; D014409:Tumor Necrosis Factor-alpha