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.
Highlights
Numbers are constant or increase in different depots with increasing age [1, 2]
Cross-link Immunoprecipitation Activity Assay— RNA oligomers (CUG) triplet repeat-binding protein-1 (CUGBP1) mRNA levels changed in a similar way with aging (27 Ϯ 3 arbitrary units by real time PCR in young and 44 Ϯ 3 in old animals; p Ͻ 0.01; n ϭ 4; t test)
We demonstrated that CUGBP1 is implicated in differentiation of primary preadipocytes through enhancing CCAAT/enhancer-binding protein (C/EBP)-liver-enriched inhibitory protein (LIP) expression
Summary
Numbers are constant or increase in different depots with increasing age [1, 2]. Because capacity for lipolysis decreases in fat cells with aging [4, 5], declines in capacity for lipid accumulation could be important in contributing to reduced adipocyte size. New fat cells arise from preadipocytes throughout the life span, because new fat cells continue to appear from preadipocytes during adulthood, and preadipocytes are present in fat depots at all ages (1, 6 –10) These findings are compatible with the possibility that reduced fat depot size with aging may be related to decreased capacity of preadipocytes to differentiate and of fat cells arising from them to accumulate lipid. Reduced expression of the key adipogenic transcription factors, CCAAT/enhancer-binding protein ␣ (C/EBP␣) and peroxisome proliferator-activated receptor ␥ (PPAR␥), contribute to decreasing capacity of preadipocytes to differentiate with aging [3, 13]. CUGBP1 Impairs Adipogenesis with Aging increases within hours after induction of adipogenesis [13] This prompted us to investigate potential upstream regulators of C/EBP mRNA translation that could contribute to decreased adipogenesis with aging. The latter is located in a small open reading frame that has been shown to regulate initiation of translation from different AUG codons of the C/EBP mRNA
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