It is hypothesized that C/EBPalpha, a key transcription factor that controls both initiation of adipogenesis and maintenance of the fat cell phenotype, plays a central role in the age-related decrease in preadipocyte differentiation and lipid accumulation.
Specific Aim 1 of the investigators is to determine effects of aging on expression and activity of C/EBPalpha and transcription factors regulating its expression during preadipocyte differentiation. They will define changes in the mRNA and protein levels and functional properties of C/EBPalpha and potential C/EBPalpha regulators (CHOP, C/EBPbeta-LIP and LAP, C/EBPbeta, CUP, c-myc, PPARy:RXRa) using Northern blot, Western blot and in vitro DNA binding assays respectively in differentiating preadipocytes from 3 and 24m rats. These experiments will 1) establish temporal relationships among age-related changes in expression of C/EBPalpha, C/EBPalpha regulators, selected differentiation-dependent target genes, and lipid accumulation (TG/DNA ratio) and 2) identify those C/EBPalpha regulators which change in amount or activity during aging.
Specific Aim 2 is to determine whether age-related changes in preadipocyte differentiation are caused directly by alterations in C/EBPalpha and C/EBPalpha regulator levels and/or activity. Two experimental approaches will be used: 1) treatment of preadipocytes with agents known to alter C/EBPalpha expression (TNFa converting enzyme inhibitors, glucocorticoids, SB203580, thiazolidinediones) and 2) transfection of appropriate DNA constructs to alter levels of C/EBPalpha and those C/EBPalpha regulators identified in Specific Aim 1 that influence related changes in expression.
Specific Aim 3 is to assess the relevance of their findings to humans. They will determine in human preadipocytes whether changes in differentiation-dependent mRNA levels are blunted with age and if C/EBPalpha expression and activity decline with age.
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