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Increased TNF and CCAAT/enhancer-binding protein homologous protein with aging predispose preadipocytes to resist adipogenesis

¹Evans Department of Medicine and Department of Biochemistry, Boston University Medical Center, Boston, Massachusetts; and ²GlaxoSmithKline, Research Triangle, North Carolina

Submitted 15 May 2007 ; accepted in final form 28 September 2007

Fat depot sizes peak in middle age but decrease by advanced old age. This phenomenon is associated with ectopic fat deposition, decreased adipocyte size, impaired differentiation of preadipocytes into fat cells, decreased adipogenic transcription factor expression, and increased fat tissue inflammatory cytokine generation. To define the mechanisms contributing to impaired adipogenesis with aging, we examined the release of TNF, which inhibits adipogenesis, and the expression of CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP), which blocks activity of adipogenic C/EBP family members, in preadipocytes cultured from young, middle-aged, and old rats. Medium conditioned by fat tissue, as well as preadipocytes, from old rats impeded lipid accumulation by preadipocytes from young animals. More TNF was released by preadipocytes from old than young rats. Differences in TNF-converting enzyme, TNF degradation, or the presence of macrophages in cultures were not responsible. TNF induced rat preadipocyte CHOP expression. CHOP was higher in undifferentiated preadipocytes from old than younger animals. Overexpression of CHOP in young rat preadipocytes inhibited lipid accumulation. TNF short interference RNA reduced CHOP and partially restored lipid accumulation in old rat preadipocytes. CHOP normally increases during late differentiation, potentially modulating the process. This late increase in CHOP was not affected substantially by aging: CHOP was similar in differentiating preadipocytes and fat tissue from old and young animals. Hypoglycemia, which normally causes an adaptive increase in CHOP, was less effective in inducing CHOP in preadipocytes from old than younger animals. Thus increased TNF release by undifferentiated preadipocytes with elevated basal CHOP contributes to impaired adipogenesis with aging.

adipocytes; CCAAT/enhancer-binding protein-; growth arrest and DNA damage 153; differentiation; stress response; hypoglycemia