title: Increased TNFalpha and CCAAT/enhancer-binding protein homologous protein with aging predispose preadipocytes to resist adipogenesis.
abstract: 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 TNFalpha, 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 TNFalpha was released by preadipocytes from old than young rats. Differences in TNFalpha-converting enzyme, TNFalpha degradation, or the presence of macrophages in cultures were not responsible. TNFalpha 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. TNFalpha 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 TNFalpha release by undifferentiated preadipocytes with elevated basal CHOP contributes to impaired adipogenesis with aging.
authors.affiliation: Evans Department of Medicine, Boston Univ. Medical Center, 88 E. Newton St., Robinson 2, Boston, MA 02118, USA.
authors.forename: Tamara
authors.initials: T
authors.lastname: Tchkonia
authors.forename: Tamar
authors.initials: T
authors.lastname: Pirtskhalava
authors.forename: Thomas
authors.initials: T
authors.lastname: Thomou
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Cartwright
authors.forename: Barton
authors.initials: B
authors.lastname: Wise
authors.forename: Iordanes
authors.initials: I
authors.lastname: Karagiannides
authors.forename: Alexander
authors.initials: A
authors.lastname: Shpilman
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Lash
authors.forename: J David
authors.initials: JD
authors.lastname: Becherer
authors.forename: James L
authors.initials: JL
authors.lastname: Kirkland
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000072198:ADAM17 Protein; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D050156:Adipogenesis / Q000187:drug effects*; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism; D000375:Aging / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004822:Epididymis / Q000166:cytology; D007668:Kidney / Q000166:cytology; D008297:Male; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D011914:Rats, Inbred BN; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D017077:Culture Media, Conditioned; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D051742:Transcription Factor CHOP; D051722:ADAM Proteins; D000072198:ADAM17 Protein