title: Selective deletion of adipocytes, but not preadipocytes, by TNF-alpha through C/EBP- and PPARgamma-mediated suppression of NF-kappaB.
abstract: Tumor necrosis factor-alpha (TNF-alpha) is a key regulator of adipose tissue mass, but mechanisms underlying this effect have not been fully elucidated. We found that exposure to TNF-alpha caused a significant decrease in the number of adipocytes, but not preadipocytes. Subsequent experiments revealed that TNF-alpha selectively deleted adipocytes through induction of apoptosis. Following exposure to TNF-alpha, rapid activation of nuclear factor-kappaB (NF-kappaB) was observed only in preadipocytes, but not in adipocytes. Inhibition of NF-kappaB rendered preadipocytes susceptible to TNF-alpha-induced apoptosis, suggesting that different activity of NF-kappaB is the determinant for the distinct apoptotic responses. During adipocyte differentiation, expression and activity of peroxisome proliferator-activated receptor-gamma (PPARgamma) were upregulated. Treatment of preadipocytes with a PPARgamma agonist attenuated NF-kappaB activation and rendered the cells vulnerable to TNF-alpha-induced apoptosis. Conversely, treatment of adipocytes with a PPARgamma antagonist enhanced NF-kappaB activation and conferred resistance to TNF-alpha-induced apoptosis, suggesting involvement of PPARgamma in the suppression of NF-kappaB in adipocytes. We also found that, following differentiation, expression and activity of CCAAT/enhancer binding protein (C/EBP), especially C/EBPalpha and C/EBPbeta, were upregulated in adipocytes. Overexpression of individual C/EBPs significantly inhibited activation of NF-kappaB in preadipocytes. Furthermore, transfection with siRNA for C/EBPalpha or C/EBPbeta enhanced activity of NF-kappaB in adipocytes, suggesting that C/EBP is also involved in the repression of NF-kappaB in adipocytes. These results suggested novel mechanisms by which TNF-alpha selectively deletes adipocytes in the adipose tissue. The C/EBP- and PPARgamma-mediated suppression of NF-kappaB may contribute to TNF-alpha-related loss of adipose tissue mass under certain pathological situations, such as cachexia.
authors.affiliation: Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan.
authors.forename: Minori
authors.initials: M
authors.lastname: Tamai
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Shimada
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Hiramatsu
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Hayakawa
authors.forename: Maro
authors.initials: M
authors.lastname: Okamura
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Tagawa
authors.forename: Shuhei
authors.initials: S
authors.lastname: Takahashi
authors.forename: Shotaro
authors.initials: S
authors.lastname: Nakajima
authors.forename: Jian
authors.initials: J
authors.lastname: Yao
authors.forename: Masanori
authors.initials: M
authors.lastname: Kitamura
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D017384:Sequence Deletion / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D016328:NF-kappa B; D047495:PPAR gamma; D014409:Tumor Necrosis Factor-alpha