Selective deletion of adipocytes, but not preadipocytes, by TNF-α through C/EBP- and PPARγ-mediated suppression of NF-B

Abstract

Tumor necrosis factor-α (TNF-α) is a key regulator of adipose tissue mass, but mechanisms underlying this effect have not been fully elucidated. We found that exposure to TNF-α caused a significant decrease in the number of adipocytes, but not preadipocytes. Subsequent experiments revealed that TNF-α selectively deleted adipocytes through induction of apoptosis. Following exposure to TNF-α, rapid activation of nuclear factor-B (NF-B) was observed only in preadipocytes, but not in adipocytes. Inhibition of NF-B rendered preadipocytes susceptible to TNF-α-induced apoptosis, suggesting that different activity of NF-B is the determinant for the distinct apoptotic responses. During adipocyte differentiation, expression and activity of peroxisome proliferator-activated receptor-γ (PPARγ) were upregulated. Treatment of preadipocytes with a PPARγ agonist attenuated NF-B activation and rendered the cells vulnerable to TNF-α-induced apoptosis. Conversely, treatment of adipocytes with a PPARγ antagonist enhanced NF-B activation and conferred resistance to TNF-α-induced apoptosis, suggesting involvement of PPARγ in the suppression of NF-B in adipocytes. We also found that, following differentiation, expression and activity of CCAAT/enhancer binding protein (C/EBP), especially C/EBPα and C/EBPΒ, were upregulated in adipocytes. Overexpression of individual C/EBPs significantly inhibited activation of NF-B in preadipocytes. Furthermore, transfection with siRNA for C/EBPα or C/EBPΒ enhanced activity of NF-B in adipocytes, suggesting that C/EBP is also involved in the repression of NF-B in adipocytes. These results suggested novel mechanisms by which TNF-α selectively deletes adipocytes in the adipose tissue. The C/EBP- and PPARγ-mediated suppression of NF-B may contribute to TNF-α-related loss of adipose tissue mass under certain pathological situations, such as cachexia. © 2010 USCAP, Inc All rights reserved.