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-Mediated Inhibition and Reversal of Adipocyte Differentiation Is Accompanied by Suppressed Expression of PPAR
without Effects on Pref-1 Expression1
Affymax Research Institute (H.X., J.P.N., J.R.G., G.M.R.), Santa Clara, California 95051; and Department of Molecular Sciences (K.E.K., J.-L.S.), GlaxoWellcome Research and Development, Research Triangle Park, North Carolina 27709
Address all correspondence and requests for reprints to: Hong Xing, Aurora Biosciences Corp., 11149 North Torrey Pines Road, La Jolla, California 92037. E-mail: XingH{at}aurorabio.com
Tumor necrosis factor 
(TNF) is a polypeptide hormone with
pleiotropic effects on cellular proliferation and differentiation. To
investigate how TNF inhibits and reverses adipocyte differentiation,
we studied the expression of two factors involved in the adipocyte
differentiation process. Peroxisome proliferator-activated receptor 
(PPAR) is a positive regulator of adipogenesis, whereas preadipocyte
factor 1 (Pref-1) inhibits adipocyte differentiation. The expression
patterns of both PPAR and Pref-1 change during early stages of
adipocyte differentiation. Decreased expression of Pref-1 and increased
expression of PPAR occur 1 day and 2 days, respectively, after
3T3-L1 cells reach confluence. During TNF-mediated inhibition of
adipocyte differentiation, PPAR messenger RNA (mRNA) expression
stays at low levels. In contrast, TNF treatment has no effect on the
normal decrease in Pref-1 gene expression that occurs during
adipogenesis. We observed that certain cytokine and growth factors
[such as TNF, basic fibroblast growth factor, transforming growth
factor ß, and protein kinase C-activating agents plus calcium
ionophore], when added to differentiated adipocytes, cause rapid
down-regulation of PPAR mRNA expression with concomitant decrease in
adipocyte-specific gene expression but fail to increase Pref-1 mRNA
expression. Moreover, addition of TNF to fully differentiated
adipocytes results in the rapid disappearance of PPAR protein
expression and the rapid loss of PPAR DNA-binding activity.
Therefore, Pref-1 seems to function as a nonreversible molecular
checkpoint whose expression is insensitive to TNF-generated signals,
whereas PPAR expression remains sensitive to TNF at all stages of
the adipogenesis program. Our results support the notion that
dedifferentiated adipocytes and preadipocytes are not identical, though
they share many similar morphological and gene expression patterns.
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