PMID- 8923470
OWN - NLM
STAT- MEDLINE
DCOM- 19970306
LR  - 20161123
IS  - 0888-8809 (Print)
IS  - 0888-8809 (Linking)
VI  - 10
IP  - 11
DP  - 1996 Nov
TI  - Negative regulation of peroxisome proliferator-activated receptor-gamma gene 
      expression contributes to the antiadipogenic effects of tumor necrosis 
      factor-alpha.
PG  - 1457-66
AB  - Recent studies indicate that a peroxisome proliferator-activated receptor, PPAR 
      gamma, functions as an important adipocyte determination factor. In contrast, 
      tumor necrosis factor-alpha (TNF alpha) inhibits adipogenesis, causes 
      dedifferentiation of mature adipocytes, and reduces the expression of several 
      adipocyte-specific genes. Here, we report that treatment of 3T3-L1 adipocytes 
      with TNF alpha resulted in a time- and concentration-dependent decrease in PPAR 
      gamma mRNA expression to the level detected in preadipocytes. PPAR gamma mRNA 
      levels were reduced by 95% with 3 nM TNF alpha treatment for 24 h. Half-maximal 
      effects were seen after 3 h treatment with 3 nM TNF alpha or with 50 pM TNF alpha 
      (24-h exposure). Parallel reductions in PPAR gamma protein levels were also 
      observed after treatment of 3T3-L1 adipocytes with TNF alpha. Using a 
      ribonuclease protection assay, both alternatively spliced PPAR gamma isoforms 
      (gamma 1 and gamma 2) were shown to be negatively regulated by TNF alpha. The 
      down-regulation of PPAR gamma by TNF-alpha preceded the diminution in expression 
      of other adipocyte-specific genes including CCAAT/enhancer binding protein and 
      adipocyte fatty acid-binding protein (aP2). The effect of TNF alpha was specific 
      for the gamma-isoform of PPARs, since the expression of PPAR delta mRNA was not 
      affected by treatment with TNF alpha. Low level constitutive expression of PPAR 
      gamma in 3T3-L1 adipocytes (at levels approximately 2- to 3-fold higher than in 
      preadipocytes) partially blocked the inhibitory effect of TNF alpha on aP2 and 
      adipsin expression. These findings support the following conclusions: 1) PPAR 
      gamma expression is necessary for the maintenance of the adipocyte phenotype. 2) 
      PPAR gamma, but not PPAR delta, expression is sufficient to attenuate TNF 
      alpha-mediated effects on adipocyte phenotype. 3) Reduced PPAR gamma gene 
      expression is likely to represent an important component of the mechanism by 
      which TNF alpha exerts its antiadipogenic effects.
FAU - Zhang, B
AU  - Zhang B
AD  - Department of Molecular Endocrinology, Merck Research Laboratories, Rahway, New 
      Jersey 07065, USA.
FAU - Berger, J
AU  - Berger J
FAU - Hu, E
AU  - Hu E
FAU - Szalkowski, D
AU  - Szalkowski D
FAU - White-Carrington, S
AU  - White-Carrington S
FAU - Spiegelman, B M
AU  - Spiegelman BM
FAU - Moller, D E
AU  - Moller DE
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Mol Endocrinol
JT  - Molecular endocrinology (Baltimore, Md.)
JID - 8801431
RN  - 0 (CCAAT-Enhancer-Binding Proteins)
RN  - 0 (Carrier Proteins)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Fabp5 protein, mouse)
RN  - 0 (Fabp7 protein, mouse)
RN  - 0 (Fatty Acid-Binding Protein 7)
RN  - 0 (Fatty Acid-Binding Proteins)
RN  - 0 (Myelin P2 Protein)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Receptors, Cytoplasmic and Nuclear)
RN  - 0 (Transcription Factors)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 3.4.21.- (Serine Endopeptidases)
RN  - EC 3.4.21.46 (Complement Factor D)
RN  - EC 3.4.21.46 (complement factor D, mouse)
SB  - IM
MH  - 3T3 Cells/drug effects
MH  - Adipocytes/cytology/*drug effects/metabolism
MH  - Animals
MH  - CCAAT-Enhancer-Binding Proteins
MH  - Carrier Proteins/biosynthesis/drug effects/genetics
MH  - Cell Differentiation/drug effects
MH  - Cells, Cultured
MH  - Complement Factor D
MH  - DNA-Binding Proteins/biosynthesis/drug effects/genetics
MH  - Dose-Response Relationship, Drug
MH  - *Down-Regulation
MH  - Fatty Acid-Binding Protein 7
MH  - Fatty Acid-Binding Proteins
MH  - Gene Expression Regulation/drug effects
MH  - Mice
MH  - Myelin P2 Protein/biosynthesis/drug effects/genetics
MH  - *Neoplasm Proteins
MH  - *Nerve Tissue Proteins
MH  - Nuclear Proteins/biosynthesis/drug effects/genetics
MH  - Receptors, Cytoplasmic and Nuclear/drug effects/*genetics
MH  - Serine Endopeptidases/biosynthesis/drug effects/genetics
MH  - Suppression, Genetic
MH  - Time Factors
MH  - Transcription Factors/drug effects/*genetics
MH  - Tumor Necrosis Factor-alpha/*pharmacology
EDAT- 1996/11/01 00:00
MHDA- 1996/11/01 00:01
CRDT- 1996/11/01 00:00
PHST- 1996/11/01 00:00 [pubmed]
PHST- 1996/11/01 00:01 [medline]
PHST- 1996/11/01 00:00 [entrez]
AID - 10.1210/mend.10.11.8923470 [doi]
PST - ppublish
SO  - Mol Endocrinol. 1996 Nov;10(11):1457-66. doi: 10.1210/mend.10.11.8923470.