The short- and long-term effects of tumor necrosis factor-alpha and BRL 49653 on peroxisome proliferator-activated receptor (PPAR)gamma2 gene expression and other adipocyte genes.
Expression of tumor necrosis factor-alpha(TNFalpha) in adipocytes has been reported to correlate with insulin resistance associated with obesity. The thiazolidinediones such as BRL 49653 have been reported to improve insulin sensitivity in obese animals and humans. Although its exact mechanism of action is not known, BRL 49653 has been shown to antagonize some of the inhibitory actions of TNFalpha. BRL 49653 binds and activates the peroxisome proliferator-activated receptor (PPARgamma2), an important nuclear transcription factor in adipocyte differentiation; however, its regulation of PPARgamma2 in differentiated adipocytes is unknown. In this paper, we find that BRL 49653 blocked the ability of TNFalpha to down-regulate the expression and transcription of several adipocyte genes, but BRL 49653 did not prevent TNFalpha from down-regulating PPARgamma2. Moreover, BRL 49653 alone initially decreased the expression of PPARgamma2 mRNA and protein greatly. After 24 h of treatment in 3T3-L1 adipocytes, BRL 49653 down-regulated PPARgamma2 by greater than 90% and potentiated the decrease of PPARgamma2 mRNA by TNFalpha at this time. These unexpected results prompted us to repeat the experiments for a longer time to determine whether BRL 49653 would continue to down-regulate PPARgamma2. With prolonged BRL 49653 treatment, PPARgamma2 mRNA expression was not decreased as greatly, and the protein levels were decreased 20-30% below control at 72 h compared to 90% at 24 h. Although BRL 49653 continued to prevent the inhibitory effects of TNFgamma on perilipin and aP2 mRNA, by 72 h, BRL 49653 was not as potent an inhibitor of TNFalpha's down-regulation of perilipin protein. Since PPARgamma2 protein was more abundant at this time, these results suggest that the level of PPARgamma2 protein is not the sole factor that regulates the transcriptional control by BRL 49653.
The USDA Human Nutrition Research Center on Aging at Tufts University, Tupper Medical Research Institute, New England Medical Center, Boston, Massachusetts 02111, USA.
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Rosenbaum
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Greenberg
D017667:Adipocytes / Q000187:drug effects*; D000818:Animals; D002352:Carrier Proteins / Q000187:drug effects / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005786:Gene Expression Regulation / Q000187:drug effects*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D051379:Mice; D018996:Myelin P2 Protein / Q000187:drug effects / Q000235:genetics; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D000070778:Perilipin-1; D010750:Phosphoproteins / Q000187:drug effects / Q000235:genetics; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D000077154:Rosiglitazone; D002787:Sterol Esterase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D013997:Time Factors; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D002352:Carrier Proteins; C082667:Fabp5 protein, mouse; C086936:Fabp7 protein, mouse; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D007004:Hypoglycemic Agents; D018996:Myelin P2 Protein; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D000070778:Perilipin-1; D010750:Phosphoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000077154:Rosiglitazone; D002787:Sterol Esterase; D015230:Prostaglandin D2