1. BRL 49653 blocks the lipolytic actions of tumor necrosis factor-alpha: a potential new insulin-sensitizing mechanism for thiazolidinediones.
- Author
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Souza SC, Yamamoto MT, Franciosa MD, Lien P, and Greenberg AS
- Subjects
- 3T3 Cells, Adipocytes drug effects, Adipocytes enzymology, Adipocytes metabolism, Animals, Carrier Proteins, Fatty Acids, Nonesterified metabolism, Glycerol metabolism, Mice, Perilipin-1, Phosphoproteins biosynthesis, Prostaglandin D2 analogs & derivatives, Prostaglandin D2 pharmacology, Rosiglitazone, Sterol Esterase biosynthesis, Hypoglycemic Agents pharmacology, Insulin Resistance, Lipolysis drug effects, Thiazoles pharmacology, Thiazolidinediones, Tumor Necrosis Factor-alpha antagonists & inhibitors
- Abstract
Thiazolidinediones (TZDs) such as BRL 49653 are a class of antidiabetic agents that are agonists for the peroxisome proliferator-activated nuclear receptor (PPAR-gamma2). In vivo, TZDs reduce circulating levels of free fatty acids (FFAs) and ameliorate insulin resistance in individuals with obesity and NIDDM. Adipocyte production of TNF-alpha is proposed to play a role in the development of insulin resistance, and because BRL 49653 has been shown to antagonize some of the effects of TNF-alpha, we examined the effects of TNF-alpha and BRL 49653 on adipocyte lipolysis. After a 24-h incubation of TNF-alpha (10 ng/ml) with 3T3-L1 adipocytes, glycerol release increased by approximately 7-fold, and FFA release increased by approximately 44-fold. BRL 49653 (10 pmol/l) reduced TNF-alpha-induced glycerol release by approximately 50% (P < 0.001) and FFA release by approximately 90% (P < 0.001). BRL 49653 also reduced glycerol release by approximately 50% in adipocytes pretreated for 24 h with TNF-alpha. Prolonged treatment (5 days) with either BRL 49653 or another PPAR-gamma2 agonist, 15-d delta-12,14-prostaglandin J2 (15-d deltaPGJ2), blocked TNF-alpha-induced glycerol release by approximately 100%. Catecholamine (isoproterenol)-stimulated lipolysis was unaffected by BRL 49653 and 15-d deltaPGJ2. BRL 49653 partially blocked the TNF-alpha-mediated reduction in protein levels of hormone-sensitive lipase and perilipin A, two proteins involved in adipocyte lipolysis. These data suggest a novel pathway that may contribute to the ability of the TZDs to reduce serum FFA and increase insulin sensitivity.
- Published
- 1998
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