BRL 49653 blocks the lipolytic actions of tumor necrosis factor-alpha: a potential new insulin-sensitizing mechanism for thiazolidinediones.
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.
Souza
S C
SC
Jean Mayer Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts 02111, USA.
Yamamoto
M T
MT
Franciosa
M D
MD
Lien
P
P
Greenberg
A S
AS
D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005990:Glycerol / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007333:Insulin Resistance; D008066:Lipolysis / Q000187:drug effects*; D051379:Mice; D000070778:Perilipin-1; D010750:Phosphoproteins / Q000096:biosynthesis; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D000077154:Rosiglitazone; D002787:Sterol Esterase / Q000096:biosynthesis; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D002352:Carrier Proteins; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D000070778:Perilipin-1; D010750:Phosphoproteins; D013844:Thiazoles; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D000077154:Rosiglitazone; D002787:Sterol Esterase; D005990:Glycerol; D015230:Prostaglandin D2