Thiazolidinediones block fatty acid release by inducing glyceroneogenesis in fat cells.
Thiazolidinediones are used to treat type 2 diabetes mellitus because they decrease plasma glucose, insulin, triglyceride, and fatty acid levels. Thiazolidinediones are agonists for peroxisome proliferator-activated receptor gamma, a nuclear receptor that is highly expressed in fat tissue. We identify glyceroneogenesis as a target of thiazolidinediones in cultured adipocytes and fat tissues of Wistar rats. The activation of glyceroneogenesis by thiazolidinediones occurs mainly in visceral fat, the same fat depot that is specifically implicated in the progression of obesity to type 2 diabetes. The increase in glyceroneogenesis is a result of the induction of its key enzyme, phosphoenolpyruvate carboxykinase, whose gene expression is peroxisome proliferator-activated receptor gamma-dependent in adipocytes. The main role of this metabolic pathway is to allow the re-esterification of fatty acids via a futile cycle in adipocytes, thus lowering fatty acid release into the plasma. The importance of such a fatty acid re-esterification process in the control of lipid homeostasis is highlighted by the existence of a second thiazolidinedione-induced pathway involving glycerol kinase. We show that glyceroneogenesis accounts for at least 75% of the whole thiazolidinedione effect. Because elevated plasma fatty acids promote insulin resistance, these results suggest that the glyceroneogenesis-dependent fatty acid-lowering effect of thiazolidinediones could be an essential aspect of the antidiabetic action of these drugs.
Tordjman
Joan
J
UMR-S 530 INSERM, Université Paris 5, Centre Universitaire, 45 rue des Saints-Pères, 75006 Paris, France.
Chauvet
Geneviève
G
Quette
Joëlle
J
Beale
Elmus G
EG
Forest
Claude
C
Antoine
Bénédicte
B
D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D004951:Esterification; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005990:Glycerol / Q000378:metabolism*; D005991:Glycerol Kinase / Q000378:metabolism; D006706:Homeostasis; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007545:Isoproterenol / Q000494:pharmacology; D050356:Lipid Metabolism; D008066:Lipolysis / Q000187:drug effects; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000096:biosynthesis / Q000235:genetics; D000077205:Pioglitazone; D019289:Pyruvic Acid / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000494:pharmacology; D014781:Viscera
D000318:Adrenergic beta-Agonists; D005227:Fatty Acids; D007004:Hypoglycemic Agents; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; D019289:Pyruvic Acid; D000242:Cyclic AMP; D005991:Glycerol Kinase; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D007545:Isoproterenol; D005990:Glycerol; D000077205:Pioglitazone