Thiazolidinediones Block Fatty Acid Release by Inducing Glyceroneogenesis in Fat Cells

Abstract

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 ␥, 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 ␥-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.

Fat-specific transgenic expression of resistin in the spontaneously hypertensive rat impairs fatty acid re-esterification

“…The glycerol-3-phosphate that is required for triglyceride synthesis during re-esterification of FFA can be produced in adipose tissue through two pathways: (a) in the presence of glucose in media or in the postprandial state, glycolysis is a classical source of glycerol-3-phosphate whereas (b) in the absence of glucose in the media or during fasting when glycolysis is suppressed, the glycerol-3-phosphate can be produced by the glyceroneogenesis, 12,13 where phosphoenolpyruvate carboxykinase (PEPCK) is considered to be a key enzyme in the regulation of glyceroneogenesis and subsequent FFA re-esterification. 14,15 In the current study, we found that expression of transgenic resistin in adipocytes induced significant reduction of FFA re-esterification. In addition, the expression of the Pck1 gene encoding the PEPCK enzyme was significantly reduced in epididymal fat tissue of the SHR-Resistin transgenic strain compared to SHR controls.…”

PPARγ agonism increases rat adipose tissue lipolysis, expression of glyceride lipases, and the response of lipolysis to hormonal control

“…Two studies found a reduction in the release of lipolytic products from rodent WAT explants and 3T3-L1 adipocytes [5,6]. These were, however, primarily designed to examine NEFA re-esterification under conditions that may have favoured the latter process.…”

“…Because of its effect on plasma NEFAs, PPARγ agonism might also be expected to reduce lipolysis; however, previous studies investigating this issue have produced conflicting results. Whereas some studies have reported lower in vitro rates of glycerol and NEFA release from WAT [5,6], others that include in vivo NEFA kinetic approaches [4,7] suggest that PPARγ agonism stimulates lipolysis, an effect that would be counteracted by its concomitant action on NEFA reuptake and re-esterification.…”

Acute and selective regulation of glyceroneogenesis and cytosolic phosphoenolpyruvate carboxykinase in adipose tissue by thiazolidinediones in type 2 diabetes

“…Thiazolidinediones induce G3P synthesis through glyceroneogenesis and glycerol phosphorylation [33]. We showed that glyceroneogenesis was the main contributor pathway for fatty acid reesterification in rat adipose tissue in both basal and thiazolidinedione-stimulated conditions [19]. This result was reinforced by elegant in vivo experiments from Chen et al [34], in which mass isotopomer analyses in mice confirmed the major contribution of glyceroneogenesis to thiazolidinedione-induced triacylglycerol synthesis, with a very minor role of glycerol phosphorylation.…”

“…This pathway occurs also in liver, in addition to gluconeogenesis [18]. Recent data identified glyceroneogenesis as a thiazolidinedione target in cultured rat adipocytes and adipose tissue, which was the result of induction of its key enzyme, the cytosolic isoform of phosphoenolpyruvate carboxykinase (PEPCK-C) [19]. In cultured explants from human s.c. adipose tissue, the prototype thiazolidinedione rosiglitazone increased the expression of the gene endoing PEPCK-C (PCK1) and glyceroneogenesis [20,21].…”