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

Cadoudal, Thomas; Blouin, Jean-Marc; Collinet, Martine; Fouque, Françoise; Tan, Garry D; Loizon, Emmanuelle; Beale, Elmus G.; Frayn, Keith N.; Karpe, Fredrik; Vidal, Hubert; Benelli, C; Forest, Claude

doi:10.1007/s00125-006-0560-5

Cited by 59 publications

(56 citation statements)

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“…The lack of induction of GyK mRNA by rosiglitazone has been confirmed in human adipose tissue explants (30). No change in Gyk mRNA expression has been observed in WAT of type 2 diabetic patients treated with thiazolidinediones (31,32).…”

Section: Discussionmentioning

confidence: 86%

The Transcriptional Coactivator Peroxisome Proliferator–Activated Receptor (PPAR)γ Coactivator-1α and the Nuclear Receptor PPARα Control the Expression of Glycerol Kinase and Metabolism Genes Independently of PPARγ Activation in Human White Adipocytes

et al. 2007

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OBJECTIVE—The purpose of this work was to determine the pattern of genes regulated by peroxisome proliferator–activated receptor (PPAR) γ coactivator 1α (PGC-1α) in human adipocytes and the involvement of PPARα and PPARγ in PGC-1α transcriptional action. RESEARCH DESIGN AND METHODS—Primary cultures of human adipocytes were transduced with a PGC-1α adenovirus and treated with PPARγ and PPARα agonists. Variation in gene expression was assessed using pangenomic microarrays and quantitative RT-PCR. To investigate glycerol kinase (GyK), a target of PGC-1α, we measured enzymatic activity and glycerol incorporation into triglycerides. In vivo studies were performed on wild-type and PPARα−/− mice. The GyK promoter was studied using chromatin immunoprecipitation and promoter reporter gene assays. RESULTS—Among the large number of genes regulated by PGC-1α independently of PPARγ, new targets involved in metabolism included the gene encoding GyK. The induction of GyK by PGC-1α was observed at the levels of mRNA, enzymatic activity, and glycerol incorporation into triglycerides. PPARα was also upregulated by PGC-1α. Its activation led to an increase in GyK expression and activity. PPARα was shown to bind and activate the GyK promoter. Experiments in mice confirmed the role of PGC-1α and PPARα in the regulation of GyK in vivo. CONCLUSIONS—This work uncovers novel pathways regulated by PGC-1α and reveals that PPARα controls gene expression in human white adipocytes. The induction of GyK by PGC-1α and PPARα may promote a futile cycle of triglyceride hydrolysis and fatty acid reesterification.

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Section: Discussionmentioning

confidence: 86%

The Transcriptional Coactivator Peroxisome Proliferator–Activated Receptor (PPAR)γ Coactivator-1α and the Nuclear Receptor PPARα Control the Expression of Glycerol Kinase and Metabolism Genes Independently of PPARγ Activation in Human White Adipocytes

et al. 2007

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“…In contrast to these chronic studies of pioglitazone and to studies involving long-term effects of other TZDs including rosiglitazone, some investigators have found that short-term treatment with rosiglitazone can decrease NEFA output, possibly due to increased NEFA reesterification mediated by activated glyceroneogenesis. 4,5,9 The reasons for the apparent discrepancies between long-term versus short-term studies of TZDs on adipose tissue NEFA output are not completely clear but could be related to differences in treatment duration and to other experimental differences as well.…”

Section: Discussionmentioning

confidence: 99%

“…In the current experiments, we found increases in adipose tissue protein content and mitochondrial DNA content, suggesting the possibility of increased numbers of smaller, more lipolytically active adipocytes with less tendency to store triglyceride than larger adipocytes. It should also be noted that Cadoudal et al 5 studied fasting Zucker rats after 4 days of rosiglitazone treatment, whereas we studied adipose tissue isolated from nonfasting SHR that had been treated with pioglitazone for 4 months. Under fasting conditions, the glyceroneogenesis pathway provides glycerol-3-phosphate required for NEFA reesterification in triglycerides from nonglucose precursors, whereas in the postprandial state, glycerol-3-phosphate is synthesized mainly from glucose during glycolysis.…”

Section: Discussionmentioning

confidence: 99%

“…There are conflicting results regarding the effects of TZDs on the adipose tissue release of NEFA. For example, Cadoudal and colleagues 4,5 reported that short-term treatment (4 days) of obese Zucker rats with rosiglitazone reduced NEFA output by inducing glyceroneogenesis and promoting fatty acid reesterification in adipocytes. 4,5 According to this hypothesis, TZDs inhibit net NEFA release by increasing the expression of the gene encoding phosphoenolpyruvate carboxykinase (PEPCK), a key enzyme involved in glyceroneogenesis.…”

Section: Introductionmentioning

confidence: 99%

“…For example, Cadoudal and colleagues 4,5 reported that short-term treatment (4 days) of obese Zucker rats with rosiglitazone reduced NEFA output by inducing glyceroneogenesis and promoting fatty acid reesterification in adipocytes. 4,5 According to this hypothesis, TZDs inhibit net NEFA release by increasing the expression of the gene encoding phosphoenolpyruvate carboxykinase (PEPCK), a key enzyme involved in glyceroneogenesis. 4 Under fasting conditions, the glyceroneogenesis pathway provides glycerol-3-phosphate from non-glucose precursors for NEFA reesterification in triglycerides, whereas in the postprandial state, glycerol-3-phosphate is synthesized mainly from glucose during glycolysis.…”

Section: Introductionmentioning

confidence: 99%

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Long-term pioglitazone treatment enhances lipolysis in rat adipose tissue

et al. 2008

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Objectives: The insulin-sensitizing effects of thiazolidinediones are believed to depend at least in part on reductions in circulating levels of nonesterified fatty acids (NEFA). The mechanisms that mediate the reductions in NEFA are not fully understood and could involve reductions in adipose tissue lipolysis, increases in glyceroneogenesis and NEFA reesterification in triglycerides in adipose tissue and increases in NEFA metabolism by oxidative tissues. Methods: In a congenic strain of spontaneously hypertensive rats that fed a high-sucrose diet to promote features of the metabolic syndrome, we studied the effects of chronic pioglitazone treatment over 4 months on adipose tissue lipolysis and NEFA metabolism. Results: We observed significant increases in basal and adrenaline-stimulated NEFA and glycerol release, and near-total suppression of NEFA reesterification in epididymal adipose tissue isolated from rats chronically treated with pioglitazone. However, pioglitazone-treated rats also exhibited significant increases in mitochondrial DNA levels in adipose tissue (3.2-fold increase, P ¼ 0.001) and potentially greater sensitivity to the antilipolytic effects of insulin than untreated controls. In addition, chronic pioglitazone treatment was associated with increased palmitate oxidation in soleus muscle, reduced fasting levels of serum NEFA and triglycerides, as well as reduced serum levels of insulin and increased serum levels of adiponectin. Conclusions: Despite suppressing NEFA reesterification and increasing basal and adrenaline-stimulated lipolysis, chronic pioglitazone treatment may decrease circulating NEFA levels in part by increasing adipose tissue sensitivity to the antilipolytic effects of insulin and by enhancing NEFA oxidation in skeletal muscle.

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Dietary n‐3 long‐chain polyunsaturated fatty acids modify phosphoenolpyruvate carboxykinase activity and lipid synthesis from glucose in adipose tissue of rats fed a high‐sucrose diet

Londero

Rieger

Hansen

et al. 2013

Cell Biochemistry & Function

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Long-chain polyunsaturated n-3 fatty acids (n-3 LCPUFAs) have hypolipidemic effects and modulate intermediary metabolism to prevent or reverse insulin resistance in a way that is not completely elucidated. Here, effects of these fatty acids on the lipid profile, phosphoenolpyruvate carboxykinase (PEPCK) activity, lipid synthesis from glucose in epididymal adipose tissue (Ep-AT) and liver were investigated. Male rats were fed a high-sucrose diet (SU diet), containing either sunflower oil or a mixture of sunflower and fish oil (SU-FO diet), and the control group was fed a standard diet. After 13 weeks, liver, adipose tissue and blood were harvested and analysed. The dietary n-3 LCPUFAs prevented sucrose-induced increase in adiposity and serum free fat acids, serum and hepatic triacylglycerol and insulin levels. Furthermore, these n-3 LCPUFAs decreased lipid synthesis from glucose and increased PEPCK activity in the Ep-AT of rats fed the SU-FO diet compared to those fed the SU diet, besides reducing lipid synthesis from glucose in hepatic tissue. Thus, the inclusion of n-3 LCPUFAs in the diet may be beneficial for the prevention or attenuation of dyslipidemia and insulin resistance, and for reducing the risk of related chronic diseases.

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

Cited by 59 publications

References 50 publications

The Transcriptional Coactivator Peroxisome Proliferator–Activated Receptor (PPAR)γ Coactivator-1α and the Nuclear Receptor PPARα Control the Expression of Glycerol Kinase and Metabolism Genes Independently of PPARγ Activation in Human White Adipocytes

The Transcriptional Coactivator Peroxisome Proliferator–Activated Receptor (PPAR)γ Coactivator-1α and the Nuclear Receptor PPARα Control the Expression of Glycerol Kinase and Metabolism Genes Independently of PPARγ Activation in Human White Adipocytes

Long-term pioglitazone treatment enhances lipolysis in rat adipose tissue

Dietary n‐3 long‐chain polyunsaturated fatty acids modify phosphoenolpyruvate carboxykinase activity and lipid synthesis from glucose in adipose tissue of rats fed a high‐sucrose diet

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