PPARα Activation by Wy 14643 Induces Transactivation of the Rat UCP-1 Promoter without Increasing UCP-1 mRNA Levels and Attenuates PPARγ-Mediated Increases in UCP-1 mRNA Levels Induced by Rosiglitazone in Fetal Rat Brown Adipocytes

Teruel, Teresa; Clapham, John C.; Smith, Stephen A.

doi:10.1006/bbrc.1999.1526

Cited by 25 publications

(25 citation statements)

References 22 publications

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“…Our results show that insulin produces a small induction of UCP-1 and UCP-3 expression while rosiglitazone induction of both UCPs, mainly UCP-1, is robust and seems to be directly due to the presence of the PPAR response element present in their promoters [13][14][15]. The concentration of rosiglitazone used in our experiments was 10 μmol/l, the optimal dose determined in previous studies for use in brown adipocytes [13], and close to the peak plasma concentration reached in humans, 2 μmol/l, after oral administration at the doses used in clinical practice [27].…”

Section: Discussionmentioning

confidence: 72%

“…Northern blotting RNA was isolated and submitted to northern blot analysis as described previously [14]. For serial hybridisation with different probes, such as FAS, LPL, HSL, UCP-1 and UCP-3 cDNAs, the blots were stripped and then rehybridised as needed in each case.…”

Section: Methodsmentioning

confidence: 99%

“…LPL activity was assayed in triplicate using an egg lecithin-stabilised emulsion of 14 C-fatty acid-labelled triolein as substrate containing: 2.5 mmol/l triolein, 2.4% BSA, 0.2 mol/l Tris, 0.1 mol/l NaCl, and 0.8% heated rat serum (pH 8.2), in the absence or presence of 1 mol/l NaCl (high saline concentrations). LPL activity was determined by subtracting the non-LPLdependent activity (high salt) from the total lipolytic activity.…”

Section: Methodsmentioning

confidence: 99%

“…Moreover, we have recently shown that rosiglitazone produces insulin sensitisation under physiological and insulin-resistance conditions in cultured brown fat cells [11,12]. Regarding gene expression, rosiglitazone up-regulated ucp-1 through binding to the PPAR response element present in the enhancer of this gene [13][14][15]. Fuels for thermogenesis are provided as fatty acids, which can be obtained: (1) via uptake from lipoproteins by the action of LPL; (2) via lipolysis from stored triglycerides by HSL; and (3) via de novo lipid synthesis by fatty acid synthase (FAS).…”

Section: Introductionmentioning

confidence: 99%

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Rosiglitazone up-regulates lipoprotein lipase, hormone-sensitive lipase and uncoupling protein-1, and down-regulates insulin-induced fatty acid synthase gene expression in brown adipocytes of Wistar rats

et al. 2005

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Aims/hypothesis: Although thiazolidinediones are now widely used to treat type 2 diabetes, their mechanism of action remains largely unknown. They are agonists for the transcription factor PPARγ, and in addition to their insulin-sensitising effects, they can promote adipogenesis and control gene expression in adipose tissues. We have explored the effect of rosiglitazone on insulin-mediated induction of pivotal genes involved in lipid metabolism and thermogenesis in brown fat. The genes studied were: (1) lipoprotein lipase (lpl), which is involved in lipid uptake; (2) hormone-sensitive lipase (hsl), which mobilises fatty acids from stored triglycerides; (3) fatty acid synthase (fas), which regulates de novo lipogenesis; and (4) the uncoupling proteins (ucp) 1 and 3, which control thermogenesis. Methods: We used fetal rat primary brown adipocytes cultured with insulin, rosiglitazone or both combined. Then, we studied gene expression by northern and western blotting, as well as 'run-on' and gel-shift assays to identify binding of potential transcription factors to the fas promoter. Results: Exposure to rosiglitazone for 24 h induced ucp-1, lpl and hsl gene expression and when rosiglitazone was combined with insulin a synergistic effect on lpl and ucp-3 mRNA expression was produced. These effects were consistent with increased LPL and HSL activities as well as respiration rates, mainly in response to exogenous palmitate. In contrast, treatment with rosiglitazone did not alter FAS mRNA basal levels but prevented the induction elicited by insulin in a time-and dose-dependent manner. Correspondingly diminished FAS protein levels and activity, as well as cellular lipid content, were observed, indicating an antilipogenic action of rosiglitazone in brown adipocytes. Furthermore, rosiglitazone impaired insulin increase in the FAS transcription rate by antagonising insulin-induced binding of upstream stimulatory factors to the E-box consensus sequence in the FAS promoter and insulin-induced binding of activating protein-1. Conclusions/interpretation: Rosiglitazone prevents insulin-induced up-regulation of the main lipogenic enzyme but increases the expression of those enzymes involved in lipid uptake and mobilisation, favouring fatty acid utilisation through uncoupled respiration.

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Section: Discussionmentioning

confidence: 72%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Rosiglitazone up-regulates lipoprotein lipase, hormone-sensitive lipase and uncoupling protein-1, and down-regulates insulin-induced fatty acid synthase gene expression in brown adipocytes of Wistar rats

et al. 2005

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“…Brown adipocytes are also a target for rosiglitazone action since they show high expression of peroxisome proliferator-activated receptor (PPAR)γ, and rosiglitazone increased expression of the thermogenic uncoupling protein by binding to the PPARγ response element described in the enhancer of this gene [27]. We have also shown that rosiglitazone produces insulin sensitisation in cultured brown adipocytes [28].…”

Section: Introductionmentioning

confidence: 73%

Rosiglitazone ameliorates insulin resistance in brown adipocytes of Wistar rats by impairing TNF-α induction of p38 and p42/p44 mitogen-activated protein kinases

et al. 2004

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Aims/hypothesis. TNF-α caused insulin resistance on glucose uptake and on insulin signalling in fetal brown adipocytes. Since treatment with TNF-α activates stress kinases, including c-jun NH2 terminal kinase (JNK), and p42/p44 and p38 mitogen-activated protein kinases (MAPK), we explored the contribution of these pathways to insulin resistance by TNF-α. Rosiglitazone is used to treat Type 2 diabetes as it improves insulin sensitivity in vivo. However, its ability to ameliorate TNF-α-induced insulin resistance in brown adipocytes remains to be explored. Methods. We used fetal rat primary brown adipocytes cultured with TNF-α, with or without stress kinase inhibitors or rosiglitazone, and further stimulated with insulin. Then, we measured glucose uptake and GLUT4 translocation. To determine the insulin signalling cascade, we submitted cells to lysis, immunoprecipitation and immunoblotting.

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Synergistic Activation of UCP-3 Expression in Cultured Fetal Rat Brown Adipocytes by PPARα and PPARγ Ligands

Teruel

Smith

Peterson

et al. 2000

Biochemical and Biophysical Research Communications

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PPARα Activation by Wy 14643 Induces Transactivation of the Rat UCP-1 Promoter without Increasing UCP-1 mRNA Levels and Attenuates PPARγ-Mediated Increases in UCP-1 mRNA Levels Induced by Rosiglitazone in Fetal Rat Brown Adipocytes

Cited by 25 publications

References 22 publications

Rosiglitazone up-regulates lipoprotein lipase, hormone-sensitive lipase and uncoupling protein-1, and down-regulates insulin-induced fatty acid synthase gene expression in brown adipocytes of Wistar rats

Rosiglitazone up-regulates lipoprotein lipase, hormone-sensitive lipase and uncoupling protein-1, and down-regulates insulin-induced fatty acid synthase gene expression in brown adipocytes of Wistar rats

Rosiglitazone ameliorates insulin resistance in brown adipocytes of Wistar rats by impairing TNF-α induction of p38 and p42/p44 mitogen-activated protein kinases

Synergistic Activation of UCP-3 Expression in Cultured Fetal Rat Brown Adipocytes by PPARα and PPARγ Ligands

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