Fenofibrate and Rosiglitazone Lower Serum Triglycerides with Opposing Effects on Body Weight

Chaput, Evelyne; Saladin, Régis; Silvestre, Martine; Edgar, Alan D.

doi:10.1006/bbrc.2000.2647

Cited by 185 publications

(164 citation statements)

References 21 publications

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“…Furthermore, a significant increase in body weight was observed for both the BVT.13-and the rosiglitazone-treated animals compared with the vehicle-treated, although no difference in food intake was observed (data not shown). Weight increase is commonly associated with PPAR␥ agonist treatment and generally associated with the pharmacological activ- ity mediated through PPAR␥ agonism (38). The ob/ob mouse, as a model for type 2 diabetes, is known to respond well to the PPAR␥ agonistic TZDs, which was also confirmed here by the rosiglitazone-treated group.…”

Section: Discussionsupporting

confidence: 75%

A New Class of Peroxisome Proliferator-activated Receptor Agonists with a Novel Binding Epitope Shows Antidiabetic Effects

Östberg

Svensson²,

Selén³

et al. 2004

Journal of Biological Chemistry

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The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the NR1 subfamily of nuclear receptors. The PPARs play key roles in the control of glucose and lipid homeostasis, and the synthetic isoform-specific PPAR agonists are used clinically to improve insulin sensitivity and to lower serum triglyceride levels. All of the previously reported PPAR agonists form the same characteristic interactions with the receptor, which have been postulated to be important for the induction of agonistic activity. Here we describe a new class of PPAR␣/␥ modulators, the 5-substituted 2-benzoylaminobenzoic acids (2-BABAs). As shown by x-ray crystallography, the representative compounds BVT.13, BVT.762, and BVT.763, utilize a novel binding epitope and lack the agonist-characteristic interactions. Despite this, some compounds within the 2-BABA family are potent agonists in a cell-based reporter gene assay. Furthermore, BVT.13 displays antidiabetic effects in ob/ob mice. We concluded that the 2-BABA binding mode can be used to design isoform-specific PPAR modulators with biological activity in vivo.

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Section: Discussionsupporting

confidence: 75%

A New Class of Peroxisome Proliferator-activated Receptor Agonists with a Novel Binding Epitope Shows Antidiabetic Effects

Östberg

Svensson²,

Selén³

et al. 2004

Journal of Biological Chemistry

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“…Since perilipin is induced by PPARγ agonists [41], such an effect of thiazolidinedione could account for the reduced NEFA levels that have been frequently reported [42,43]. However, perilipin mRNA and protein levels were not changed by thiazolidinedione in the present study nor were the NEFA levels changed.…”

Section: Discussioncontrasting

confidence: 44%

Improved insulin sensitivity and adipose tissue dysregulation after short-term treatment with pioglitazone in non-diabetic, insulin-resistant subjects

et al. 2004

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Aims/hypothesis: We examined whether shortterm treatment with a thiazolidinedione improves insulin sensitivity in non-obese but insulin-resistant subjects and whether this is associated with an improvement in dysregulated adipose tissue (reduced expression of IRS-1, GLUT4, PPARγ co-activator 1 and markers of terminal differentiation) that we have previously documented to be associated with insulin resistance. Methods: Ten nondiabetic subjects, identified as having low IRS-1 and GLUT-4 protein in adipose cells as markers of insulin resistance, underwent 3 weeks of treatment with pioglitazone. The euglycaemic-hyperinsulinaemic clamp technique was used to measure insulin sensitivity before and after treatment. Serum samples were analysed for glucose, insulin, lipids, total and high-molecular-weight (HMW) adiponectin levels. Biopsies from abdominal subcutaneous adipose tissue were taken, cell size measured, mRNA and protein extracted and quantified using real-time RT-PCR and Western blot. Results: Insulin sensitivity was improved after 3 weeks treatment and circulating total as well as HMW adiponectin increased in all subjects, while no effect was seen on serum lipids. In the adipose cells, gene and protein expression of IRS-1 and PPARγ co-activator 1 remained unchanged, while adiponectin, adipocyte P 2, uncoupling protein 2, GLUT4 and liver X receptor-α increased. Insulin-stimulated tyrosine phosphorylation and p-ser-PKB/Akt increased, while no significant effect of thiazolidinedione treatment was seen on the inflammatory status of the adipose tissue in these non-obese subjects. Conclusions/interpretation: Short-term treatment with pioglitazone improved insulin sensitivity in the absence of any changes in circulating NEFA or lipid levels. Several markers of adipose cell differentiation, previously shown to be reduced in insulin resistance, were augmented, supporting the concept that insulin resistance in these individuals is associated with impaired terminal differentiation of the adipose cells.

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“…This notion is further supported by the results of metabolic profiling of BN-Lx congenic strain, which carries a segment of chromosome 8 including the ApoAI/C-III/A-IV/A-V cluster of PD/Cub origin on the Brown Norway genetic background and shows significant altera- Isotretinoin and fenofibrate induce adiposity L Sedova et al tions of carbohydrate and lipid metabolism. 14 No change in weight gain, ApoC-III expression and the increase of insulin levels observed in the fenofibrate-treated PD/Cub rats is in contrast with the findings in other models, such as Zucker fatty (fa/fa) rats, db/db mice, 36 OLETF rats 37 or fat-fed Wistar rats. 38 This fact further underlines the specific allelic combination present in the PD/Cub rat strain and provides an example of usefulness of defined genetic modelsFwhen exposed to similar conditions, the responses specifically elicited in a particular strain facilitate the identification of the causal allelic variant.…”

Section: Discussionmentioning

confidence: 91%

Isotretinoin and fenofibrate induce adiposity with distinct effect on metabolic profile in a rat model of the insulin resistance syndrome

et al. 2004

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OBJECTIVE:To investigate the effect of transcription-modulating drugs, fenofibrate and isotretinoin, on metabolic profile, insulin sensitivity of adipose and muscle tissues and gene expression in a genetic model of insulin resistance syndrome, polydactylous rat strain (PD/Cub). DESIGN: Administration of fenofibrate (100 mg/kg/day), isotretinoin (30 mg/kg/day) or vehicle to adult male PD/Cub rats fed standard laboratory chow for 15 days. MEASUREMENTS: Parameters of lipid and carbohydrate metabolismForal glucose tolerance test, serum concentrations of insulin, triglycerides (TG), free fatty acids (FFA), glycerol, total cholesterol (CH); morphometric variables, in vitro insulin sensitivity of adipose and muscle tissues, catecholamine-stimulated lipolysis and the expression of ApoC-III and Hnf-4 genes in liver. RESULTS: Both experimental groups displayed an increase in adiposity with contrasting effects on TG (lowered by fenofibrate and increased by isotretinoin) and gene expression (no change in fibrate-treated rats and increased expression of ApoC-III and Hnf-4 in isotretinoin-treated group). Fenofibrate-treated rats also showed decreased concentrations of FFA and CH with concomitant decrease of catecholamine-induced lipolysis in adipocytes, but also hyperinsulinemia and the highest insulin/ glucose ratio. Isotretinoin increased glycerol concentrations and decreased the insulin sensitivity of peripheral tissues. CONCLUSION: The PD/Cub rat showed a distinct pharmacogenetic reaction to fenofibrate and isotretinoin administration. Several lines of evidence now implicate specific variant(s) of ApoC-III and/or ApoA-V alleles as responsible for the dyslipidemia observed in this genetic model. The PD/Cub strain may also serve as a pharmacogenetic model for dissection of the retinoidinduced hypertriglyceridemia.

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Fenofibrate and Rosiglitazone Lower Serum Triglycerides with Opposing Effects on Body Weight

Cited by 185 publications

References 21 publications

A New Class of Peroxisome Proliferator-activated Receptor Agonists with a Novel Binding Epitope Shows Antidiabetic Effects

A New Class of Peroxisome Proliferator-activated Receptor Agonists with a Novel Binding Epitope Shows Antidiabetic Effects

Improved insulin sensitivity and adipose tissue dysregulation after short-term treatment with pioglitazone in non-diabetic, insulin-resistant subjects

Isotretinoin and fenofibrate induce adiposity with distinct effect on metabolic profile in a rat model of the insulin resistance syndrome

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