Treatment with the Thiazolidinedione (BRL 49653) Decreases Insulin Resistance in Obese Zucker Hindlimb

Eldershaw, T. P. D.; Rattigan, Stephen; Cawthorne, Michael A.; Buckingham, Robin E.; Colquhoun, Eric Q.; Clark, MG

doi:10.1055/s-2007-979932

Cited by 32 publications

(19 citation statements)

References 3 publications

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“…These findings are consistent with recently published data in mice (31) and suggest that PPAR␥1 might be the relevant target for thiazolidinediones in human skeletal muscle. The close conservation of sequence, subtype, and tissue distribution of PPAR␥ between mice and humans is consistent with the observation that thiazolidinediones act as insulin sensitizers in both species (17,37). However, we do not yet know the distribution of PPAR␥1 versus PPAR␥2 protein in these tissues.…”

Section: Fig 3 Hppar␥2 Binds To Ppres As a Heterodimer With Rxrsupporting

confidence: 81%

Identification, Characterization, and Tissue Distribution of Human Peroxisome Proliferator-activated Receptor (PPAR) Isoforms PPARγ2 versus PPARγ1 and Activation with Retinoid X Receptor Agonists and Antagonists

Mukherjee¹,

Jow²,

Croston

et al. 1997

Journal of Biological Chemistry

384

258

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We describe the cloning, characterization, and tissue distribution of the two human peroxisome proliferator activated receptor isoforms hPPAR␥2 and hPPAR␥1. In cotransfection assays the two isoforms were activated to approximately the same extent by known PPAR␥ activators. Human PPAR␥ binds to DNA as a heterodimer with the retinoid X receptor (RXR). This heterodimer was activated by both RXR agonists and antagonists and the addition of PPAR␥ ligands with retinoids resulted in greater than additive activation. Such heterodimer-selective modulators may have a role in the treatment of PPAR␥/RXR-modulated diseases like diabetes. Northern blot analysis indicated the presence of PPAR␥ in skeletal muscle, and a sensitive RNase protection assay confirmed the presence of only PPAR␥1 in muscle that was not solely due to fat contamination. However, both PPAR␥1 and PPAR␥2 RNA were detected in fat, and the ratio of PPAR␥1 to PPAR␥2 RNA varied in different individuals. The presence of tissue-specific distribution of isoforms and the variable ratio of PPAR␥1 to PPAR␥2 raised the possibility that isoform expression may be modulated in disease states like non-insulin-dependent diabetes mellitus. Interestingly, a third protected band was detected with fat RNA indicating the possible existence of a third human PPAR␥ isoform.

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Section: Fig 3 Hppar␥2 Binds To Ppres As a Heterodimer With Rxrsupporting

confidence: 81%

Identification, Characterization, and Tissue Distribution of Human Peroxisome Proliferator-activated Receptor (PPAR) Isoforms PPARγ2 versus PPARγ1 and Activation with Retinoid X Receptor Agonists and Antagonists

Mukherjee¹,

Jow²,

Croston

et al. 1997

Journal of Biological Chemistry

384

258

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“…In contrast to the rexinoids, the daily food intake in BRL 49653-treated animals was signi®cantly increased in the present study (experiment 1). Such an effect has also been observed in other studies with BRL 49653 18,19 and other thiazolidinediones, such as MCC-555, 20 suggesting that this phenomenon is a general property of these compounds and it has been shown to be independent of leptin and NPY. 19 Treatment with the rexinoids resulted in a trend towards a lowering of the blood glucose concentration in ad-lib fed rats by almost 1 mmolal.…”

Section: Effects Of Rexinoids In Zucker Faafa Rats Y-l Liu Et Alsupporting

confidence: 75%

Retinoid X receptor agonists have anti-obesity effects and improve insulin sensitivity in Zucker fa/fa rats

et al. 2000

Int J Obes

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OBJECTIVE: To investigate whether retinoid X receptor agonists act as insulin sensitizers and compare their effects with that of thiazolidinedione BRL 49653 in obese Zucker rats. DESIGN: In two independent studies, obese Zucker rats were dosed orally once daily for 14 days with one of the following treatments: LG 100268 (20 mgakg), LG 100324 (20 mgakg), BRL 49653 (3 mgakg) or vehicle. MEASUREMENTS: Daily food intake and body weight gain, blood glucose, plasma and pancreatic insulin, whole body glucose disposal (by euglycaemic ± hyperinsulinaemic clamp) and tissue glucose utilization. RESULTS: The retinoid X receptor agonists (rexinoids) LG 100268 and LG 100324 caused a reduction in the food intake of obese Zucker rats relative to controls and to rats receiving BRL 49653. The two rexinoids also produced a marked decrease in the body weight gain, whereas the growth rate of rats treated with BRL 49653 tended to increase. Both rexinoids and BRL 49653 reduced the plasma insulin concentration of fed rats.LG 100268 and LG 100324 also signi®cantly lowered blood glucose concentrations after 1 week of treatment. The 5 h fasted plasma insulin concentration was signi®cantly lower in the rexinoid-treated groups and the terminal insulin level (at the end of the clamp) tended to be lower in all treated groups compared with animals given the dosing vehicle. However, pancreatic insulin content was not affected by any of the treatments. Under euglycaemic ± hyperinsulinaemic clamp conditions, there were no signi®cant differences in the rate of hepatic glucose output and whole body glucose disposal, except that, in experiment 1, BRL 49653 caused signi®cant increase in the glucose infusion rate and muscle glucose utilization. In experiment 2, a similar glucose infusion rate to the controls was achieved in all treatment groups but the steady-state insulin concentration in the treated animals was only about 50% of that in the control animals, despite the fact that all rats received a similar insulin infusion concentration. This suggests that both the rexinoids and BRL 49653 increased insulin clearance. CONCLUSIONS: Chronic administration of retinoid X receptor agonists LG 100268 and LG 100324 to Zucker faafa rats reduces food intake and body weight gain, lowers plasma insulin concentrations while maintaining normoglycaemia, indicating an improvement of insulin sensitivity.

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“…Increased body weight gain has been observed following 10 days of pioglitazone treatment to diabetic ZDF rats, but as there was no increase in fat deposition, the increased weight was attributed to water retention (deSouza et al, 1995). The physiological mechanism resulting in the slight increase in food intake during MCC-555 treatment to obese Zucker rats is currently unknown, but has been also observed with other thiazolidinediones, such as BRL 49653 (rosiglitazone) (Eldershaw et al, 1995;Wang et al, 1997), suggesting that this phenomenon is a general property of these compounds.…”

Section: Discussionmentioning

confidence: 99%

Improved metabolic status and insulin sensitivity in obese fatty (fa/fa) Zucker rats and Zucker Diabetic Fatty (ZDF) rats treated with the thiazolidinedione, MCC‐555

Upton

Widdowson

Ishii

et al. 1998

British J Pharmacology

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1 We examined the e ect of chronic (21 days) oral treatment with the thiazolidinedione, MCC-555 ((+)-5-[{6-(2-¯uorbenzyl)-oxy-2-naphy}methyl]-2,4-thiazolidinedione) on metabolic status and insulin sensitivity in obese (fa/fa) Zucker rats and Zucker Diabetic Fatty (ZDF) rats which display an impaired glucose tolerance (IGT) or overt diabetic symptoms, respectively. 2 MCC-555 treatment to obese Zucker rats (10 and 30 mg kg 71 ) and diabetic ZDF rats (10 mg kg 71 ) reduced non-esteri®ed fatty acid concentrations in both rat strains and reduced plasma glucose and triglyceride concentrations in the obese Zucker rats. Liver glycogen concentrations were signi®cantly increased by chronic MCC-555 treatment in both obese Zucker rats (30 mg kg 71 day 71 ) and diabetic ZDF rats (10 mg kg 71 day 71 ), as compared with vehicle-treated lean and obese rats and there was a signi®cant increase in hepatic glycogen synthase activity in MCC-555-treated diabetic ZDF rats as compared to vehicle-treated controls. 3 During a euglycaemic hyperinsulinaemic clamp, MCC-555-treated obese Zucker rats and diabetic ZDF rats required signi®cantly higher glucose infusion rates to maintain stable glucose concentrations (2.01+0.19 mg min 71 and 6.42+1.03 mg min 71 , respectively) than vehicle-treated obese controls (0.71+0.17 mg min 71 and 2.09+0.71 mg min 71 ; P50.05), demonstrating improved insulin sensitivity in both Zucker and ZDF rats. MCC-555 treatment also enhanced insulin-induced suppression of hepatic glucose production in ZDF rats as measured using infusions of [6-3 H]-glucose under clamp conditions. 4In conclusion, we have demonstrated that MCC-555 improves metabolic status and insulin sensitivity in obese Zucker and diabetic ZDF rats. MCC-555 may prove a useful compound for alleviating the metabolic disturbances and IGT associated with insulin resistance in man.

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Treatment with the Thiazolidinedione (BRL 49653) Decreases Insulin Resistance in Obese Zucker Hindlimb

Cited by 32 publications

References 3 publications

Identification, Characterization, and Tissue Distribution of Human Peroxisome Proliferator-activated Receptor (PPAR) Isoforms PPARγ2 versus PPARγ1 and Activation with Retinoid X Receptor Agonists and Antagonists

Identification, Characterization, and Tissue Distribution of Human Peroxisome Proliferator-activated Receptor (PPAR) Isoforms PPARγ2 versus PPARγ1 and Activation with Retinoid X Receptor Agonists and Antagonists

Retinoid X receptor agonists have anti-obesity effects and improve insulin sensitivity in Zucker fa/fa rats

Improved metabolic status and insulin sensitivity in obese fatty (fa/fa) Zucker rats and Zucker Diabetic Fatty (ZDF) rats treated with the thiazolidinedione, MCC‐555

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