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

Upton, R; Widdowson, Peter; Ishii, Shin‐ichi; Tanaka, Hideho; Williams, Gareth

doi:10.1038/sj.bjp.0702245

Cited by 54 publications

(35 citation statements)

References 25 publications

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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: 57%

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

confidence: 57%

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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“…ZF rats are reportedly used as a model of insulin resistance, presenting symptoms of hyperinsulinemia, hyperlipidemia, moderate hyperglycemia, and marked glucose intolerance. Several groups have used ZF rats to study the ameliorating effects of insulin resistance by insulin sensitizers such as TZDs or non-TZD PPARγ agonists (5,6,10,11).…”

Section: Discussionmentioning

confidence: 99%

The Novel Hypoglycemic Agent YM440 Improves Hepatic Insulin Resistance in Obese Zucker Fatty Rats

et al. 2006

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Abstract. The novel hypoglycemic agent YM440 ((Z)-1,4-bis{4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl] phenoxy}but-2-ene) is a ligand of the peroxisome proliferator-activated receptor (PPAR) γ. YM440 has unique pharmacological profiles both in vitro and in vivo, but, it is not clear whether the compound has a significant effect on hepatic or peripheral insulin response throughout the body. The aim of this study is to examine the effects of YM440 on hepatic and peripheral insulin resistance in Zucker fatty (ZF) rats using the euglycemic-hyperinsulinaemic clamp technique. Treatment of ZF rats with YM440 (300 mg / kg per day) for 2 weeks significantly decreased plasma concentrations of glucose and insulin without inducing obesity. YM440 caused a 2-fold increase in the glucose infusion rate during euglycemic clamping compared with the vehicle control. YM440 also decreased the percent change in hepatic glucose production rate caused by intravenous insulin infusion in ZF rats. YM440 had no significant effect on the glucose disposal rate. These results indicate that YM440 ameliorates hepatic, but not peripheral insulin resistance in ZF rats. These findings strongly suggest that the main target organ of YM440 is the liver, unlike other PPARγ agonist.

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“…At present, non-esterified fatty acids (NEFA) are regarded as the main candidate, because TZD treatment reduces plasma NEFA [5,11,71,72,82,91,92] and because NEFA are established modulators of insulin-stimulated glucose transport and glycogen synthesis in skeletal muscle in vitro and in vivo [93,94,95,96]. The causal sequence would be that adipogenic TZD action on fat supports triglyceride storage and, hence, the withdrawal of NEFA from the circulation which improves muscle insulin sensitivity and glucose homeostasis [97].…”

Section: Adipose Tissuementioning

confidence: 99%

“…The new TZDs RWJ241947 (MCC-555), NC-2100, and PAT5A, and also the antidiabetic oxadiazolidinedione YM440 (molecular structures in Fig. 1), carry antihyperglycaemic and insulin sensitizing potentials at least equal to those of established TZDs [38,39,80,81,82], although they have markedly lower efficacies for PPARγ affinity, PPARγ transactivation, and adipocyte differentiation in vitro [38,39,80,81]. In addition, no increases in fat and body weight which characterize most TZDs [57,58,59] are found in response to treatment with NC-2100 or YM440 [38,81], which suggests little adipogenic action in vitro and in vivo.…”

Section: Adipose Tissuementioning

confidence: 99%

Thiazolidinediones: metabolic actions in vitro

Fürnsinn¹,

Waldhäusl

2002

Diabetologia

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To unravel the molecular mechanisms and the causal chain of how thiazolidinediones (TZDs) affect glucose homeostasis, it is helpful to analyse their direct influence on isolated specimens of fat, muscle, and liver in vitro. Studies on isolated adipocytes have shown that the nuclear peroxisome proliferator-activated receptor-γ (PPARγ) is an important molecular target for TZDs, through which they trigger adipocyte differentiation and adipose tissue remodelling. It is not clear, however, if the activation of PPARγ in adipose tissue is the cause of all the metabolic actions of TZDs. Based on in vitro studies, two hypotheses have been developed. The first emphasizes PPARγ-mediated actions on adipose tissue, suggesting that insulin sensitization of skeletal muscle and liver is triggered indirectly by changes in circulating concentrations of adipocyte-derived non-esterified fatty acids and peptide hormones. The second states that TZDs improve glucose homeostasis independently from adipose tissue actions by the direct interaction with muscle and liver. This hypothesis is supported by direct TZD actions on fuel metabolism of skeletal muscle and liver in vitro, which seem to be independent from PPARγ signalling. Major progress has been made in understanding the mechanisms involved in the effects of TZDs on adipose tissue but the causal chain responsible for their antihyperglycaemic action is still not clear. The involvement of other molecular targets in addition to PPARγ, of adipocyte-derived messengers, and of direct interaction with skeletal muscle and liver have yet to be clarified. [Diabetologia (2002[Diabetologia ( ) 45:1211[Diabetologia ( -1223

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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

Cited by 54 publications

References 25 publications

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

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

The Novel Hypoglycemic Agent YM440 Improves Hepatic Insulin Resistance in Obese Zucker Fatty Rats

Thiazolidinediones: metabolic actions in vitro

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