A novel insulin sensitizer acts as a coligand for peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and PPAR-gamma: effect of PPAR-alpha activation on abnormal lipid metabolism in liver of Zucker fatty rats.

Murakami, Koji; Tobe, Kazuyuki; Ide, Tomohiro; Mochizuki, Toru; Ohashi, Makoto; Akanuma, Yasuo; Yazaki, Yoshio; Kadowaki, Takashi

doi:10.2337/diabetes.47.12.1841

Cited by 247 publications

(136 citation statements)

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“…Recently, some investigations have reported the effects of dual PPARa/g agonist in animal models of dyslipidemia and type 2 diabetes. [27][28][29][30][31] Our data are in good agreement with these reports, although in most of them, either no comparison was made with a specific PPARg agonist, or the dual agonist did not show a beneficial effect. The most striking result of the present study concerns the effect of Fenofibrate on body fat mass and body weight.…”

Section: Discussionsupporting

confidence: 82%

“…As reported repeatedly, Rosiglitazone improves blood levels of glucose, insulin, triglycerides, NEFA and cholesterol. 7,27,29,31,34,35 On the other hand, Fenofibrate alone was, indeed, able to reduce serum lipid levels (TG, NEFA and cholesterol). 7,25,36 Surprisingly, it was also able to reduce significantly blood glucose concentration despite no effect on plasma insulin.…”

Section: Discussionmentioning

confidence: 99%

“…26 In the past few years, dual PPARa and PPARg agonists have been developed and their utility as antidiabetic drugs has been suggested. [27][28][29][30][31] Nevertheless, only few reports have explored the effects of cotreatment with PPARa and PPARg agonists, 7,30 particularly when focusing on body weight regulation.…”

Section: Introductionmentioning

confidence: 99%

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Fenofibrate prevents Rosiglitazone-induced body weight gain in ob/ob mice

et al. 2005

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AIMS/HYPOTHESIS:Fibrates and thiazolidinediones are commonly used for the treatment of dyslipidemia and type 2 diabetes, respectively. The aim of this study was to investigate the effects on body weight as well as on glucose and lipid homeostasis of ligands for PPARa and PPARg, Fenofibrate and Rosiglitazone, alone or in association. METHODS: Ob/ob mice were divided into four groups: control, and mice daily injected (intraperitoneally), either with 10 mg/kg Rosiglitazone, 100 mg/kg Fenofibrate or both molecules. Body weight and food intake were monitored daily. After 13 days of treatment, mice were killed, and blood samples were collected for posterior metabolite quantification. The liver and adipose tissues were dissected and weighed. RESULTS: Body weight was significantly reduced or increased by Fenofibrate and Rosiglitazone, respectively. The effect of Rosiglitazone was prevented by coadministration of Fenofibrate. This was accompanied by a normalization of the daily food efficiency. Compared to those treated with Rosiglitazone, animals treated with Fenofibrate alone or in combination presented a decreased white adipose tissue mass. Fenofibrate or Rosiglitazone alone significantly reduced the levels of plasma lipid parameters. Surprisingly, Fenofibrate also decreased blood glucose levels in ob/ob mice, despite having no effect on insulin levels. By contrast, both glucose and insulin levels were decreased by Rosiglitazone treatment. Coadministration of both drugs improved all parameters as with Rosiglitazone. Fenofibrate restored almost normal hepatocyte morphology and significantly reduced the triglyceride content of the liver. This was accompanied by an increase in fatty acid oxidation in the liver in all groups receiving Fenofibrate. CONCLUSION/INTERPRETATION: These biological effects suggest that combined therapy with a PPARa and a PPARg ligand is more effective in ameliorating, specifically, lipid homeostasis than in activating any of this receptor separately. Furthermore, Fenofibrate prevents one of the most undesirable effects of Rosiglitazone, namely increased adiposity and body weight gain.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

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Fenofibrate prevents Rosiglitazone-induced body weight gain in ob/ob mice

et al. 2005

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“…The combination therapy of these medications is an attractive option for the treatment of obese type 2 diabetics (10,11). Compounds that have dual agonistic activity on both of these receptors have been shown to improve insulin sensitivity and dyslipidemia in obese diabetic animals (6,27). In the present study, we showed that isohumulones, the bitter compounds present in beer, activated PPARs ␣ and ␥ ameliorated insulin resistance and dyslipidemia in diabetic animals and reduced hyperglycemia in patients with type 2 diabetes.…”

Section: Isohumulones Up-regulated the Expression Of Genes Involved Isupporting

confidence: 51%

Isohumulones, Bitter Acids Derived from Hops, Activate Both Peroxisome Proliferator-activated Receptor α and γ and Reduce Insulin Resistance

Yajima

Ikeshima

Shiraki

et al. 2004

Journal of Biological Chemistry

152

132

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The peroxisome proliferator-activated receptors (PPARs) are dietary lipid sensors that regulate fatty acid and carbohydrate metabolism. The hypolipidemic effects of fibrate drugs and the therapeutic benefits of the thiazolidinedione drugs are due to their activation of PPAR␣ and -␥, respectively. In this study, isohumulones, the bitter compounds derived from hops that are present in beer, were found to activate PPAR␣ and -␥ in transient co-transfection studies. Among the three major isohumulone homologs, isohumulone and isocohumulone were found to activate PPAR␣ and -␥. Diabetic KK-A y mice that were treated with isohumulones (isohumulone and isocohumulone) showed reduced plasma glucose, triglyceride, and free fatty acid levels (65.3, 62.6, and 73.1%, respectively, for isohumulone); similar reductions were found following treatment with the thiazolidinedione drug, pioglitazone. Isohumulone treatment did not result in significant body weight gain, although pioglitazone treatment did increase body weight (10.6% increase versus control group). C57BL/6N mice fed a high fat diet that were treated with isohumulones showed improved glucose tolerance and reduced insulin resistance. Furthermore, these animals showed increased liver fatty acid oxidation and a decrease in size and an increase in apoptosis of their hypertrophic adipocytes. A double-blind, placebo-controlled pilot study for studying the effect of isohumulones on diabetes suggested that isohumulones significantly decreased blood glucose and hemoglobin A1c levels after 8 weeks (by 10.1 and 6.4%, respectively, versus week 0). These results suggest that isohumulones can improve insulin sensitivity in high fat diet-fed mice with insulin resistance and in patients with type 2 diabetes.

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“…This differential behavior to dietary manipulations over time may be considered as a physiological adaptation of WAT to dietary fat excess. That is, sudden and short periods of dietary changes (fat elevation) down-regulate PPAR␥2 levels, perhaps to avoid an excess of new adipocyte appearance (38), while the maintenance of high-fat feeding over longer time periods modifies WAT, possibly via PPAR␥2-induced adipocyte differentiation (39).…”

Section: Fig 1 Ucp3 Ppar␥2mentioning

confidence: 99%

Time-Dependent Effects of a High-Energy-Yielding Diet on the Regulation of Specific White Adipose Tissue Genes

Margareto

Gómez-Ambrosi

Marti

et al. 2001

Biochemical and Biophysical Research Communications

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White adipose tissue development is regulated by many factors, including the energy content of food and the genetic background. Nevertheless, little is known about possible differential effects of high-fat palatable diets when fed for short or long-time periods. Thus, the expression of certain genes involved with lipid metabolism (peroxisome proliferator-activated receptor gamma, PPAR␥2; retinoic receptors; fatty acid binding protein, aP2 and uncoupling proteins, UCP) may be affected by those dietary manipulations (highenergy-yielding diet and time duration of feeding). High-fat feeding for 8 days decreased mRNA UCP3 levels compared to control fed animals, while feeding for 30 days increased them over controls. Similar findings occurred for PPAR␥2 and aP2. Furthermore, statistically significant associations were found among PPAR␥2, aP2 and UCP3 mRNA levels. These data suggest a physiological time-dependent response seeking to prevent excessive fat deposition when animals are fed for short-term with a high amount of dietary fat, which was followed by an adaptive period to the highenergy content of diet throughout a coregulation among certain lipid metabolism related genes: PPAR␥2, aP2, UCP3.

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A novel insulin sensitizer acts as a coligand for peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and PPAR-gamma: effect of PPAR-alpha activation on abnormal lipid metabolism in liver of Zucker fatty rats.

Cited by 247 publications

References 0 publications

Fenofibrate prevents Rosiglitazone-induced body weight gain in ob/ob mice

Fenofibrate prevents Rosiglitazone-induced body weight gain in ob/ob mice

Isohumulones, Bitter Acids Derived from Hops, Activate Both Peroxisome Proliferator-activated Receptor α and γ and Reduce Insulin Resistance

Time-Dependent Effects of a High-Energy-Yielding Diet on the Regulation of Specific White Adipose Tissue Genes

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