AZ 242, a novel PPARα/γ agonist with beneficial effects on insulin resistance and carbohydrate and lipid metabolism in ob/ob mice and obese Zucker rats

Ljung, Bengt; Bamberg, Krister; Dahllöf, Björn; Kjellstedt, Ann; Oakes, Nicholas D.; Östling, Jörgen; Svensson, Lennart; Camejo, Germán

doi:10.1194/jlr.m200127-jlr200

Cited by 106 publications

(86 citation statements)

References 43 publications

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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%

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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

151

128

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

confidence: 51%

“…Recent studies (3,4) suggested that the activation of PPAR␣ improved the insulin resistance that was triggered by the oversupply and accumulation of lipid. It has also been reported (5,6) that several novel compounds that act as co-ligands for PPAR␣ and -␥ can improve insulin sensitivity and correct diabetic dyslipidemia in obese diabetic animals.…”

mentioning

confidence: 99%

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

151

128

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“…Muraglitazar is a novel dual (␣/␥) PPAR activator that selectively binds to and activates human PPAR␥ and human PPAR␣ (13,(33)(34)(35)(36)(37). The in vivo pharmacological data in lean normal mice and in db/db mice demonstrate that muraglitazar modulates the expression of PPAR target genes implicated in the regulation of glucose and lipid metabolic pathways in WAT and in liver.…”

Section: Discussionmentioning

confidence: 99%

Muraglitazar, a Novel Dual ( / ) Peroxisome Proliferator-Activated Receptor Activator, Improves Diabetes and Other Metabolic Abnormalities and Preserves -Cell Function in db/db Mice

Harrity

2006

Diabetes

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1Muraglitazar, a novel dual (␣/␥) peroxisome proliferatoractivated receptor (PPAR) activator, was investigated for its antidiabetic properties and its effects on metabolic abnormalities in genetically obese diabetic db/db mice. In db/db mice and normal mice, muraglitazar treatment modulates the expression of PPAR target genes in white adipose tissue and liver. In young hyperglycemic db/db mice, muraglitazar treatment (0.03-50 mg ⅐ kg ؊1 ⅐ day ؊1 for 2 weeks) results in dose-dependent reductions of glucose, insulin, triglycerides, free fatty acids, and cholesterol. In older hyperglycemic db/db mice, longer-term muraglitazar treatment (30 mg ⅐ kg ؊1 ⅐ day ؊1 for 4 weeks) prevents time-dependent deterioration of glycemic control and development of insulin deficiency. In severely hyperglycemic db/db mice, muraglitazar treatment (10 mg ⅐ kg ؊1 ⅐ day ؊1 for 2 weeks) improves oral glucose tolerance and reduces plasma glucose and insulin levels. In addition, treatment increases insulin content in the pancreas. Finally, muraglitazar treatment increases abnormally low plasma adiponectin levels, increases high-molecular weight adiponectin complex levels, reduces elevated plasma corticosterone levels, and lowers elevated liver lipid content in db/db mice. The overall conclusions are that in db/db mice, the novel dual (␣/␥) PPAR activator muraglitazar 1) exerts potent and efficacious antidiabetic effects, 2) preserves pancreatic insulin content, and 3) improves metabolic abnormalities such as hyperlipidemia, fatty liver, low adiponectin levels, and elevated corticosterone levels.

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“…Preliminary data from animal models of obesity and diabetes are encouraging (55), and early clinical trials have shown that these agents improve both the hyperglycemia and the dyslipidemia that are characteristic of type 2 diabetes (56). Because of caution surrounding possible carcinogenicity in animals, regulatory authorities have requested 2-year toxicology data before approving initiation of clinical trials of Ն6 months.…”

Section: Therapeutic Roles Of Ppar Agonistsmentioning

confidence: 99%

Therapeutic Roles of Peroxisome Proliferator–Activated Receptor Agonists

2005

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Peroxisome proliferator-activated receptors (PPARs) play key roles in the regulation of energy homeostasis and inflammation, and agonists of PPAR␣ and -␥ are currently used therapeutically. Fibrates, first used in the 1970s for their lipid-modifying properties, were later shown to activate PPAR␣. These agents lower plasma triglycerides and VLDL particles and increase HDL cholesterol, effects that are associated with cardiovascular benefit. Thiazolidinediones, acting via PPAR␥, influence free fatty acid flux and thus reduce insulin resistance and blood glucose levels. PPAR␥ agonists are therefore used to treat type 2 diabetes. PPAR␣ and -␥ agonists also affect inflammation, vascular function, and vascular remodeling. As knowledge of the pleiotropic effects of these agents advances, further potential indications are being revealed, including roles in the management of cardiovascular disease (CVD) and the metabolic syndrome. Dual PPAR␣/␥ agonists (currently in development) look set to combine the properties of thiazolidinediones and fibrates, and they hold considerable promise for improving the management of type 2 diabetes and providing an effective therapeutic option for treating the multifactorial components of CVD and the metabolic syndrome. The functions of a third PPAR isoform, PPAR␦, and its potential as a therapeutic target are currently under investigation.

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AZ 242, a novel PPARα/γ agonist with beneficial effects on insulin resistance and carbohydrate and lipid metabolism in ob/ob mice and obese Zucker rats

Cited by 106 publications

References 43 publications

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

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

Muraglitazar, a Novel Dual ( / ) Peroxisome Proliferator-Activated Receptor Activator, Improves Diabetes and Other Metabolic Abnormalities and Preserves -Cell Function in db/db Mice

Therapeutic Roles of Peroxisome Proliferator–Activated Receptor Agonists

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