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J. Biol. Chem., Vol. 279, Issue 32, 33456-33462, August 6, 2004

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

Hiroaki Yajima, Emiko Ikeshima, Maho Shiraki, Tomoka Kanaya, Daisuke Fujiwara, Hideharu Odai, Nobuyo Tsuboyama-Kasaoka¶, Osamu Ezaki¶, Shinichi Oikawa||, and Keiji Kondo

From the Central Laboratories for Key Technology, Kirin Brewery Co., Ltd., Kanagawa 236-0004, ^¶Division of Clinical Nutrition, National Institute of Health and Nutrition, Tokyo 162-8636, and the ^||Department of Medicine, Nippon Medical School, Tokyo 113-8603, Japan

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.

Received for publication, March 29, 2004 , and in revised form, May 26, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Central Laboratories for Key Technology, Kirin Brewery Co., Ltd., 1-13-5, Fukuura Kanazawa-ku Yokohama, Kanagawa 236-0004, Japan. Tel.: 81-45-788-7244; Fax: 81-45-788-4042; E-mail: hyajima{at}kirin.co.jp.

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