Isohumulones, bitter acids derived from hops, activate both peroxisome proliferator-activated receptor alpha and gamma and reduce insulin resistance.

Abstract

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 PPARalpha and -gamma, respectively. In this study, isohumulones, the bitter compounds derived from hops that are present in beer, were found to activate PPARalpha and -gamma in transient co-transfection studies. Among the three major isohumulone homologs, isohumulone and isocohumulone were found to activate PPARalpha and -gamma. Diabetic KK-Ay 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.

• Authors: Hiroaki Yajima, Emiko Ikeshima, Maho Shiraki, Tomoka Kanaya, Daisuke Fujiwara, Hideharu Odai, Nobuyo Tsuboyama-Kasaoka, Osamu Ezaki, Shinichi Oikawa, Keiji Kondo
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 279 Issue 32 Pg. 33456-62 (Aug 06 2004) ISSN: 0021-9258 [Print] United States
• PMID: 15178687 (Publication Type: Clinical Trial, Journal Article, Randomized Controlled Trial)

Chemical References

• Blood Glucose
• Cyclopentanes
• DNA-Binding Proteins
• Dietary Fats
• Fatty Acids, Nonesterified
• GAL4 protein, S cerevisiae
• Glycated Hemoglobin A
• Placebos
• Plant Extracts
• RNA, Messenger
• Receptors, Cytoplasmic and Nuclear
• Recombinant Fusion Proteins
• Saccharomyces cerevisiae Proteins
• Thiazolidinediones
• Transcription Factors
• Triglycerides
• isohumulone
• Lipoprotein Lipase
• Pioglitazone

Topics

• Aged
• Animals
• Blood Glucose (analysis)
• Body Weight (drug effects)
• Cyclopentanes (pharmacology, therapeutic use)
• DNA-Binding Proteins
• Diabetes Mellitus, Type 2 (blood, drug therapy)
• Dietary Fats (administration & dosage)
• Double-Blind Method
• Fatty Acids, Nonesterified (blood)
• Female
• Glycated Hemoglobin (analysis)
• Humans
• Humulus (chemistry)
• Insulin Resistance (physiology)
• Lipoprotein Lipase (genetics)
• Male
• Mice
• Mice, Inbred C57BL
• Middle Aged
• Pilot Projects
• Pioglitazone
• Placebos
• Plant Extracts (chemistry)
• RNA, Messenger (analysis)
• Receptors, Cytoplasmic and Nuclear (drug effects, physiology)
• Recombinant Fusion Proteins
• Saccharomyces cerevisiae Proteins (genetics)
• Thiazolidinediones (pharmacology)
• Transcription Factors (drug effects, genetics, physiology)
• Transfection
• Triglycerides (blood)
• Weight Gain