Isohumulones, bitter acids derived from hops, activate both peroxisome proliferator-activated receptor alpha and gamma and reduce insulin resistance.
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.
Yajima
Hiroaki
H
Central Laboratories for Key Technology, Kirin Brewery Co., Ltd., Kanagawa 236-0004, Japan. hyajima@kirin.co.jp
Ikeshima
Emiko
E
Shiraki
Maho
M
Kanaya
Tomoka
T
Fujiwara
Daisuke
D
Odai
Hideharu
H
Tsuboyama-Kasaoka
Nobuyo
N
Ezaki
Osamu
O
Oikawa
Shinichi
S
Kondo
Keiji
K
D000368:Aged; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight / Q000187:drug effects; D003517:Cyclopentanes / Q000494:pharmacology* / Q000627:therapeutic use; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy; D004041:Dietary Fats / Q000008:administration & dosage; D004311:Double-Blind Method; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D027582:Humulus / Q000737:chemistry*; D007333:Insulin Resistance / Q000502:physiology*; D008071:Lipoprotein Lipase / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D010865:Pilot Projects; D000077205:Pioglitazone; D010919:Placebos; D010936:Plant Extracts / Q000737:chemistry; D012333:RNA, Messenger / Q000032:analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects* / Q000502:physiology; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics; D045162:Thiazolidinediones / Q000494:pharmacology; D014157:Transcription Factors / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D014162:Transfection; D014280:Triglycerides / Q000097:blood; D015430:Weight Gain
D001786:Blood Glucose; D003517:Cyclopentanes; D004268:DNA-Binding Proteins; D004041:Dietary Fats; D005230:Fatty Acids, Nonesterified; D006442:Glycated Hemoglobin; D008071:Lipoprotein Lipase; D000077205:Pioglitazone; D010919:Placebos; D010936:Plant Extracts; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; D045162:Thiazolidinediones; D014157:Transcription Factors; D014280:Triglycerides; C052130:GAL4 protein, S cerevisiae; C081209:isohumulone