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.
Highlights
Type 2 diabetes represents a heterogeneous group of disorders characterized by increased insulin resistance
Because mammalian cell lines contain endogenous nuclear receptors that can complicate the interpretation of the results, chimera systems were used in which the ligand binding domain of peroxisome proliferator-activated receptor (PPAR)␣ or PPAR␥ was fused to the DNA binding domain of the yeast transcription factor GAL4 [23]
Histological analysis of subcutaneous white adipose tissue (WAT) of the high fat diet-fed C57BL/6N mice treated with isohumulone, isocohumulone, or pioglitazone for 10 days revealed an increase in the number of small adipocytes by treatment with all three of these compounds compared with vehicle-treated mice (Fig. 5D)
Summary
Chemicals—Isomerized hop extract (IHE; ISOHOPCON2) was purchased from English Hop Products Co. Six-week-old female C57BL/6N mice were maintained on a high fat diet for 10 weeks as described previously [17] Some of these animals were administered isocohumulone or isohumulone, in 0.2 M sodium carbonate buffer (pH 9.7), orally, each at doses of 10 or 100 mg/kg body weight for their final 14 days on the diet; oral glucose tolerance tests (OGTT) were performed on these animals. 6-week-old female C57BL/6N mice fed a standard diet were orally administered 100 mg/kg body weight of isohumulone or isocohumulone for 6 days. Their livers were isolated and homogenized in a solution containing 0.25 M sucrose, 1 mM EDTA, and 3 mM Tris-Cl (pH 7.2).
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