Abstract
ObjectivesExtracts of the hops plant have been shown to reduce weight and insulin resistance in rodents and humans, but elucidation of the mechanisms responsible for these benefits has been hindered by the use of heterogeneous hops-derived mixtures. Because hop extracts are used as flavoring agents for their bitter properties, we hypothesized that bitter taste receptors (Tas2rs) could be mediating their beneficial effects in metabolic disease. Studies have shown that exposure of cultured enteroendocrine cells to bitter tastants can stimulate release of hormones, including glucagon-like peptide 1 (GLP-1). These findings have led to the suggestion that activation of Tas2rs may be of benefit in diabetes, but this tenet has not been tested. Here, we have assessed the ability of a pure derivative of a hops isohumulone with anti-diabetic properties, KDT501, to signal through Tas2rs. We have further used this compound as a tool to systematically assess the impact of bitter taste receptor activation in obesity-diabetes. MethodsKDT501 was tested in a panel of bitter taste receptor signaling assays. Diet-induced obese mice (DIO) were dosed orally with KDT501 and acute effects on glucose homeostasis determined. A wide range of metabolic parameters were evaluated in DIO mice chronically treated with KDT501 to establish the full impact of activating gut bitter taste signaling. ResultsWe show that KDT501 signals through Tas2r108, one of 35 mouse Tas2rs. In DIO mice, acute treatment stimulated GLP-1 secretion and enhanced glucose tolerance. Chronic treatment caused weight and fat mass loss, increased energy expenditure, enhanced glucose tolerance and insulin sensitivity, normalized plasma lipids, and induced broad suppression of inflammatory markers. Chronic KDT501 treatment altered enteroendocrine hormone levels and bile acid homeostasis and stimulated sustained GLP-1 release. Combined treatment with a dipeptidyl peptidase IV inhibitor amplified the incretin-based benefits of this pure isohumulone. ConclusionsActivation of Tas2r108 in the gut results in a remodeling of enteroendocrine hormone release and bile acid metabolism that ameliorates multiple features of metabolic syndrome. Targeting extraoral bitter taste receptors may be useful in metabolic disease.
Highlights
Extracts of the hops plant (Humulus lupulus L.) used as flavoring agents in beer production have been shown to reduce weight and improve glucose homeostasis in rodents [1e8] and humans [1,9,10]
KDT501 is a selective ligand of the bitter taste receptor Tas2r108 As a first step to discern the utility of targeting extraoral bitter taste receptors in metabolic disease, we tested the hypothesis that the beneficial effects of KDT501 and isohumulones are mediated by activation of Tas2rs by evaluating KDT501 in assays indicative of bitter taste receptor signaling
We have found that one way whereby KDT501 elicits multifaceted improvements in Diet Induced Obesity (DIO) mice is via modulation of a primary molecular target, the bitter taste receptor Tas2r108
Summary
Extracts of the hops plant (Humulus lupulus L.) used as flavoring agents in beer production have been shown to reduce weight and improve glucose homeostasis in rodents [1e8] and humans [1,9,10]. Hop a-acids are isomerized during brewing to iso-a-acids, or isohumulones, that impart beer its characteristic bitter flavor. There are three main isohumulones (n-humulone, cohumulone, and adhumulone) that account for more than 80% of the hops-derived matter in beer [11]. Each isohumulone occurs as a mixture of cis and trans isomers that can be reduced into rho, tetrahydro, or hexahydro analogs. This level of chemical complexity has hampered efforts to uncover the mechanism of action of isohumulones in metabolic syndrome. An initial study [1] with mixtures of isohumulones showed that obesediabetic KK-Ay mice treated with these compounds had reduced glycemia and decreased plasma triglycerides and free fatty acid levels.
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