Intestinal bitter taste receptor activation alters hormone secretion and imparts metabolic benefits

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.

Obesity alters adrenergic and chemosensory signaling pathways that regulate ghrelin secretion in the human gut

“…Additionally, the broadly tuned (30) bitter agonist chloroquine (TAS2R3, ‐R7, ‐RIO, ‐R14, and ‐R39; P < 0.05) and the more selective bitter agonists (30, 31) emetine (TAS2R1, indirect evidence; P < 0.001) and 1,10‐phenanthroline (TAS2R5; P < 0.05) also increased ghrelin secretion in a concentration‐dependent manner in fundic cultures from obese patients (Fig. 3 and Table 2 ).…”

“…A recent study by Kok et al . (31) showed that KTD‐501, a pure derivative of a hops iso‐humulone present in beer, stimulated GLP‐1 secretion and improved several features of the metabolic syndrome in diet‐induced obese mice. The effect was mimicked by emetine.…”

“…Apart from DB, our pharmacological study showed that other bitter agonists, which either target several TAS2Rs (chloroquine) or a more specific TAS2R such as emetine, 1,10-phenanthroline, or erythromycin A, could also stimulate ghrelin secretion in fundic cultures of obese patients. A recent study by Kok et al (31) showed that KTD-501, a pure derivative of a hops isohumulone present in beer, stimulated GLP-1 secretion and improved several features of the metabolic syndrome in diet-induced obese mice. The effect was mimicked by emetine.…”

A role for taste receptors in (neuro)endocrinology?

“…93 Indeed, a nonfunctional haplotype of human TAS2R9 has been associated with an increased risk for type II diabetes. 89 Recently, it was demonstrated that a synthetic bitter substance activating mouse Tas2r108, a receptor expressed in the small intestine and STC-1 cells, is capable of inducing GLP-1 secretion and improving the metabolic state in a mouse model, 94 thus confirming a role of bitter signalling in digestive processes.…”

Mechanism of glucose‐lowering by metformin in type 2 diabetes: Role of bile acids

“…66 In rodents, stimulation of intestinal bitter taste receptors induces GLP-1 secretion and weight loss and improves glucose tolerance. 67,68 There is limited information about bitter taste receptor activation in humans, with some evidence that it may alter gastrointestinal motility and hunger. 69 Hitherto, no study has evaluated effects on GLP-1 secretion or glycaemic control.…”