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Endocrinology. 2019 Jan 1;160(1):143-155. doi: 10.1210/en.2018-00711.
Bitter Taste Receptor Ligand Improves Metabolic and Reproductive Functions in a Murine Model of PCOS.
Wu S1, Xue P1, Grayson N2, Bland JS2, Wolfe A1.
Abstract
Polycystic ovary syndrome (PCOS) results from functional ovarian hyperandrogenism due to dysregulation of androgen secretion. Cultured theca cells from polycystic ovaries of women with the most common form of PCOS overexpress most androgen producing enzymes, particularly CYP450c17. In this study, a murine model was used of PCOS induced by chronic feeding with a high-fat diet that exhibits the reproductive, hyperandrogenic, and metabolic constellation of PCOS symptoms seen in women. Oral administration of KDT501, a hops-derived bitter taste receptor (Tas2R 108) isohumulone ligand resulted in resolution of PCOS-associated endocrine and metabolic disturbances and restored reproductive function. Pioglitazone, a PPARγ agonist, also improved metabolic and reproductive function, though not to the same degree as KDT501. Specifically, treatment of the murine PCOS model with KDT501 resulted in reduced testosterone and androstenedione levels in the absence of significant changes in LH or FSH, improved glucose tolerance and lipid metabolism, and reduced hepatic lipid infiltration and adiposity. There was significant improvement in estrous cyclicity and an increase in the number of ovarian corpora lutea, indicative of improved reproductive function after exposure to KDT501. Finally, ex vivo exposure of murine ovaries to KDT501 attenuated androgen production and ovarian expression of CYP450c17. Interestingly, the ovaries expressed Tas2R 108, suggesting a potential regulation of ovarian steroidogenesis through this chemosensory receptor family. In summary, a therapeutic strategy for PCOS possibly could include direct influences on ovarian steroidogenesis that are independent of gonadotrophic hormone regulation.
PMID: 30418546
Mol Metab. 2018 Oct;16:76-87. doi: 10.1016/j.molmet.2018.07.013. Epub 2018 Aug 4.
Intestinal bitter taste receptor activation alters hormone secretion and imparts metabolic benefits.
Kok BP1, Galmozzi A1, Littlejohn NK1, Albert V1, Godio C1, Kim W1, Kim SM1, Bland JS2, Grayson N2, Fang M3, Meyerhof W4, Siuzdak G3, Srinivasan S1, Behrens M5, Saez E6.
Author information:
- Department of Molecular Medicine, USA.
- Kindex Pharmaceuticals, 800 Fifth Avenue, Seattle, WA, 98104, USA.
- Center for Metabolomics, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA.
- Department of Molecular Genetics, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany.
- Department of Molecular Genetics, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany; Leibniz-Institute for Food Systems Biology at the Technical University of Munich, Lise-Meitner-Str. 34, 85354, Freising, Germany.
- Department of Molecular Medicine, USA. Electronic address: esaez@scripps.edu.
Abstract
OBJECTIVES:
Extracts 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.
RESULTS:
We 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.
CONCLUSIONS:
Activation 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.
Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.
PMCID: PMC6158035
PMID: 30120064
Mol Metab. 2018 Oct;16:76-87. doi: 10.1016/j.molmet.2018.07.013. Epub 2018 Aug 4.
Intestinal bitter taste receptor activation alters hormone secretion and imparts metabolic benefits.
Kok BP1, Galmozzi A1, Littlejohn NK1, Albert V1, Godio C1, Kim W1, Kim SM1, Bland JS2, Grayson N2, Fang M3, Meyerhof W4, Siuzdak G3, Srinivasan S1, Behrens M5, Saez E6.
Author information:
- Department of Molecular Medicine, USA.
- Kindex Pharmaceuticals, 800 Fifth Avenue, Seattle, WA, 98104, USA.
- Center for Metabolomics, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA.
- Department of Molecular Genetics, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany.
- Department of Molecular Genetics, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany; Leibniz-Institute for Food Systems Biology at the Technical University of Munich, Lise-Meitner-Str. 34, 85354, Freising, Germany.
- Department of Molecular Medicine, USA. Electronic address: esaez@scripps.edu.
Abstract
OBJECTIVES:
Extracts 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.
RESULTS:
We 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.
CONCLUSIONS:
Activation 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.
Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.
PMCID: PMC6158035
PMID: 30120064
