Bitter Taste Receptor Ligand Improves Metabolic and Reproductive Functions in a Murine Model of PCOS

Sheng Wu, Ping Xue, Neile Grayson, Jeffrey S. Bland, Andrew Wolfe

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)143-155
Number of pages13
JournalEndocrinology
Volume160
Issue number1
DOIs
StatePublished - Jan 1 2019

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Polycystic Ovary Syndrome
Ligands
Androgens
Ovary
pioglitazone
Theca Cells
Hyperandrogenism
Humulus
Peroxisome Proliferator-Activated Receptors
Androstenedione
Corpus Luteum
Adiposity
High Fat Diet
Periodicity
Lipid Metabolism
Oral Administration
Testosterone
Cultured Cells
Hormones
Lipids

ASJC Scopus subject areas

  • Endocrinology

Cite this

Bitter Taste Receptor Ligand Improves Metabolic and Reproductive Functions in a Murine Model of PCOS. / Wu, Sheng; Xue, Ping; Grayson, Neile; Bland, Jeffrey S.; Wolfe, Andrew.

In: Endocrinology, Vol. 160, No. 1, 01.01.2019, p. 143-155.

Research output: Contribution to journalArticle

Wu, Sheng ; Xue, Ping ; Grayson, Neile ; Bland, Jeffrey S. ; Wolfe, Andrew. / Bitter Taste Receptor Ligand Improves Metabolic and Reproductive Functions in a Murine Model of PCOS. In: Endocrinology. 2019 ; Vol. 160, No. 1. pp. 143-155.
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