Neurokinin 3 Receptor Antagonism Ameliorates Key Metabolic Features in a Hyperandrogenic PCOS Mouse Model

Polycystic ovary syndrome (PCOS) is a prevalent endocrine condition characterized by a range of endocrine, reproductive, and metabolic abnormalities. At present, management of women with PCOS is suboptimal as treatment is only symptomatic. Clinical and experimental advances in our understanding of P...

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Published in:Endocrinology (Philadelphia) 2021-05, Vol.162 (5), p.1
Main Authors: Sucquart, Irene E, Nagarkar, Ruchi, Edwards, Melissa C, Rodriguez Paris, Valentina, Aflatounian, Ali, Bertoldo, Michael J, Campbell, Rebecca E, Gilchrist, Robert B, Begg, Denovan P, Handelsman, David J, Padmanabhan, Vasantha, Anderson, Richard A, Walters, Kirsty A
Format: Article
Language:English
Subjects:
Abnormalities
Adipose tissue
Androgens
Blood levels
Blood sugar
Body weight
Dihydrotestosterone
Dynorphin
Endocrinology
Glucose
Health aspects
Health services
Hypertrophy
Kiss1 protein
Metabolism
Neurokinin
Neurokinin B
Neurokinin NK3 receptors
Pathogenesis
Polycystic ovary syndrome
Receptors
Stein-Leventhal syndrome
Triglycerides
Type 2 diabetes
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Summary:Polycystic ovary syndrome (PCOS) is a prevalent endocrine condition characterized by a range of endocrine, reproductive, and metabolic abnormalities. At present, management of women with PCOS is suboptimal as treatment is only symptomatic. Clinical and experimental advances in our understanding of PCOS etiology support a pivotal role for androgen neuroendocrine actions in PCOS pathogenesis. Hyperandrogenism is a key PCOS trait and androgen actions play a role in regulating the kisspeptin-/neurokinin B-/dynorphin (KNDy) system. This study aimed to investigate if targeted antagonism of neurokinin B signaling through the neurokinin 3 receptor (NK3R) would reverse PCOS traits in a dihydrotestosterone (DHT)-induced mouse model of PCOS. After 3 months, DHT exposure induced key reproductive PCOS traits of cycle irregularity and ovulatory dysfunction, and PCOS-like metabolic traits including increased body weight; white and brown fat pad weights; fasting serum triglyceride and glucose levels, and blood glucose incremental area under the curve. Treatment with a NK3R antagonist (MLE4901) did not impact the observed reproductive defects. In contrast, following NK3R antagonist treatment, PCOS-like females displayed decreased total body weight, adiposity, and adipocyte hypertrophy, but increased respiratory exchange ratio, suggesting NK3R antagonism altered the metabolic status of the PCOS-like females. NK3R antagonism did not improve circulating serum triglyceride or fasted glucose levels. Collectively, these findings demonstrate that NK3R antagonism may be beneficial in the treatment of adverse metabolic features associated with PCOS and support neuroendocrine targeting in the development of novel therapeutic strategies for PCOS.
ISSN:0013-7227
1945-7170
DOI:10.1210/endocr/bqab020