scholarly journals SAT-018 Androgen Actions in Adipose Tissue and the Brain Are Key Mediators in the Development of Polycystic Ovary Syndrome

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Madeleine J Cox ◽  
Melissa C Edwards ◽  
Ali Aflatounian ◽  
Valentina Rodriguez Paris ◽  
William L Ledger ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Polycystic Ovary Syndrome ◽  
Mouse Model ◽  
Hepatic Steatosis ◽  
Polycystic Ovary ◽  
Reproductive Traits ◽  
Reproductive Age ◽  
Ovary Syndrome ◽  
Adipocyte Hypertrophy ◽  
The Brain

Abstract Polycystic ovary syndrome (PCOS) is a complex disorder characterised by endocrine, reproductive and metabolic abnormalities. Despite PCOS being the most common endocrinopathy affecting women of reproductive age, its etiology is poorly understood so there is no cure and symptom-oriented treatment is suboptimal. Elucidation of the underlying mechanisms involved in the pathogenesis of PCOS would pave the way for the development of new interventions for PCOS. Hyperandrogenism is the most consistent feature observed in PCOS patients, and recently aberrant neuroendocrine signalling and adipose tissue function have been proposed as playing a pathogenic role in the development of experimental PCOS. To investigate the role of adipose tissue and the brain as potential key sites for androgen receptor (AR)-mediated development of PCOS, we combined an adipocyte and brain-specific ARKO knockout (AdBARKO) mouse model with a dihydrotestosterone (DHT)-induced mouse model of PCOS. Wildtype (WT) and AdBARKO prepubertal mice were implanted with a blank or DHT implant and examined after 12 weeks. In WT control females, DHT exposure induced the PCOS reproductive traits of cycle irregularity, ovulatory dysfunction and reduced follicle health. In contrast, these reproductive features of PCOS were absent in DHT-treated AdBARKO females. The PCOS metabolic characteristics of increased adiposity, adipocyte hypertrophy and hepatic steatosis were induced by DHT in WT females. Despite DHT treatment, AdBARKO females displayed normal white adipose tissue weight, and adipocyte hypertrophy and hepatic steatosis were not evident. However, as with WT mice, DHT treatment induced increased fasting glucose levels in AdBARKO females. These results demonstrate that adipose tissue and the brain are key loci for androgen-mediated actions involved in the developmental origins of PCOS. These findings support targeting adipocyte and neuroendocrine AR-driven pathways in the future development of novel therapeutic strategies for PCOS.

Androgen Action in Adipose Tissue and the Brain are Key Mediators in the Development of PCOS Traits in a Mouse Model

Endocrinology ◽  
2020 ◽  
Vol 161 (7) ◽  
Author(s):  
Madeleine J Cox ◽  
Melissa C Edwards ◽  
Valentina Rodriguez Paris ◽  
Ali Aflatounian ◽  
William L Ledger ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Mouse Model ◽  
Polycystic Ovary ◽  
Liver Steatosis ◽  
Symptomatic Treatment ◽  
Reproductive Age ◽  
Glucose Levels ◽  
Brown Adipose ◽  
Adipocyte Hypertrophy ◽  
The Brain

Abstract Polycystic ovary syndrome (PCOS) is a complex disorder characterized by endocrine, reproductive, and metabolic abnormalities. Despite PCOS being the most common endocrinopathy affecting women of reproductive age, the etiology of PCOS is poorly understood, so there is no cure and symptomatic treatment is suboptimal. Hyperandrogenism is the most consistent feature observed in PCOS patients, and recently aberrant neuroendocrine signaling and adipose tissue function have been proposed as playing a role in the development of PCOS. To investigate the role of adipose tissue and the brain as key sites for androgen receptor (AR)-mediated development of PCOS, we combined a white and brown adipose and brain-specific AR knockout (AdBARKO) mouse model with a dihydrotestosterone (DHT)-induced mouse model of PCOS. As expected, in wildtype (WT) control females, DHT exposure induced the reproductive PCOS traits of cycle irregularity, ovulatory dysfunction, and reduced follicle health, whereas in AdBARKO females, DHT did not produce the reproductive features of PCOS. The metabolic PCOS characteristics of increased adiposity, adipocyte hypertrophy, and hepatic steatosis induced by DHT in WT females were not evident in DHT-treated AdBARKO females, which displayed normal white adipose tissue weight and no adipocyte hypertrophy or liver steatosis. Dihydrotestosterone treatment induced increased fasting glucose levels in both WT and AdBARKO females. These findings demonstrate that adipose tissue and the brain are key loci of androgen-mediated actions involved in the developmental origins of PCOS. These data support targeting adipocyte and neuroendocrine AR-driven pathways in the future development of novel therapeutic strategies for PCOS.

scholarly journals The Role of Microglia in the Polycystic Ovary Syndrome (PCOS)-Like Brain

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A556-A556
Author(s):  
Aisha Sati ◽  
Melanie Prescott ◽  
Christine Louise Jasoni ◽  
Elodie Desroziers ◽  
Rebecca Elaine Campbell
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Mouse Model ◽  
Polycystic Ovary ◽  
Disease Onset ◽  
Reproductive Age ◽  
Specific Marker ◽  
Ovary Syndrome ◽  
Time Specific ◽  
The Brain ◽  
Amoeboid Microglia

Abstract Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility, affecting roughly 1 in 8 women of reproductive age. Accumulating evidence from animal models suggests that the brain plays a key role in the development and maintenance of PCOS. In a well-characterised prenatally androgenised (PNA) mouse model of PCOS, aberrant neuronal wiring associated with PCOS deficits in adulthood are detected as early as postnatal day (P) 25, prior to disease onset. However, the mechanisms by which prenatal androgen exposure alters brain wiring remains unknown. Microglia, the immune cells of the brain, are active sculptors of neuronal wiring across development, mediating both the formation and removal of neuronal inputs. Therefore, microglia may play an important role in driving the abnormal neuronal wiring that leads to PCOS-like features in the PNA brain. Here, to assess whether microglia are altered in the brain of PNA mice, microglia number and morphology-associated activation states were quantified in two hypothalamic regions implicated in fertility regulation. Microglia were identified by immunolabelling for the microglia-specific marker, Iba-1, across developmental timepoints, including embryonic day 17.5, P0, P25, P40 and P60 (n = 7–14/group). At P0, PNA mice had significantly fewer “activated” amoeboid microglia compared to controls (P < 0.05). Later in development at P25, PNA mice exhibited significantly fewer “sculpting” microglia (P < 0.001), whereas at P60, PNA mice possessed a greater number of “activated” amoeboid microglia relative to controls (P < 0.01). This study demonstrates time-specific changes in the number and morphology of microglia in a mouse model of PCOS and suggests a role for microglia in driving the brain wiring abnormalities associated with PCOS. These findings support the need for future functional experiments to determine the relative importance of microglia function in shaping the PCOS-like brain and associated reproductive dysfunction.

scholarly journals Adipose tissue dysfunction, adipokines, and low-grade chronic inflammation in polycystic ovary syndrome

Reproduction ◽  
2015 ◽  
Vol 149 (5) ◽  
pp. R219-R227 ◽  
Author(s):  
Poli Mara Spritzer ◽  
Sheila B Lecke ◽  
Fabíola Satler ◽  
Debora M Morsch
Keyword(s):  
Adipose Tissue ◽  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Lifestyle Changes ◽  
Reproductive Age ◽  
Sufficient Evidence ◽  
Low Grade ◽  
Androgen Excess ◽  
Ovary Syndrome ◽  
Increased Risk

Polycystic ovary syndrome (PCOS), a complex condition that affects women of reproductive age, is characterized by ovulatory dysfunction and androgen excess. Women with PCOS present higher prevalence of obesity, central adiposity, and dyslipidemia, and face increased risk of type 2 diabetes. PCOS is closely linked to functional derangements in adipose tissue. Adipocytes seem to be prone to hypertrophy when exposed to androgen excess, as experienced by women with PCOS, and both adipose tissue hypertrophy and hyperandrogenism are related to insulin resistance. Hypertrophic adipocytes are more susceptible to inflammation, apoptosis, fibrosis, and release of free fatty acids. Disturbed secretion of adipokines may also impact the pathophysiology of PCOS through their influence on metabolism and on sex steroid secretion. Chronic low-grade inflammation in PCOS is also related to hyperandrogenism and to the hypertrophy of adipocytes, causing compression phenomena in the stromal vessels, leading to adipose tissue hypoperfusion and altered secretion of cytokines. Lifestyle changes are the first-line intervention for reducing metabolic risks in PCOS and the addition of an insulin-sensitizing drug might be required. Nevertheless, there is not sufficient evidence in favor of any specific pharmacologic therapies to directly oppose inflammation. Further studies are warranted to identify an adipokine that could serve as an indirect marker of adipocyte production in PCOS, representing a reliable sign of metabolic alteration in this syndrome.

M395 GENES RELATED TO GLYCOSYLATION IN THE BRAIN OF MICE WITH POLYCYSTIC OVARY SYNDROME TRANSPLANTED WITH ADIPOSE TISSUE

2012 ◽  
Vol 119 ◽  
pp. S658-S658
Author(s):  
M. de N.G. Ritto ◽  
C.F. Baptista ◽  
E.H.S. Freitas ◽  
S.M.R. de Noronha ◽  
S.A.A. Corrêa-Noronha ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Ovary Syndrome ◽  
The Brain

Adiposity and metabolic dysfunction in polycystic ovary syndrome

2015 ◽  
Vol 21 (2) ◽  
Author(s):  
Susan Sam
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Polycystic Ovary Syndrome ◽  
Metabolic Disorders ◽  
Polycystic Ovary ◽  
Reproductive Age ◽  
Metabolic Dysfunction ◽  
Obese Women ◽  
Ovary Syndrome ◽  
Insulin Resistant

AbstractPolycystic ovary syndrome (PCOS) is the most common hormonal disorder among reproductive-age women and is associated with a high risk for metabolic disorders. Adiposity and insulin resistance are two prevalent conditions in PCOS and the likely culprits for the heightened metabolic risk. Up to 60% of women with PCOS are considered to be overweight or obese, and even among non-obese women with PCOS there is an increased accumulation of adipose tissue in abdominal depots. Insulin resistance in PCOS is unique and independent of obesity, as even non-obese women with this condition are frequently insulin resistant. However, obesity substantially aggravates the insulin resistance and the metabolic and reproductive abnormalities in women with PCOS. Recently, it has been shown that many aspects of adipose tissue function in PCOS are abnormal, and these abnormalities likely predispose to development of insulin resistance even in the absence of obesity. This review provides an overview of these abnormalities and their impact on development of metabolic disorders. At the end, an overview of the therapeutic options for management of adiposity and its complications in PCOS are discussed.

scholarly journals Adipocyte Dysfunction in a Mouse Model of Polycystic Ovary Syndrome (PCOS): Evidence of Adipocyte Hypertrophy and Tissue-Specific Inflammation

PLoS ONE ◽  
2012 ◽  
Vol 7 (10) ◽  
pp. e48643 ◽  
Author(s):  
Joseph S. Marino ◽  
Jeffrey Iler ◽  
Abigail R. Dowling ◽  
Streamson Chua ◽  
Jens C. Bruning ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Mouse Model ◽  
Polycystic Ovary ◽  
Ovary Syndrome ◽  
Tissue Specific ◽  
Adipocyte Hypertrophy

scholarly journals Adipokines in reproductive function: a link between obesity and polycystic ovary syndrome

2013 ◽  
Vol 50 (2) ◽  
pp. R21-R37 ◽  
Author(s):  
Xinwang Chen ◽  
Xiao Jia ◽  
Jie Qiao ◽  
Youfei Guan ◽  
Jihong Kang
Keyword(s):  
Adipose Tissue ◽  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Reproductive Function ◽  
Reproductive Age ◽  
Women Of Reproductive Age ◽  
Ovary Syndrome ◽  
Underlying Mechanisms ◽  
Insight Into

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy associated with infertility and metabolic disorder in women of reproductive age. Dysfunction of adipose tissue has been implicated in the pathophysiology of PCOS. Increasing evidence shows that the dysregulated expression of adipokines, the secreted products of adipose tissue, plays an important role in the pathology of PCOS. Here, we review the role of several identified adipokines that may act as a link between obesity and PCOS. PCOS also reciprocally influences the profile of adipokines. Insight into the underlying mechanisms will help better understand the pathology of PCOS and identify new therapeutic targets of this syndrome.

scholarly journals Pentraxin 3 – a potential link between inflammation, obesity and cardiovascular complications in polycystic ovary syndrome

2018 ◽  
Vol 72 ◽  
pp. 634-641
Author(s):  
Wojciech Gruszka ◽  
Katarzyna Wyskida ◽  
Jerzy Chudek ◽  
Magdalena Olszanecka-Glinianowicz
Keyword(s):  
Adipose Tissue ◽  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Cardiovascular Complications ◽  
Reproductive Age ◽  
Pentraxin 3 ◽  
Metabolic Disturbances ◽  
Ovary Syndrome ◽  
Ptx3 Level ◽  
Potential Link

Polycystic ovary syndrome (PCOS) is the most frequently diagnosed endocrine disorder among women in reproductive age. Metabolic disturbances in PCOS include among others increased incidence of insulin resistance and hyperinsulinemia, type 2 diabetes, dyslipidemia, pre-thrombotic state, hypertension, sleep apnea, atherosclerosis and cardiovascular diseases. Adipose tissue disturbances, including inflammation, were shown to play an important role in the development of both endocrine and metabolic disturbances, accelerating the progression of arteriosclerosis, which leads to premature cardiovascular disease development in PCOS. Pentraxin 3 (PTX3) seems to be one of the factors linking obesity and cardiovascular complications observed in PCOS. PTX3 belongs to a family of long pentraxin proteins. It primarily plays a role in acute immunological response; however, some data suggests that it may also be involved in oocyte maturation. In contrast to the short pentraxin, C-reactive protein, which is primarily produced in the liver, PTX3 is produced locally in the site of the inflammation by several types of cells, for example, adipose tissue during development of inflammation. Increased PTX3 expression was found in visceral fat tissue in obese subjects, and was shown to be under TNF-α control. PTX3 expression has not been tested in PCOS women, yet. Up to now there are only 5 studies investigating PTX3 in PCOS. Only in one study PTX3 level in PCOS women was increased compared to the control groups, in two other studies – decreased, and in two – similar. Also, the association between PTX3, PCOS and obesity remains uncertain. Further research, including ones with a greater number of subjects, especially obese and older women, are necessary to assess the role of PTX3 as a potential link between the inflammation, obesity and polycystic ovary syndrome.

M397 GENES RELATED TO GLUCOSE METABOLISM IN THE BRAIN OF MICE WITH POLYCYSTIC OVARY SYNDROME TRANSPLANTED WITH ADIPOSE TISSUE

2012 ◽  
Vol 119 ◽  
pp. S658-S659
Author(s):  
C.F. Baptista ◽  
M. de N.G. Ritto ◽  
S.M.R. de Noronha ◽  
J. Kede ◽  
S.A.A. Corrêa-Noronha ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Glucose Metabolism ◽  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Ovary Syndrome ◽  
The Brain

scholarly journals Characterization of Reproductive, Metabolic, and Endocrine Features of Polycystic Ovary Syndrome in Female Hyperandrogenic Mouse Models

Endocrinology ◽  
2014 ◽  
Vol 155 (8) ◽  
pp. 3146-3159 ◽  
Author(s):  
A. S. L. Caldwell ◽  
L. J. Middleton ◽  
M. Jimenez ◽  
R. Desai ◽  
A. C. McMahon ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Reproductive Age ◽  
Polycystic Ovaries ◽  
Ovary Syndrome ◽  
Increased Risk ◽  
Long Term Treatment ◽  
Adipocyte Hypertrophy

Polycystic ovary syndrome (PCOS) affects 5–10% of women of reproductive age, causing a range of reproductive, metabolic and endocrine defects including anovulation, infertility, hyperandrogenism, obesity, hyperinsulinism, and an increased risk of type 2 diabetes and cardiovascular disease. Hyperandrogenism is the most consistent feature of PCOS, but its etiology remains unknown, and ethical and logistic constraints limit definitive experimentation in humans to determine mechanisms involved. In this study, we provide the first comprehensive characterization of reproductive, endocrine, and metabolic PCOS traits in 4 distinct murine models of hyperandrogenism, comprising prenatal dihydrotestosterone (DHT, potent nonaromatizable androgen) treatment during days 16–18 of gestation, or long-term treatment (90 days from 21 days of age) with DHT, dehydroepiandrosterone (DHEA), or letrozole (aromatase inhibitor). Prenatal DHT-treated mature mice exhibited irregular estrous cycles, oligo-ovulation, reduced preantral follicle health, hepatic steatosis, and adipocyte hypertrophy, but lacked overall changes in body-fat composition. Long-term DHT treatment induced polycystic ovaries displaying unhealthy antral follicles (degenerate oocyte and/or > 10% pyknotic granulosa cells), as well as anovulation and acyclicity in mature (16-week-old) females. Long-term DHT also increased body and fat pad weights and induced adipocyte hypertrophy and hypercholesterolemia. Long-term letrozole-treated mice exhibited absent or irregular cycles, oligo-ovulation, polycystic ovaries containing hemorrhagic cysts atypical of PCOS, and displayed no metabolic features of PCOS. Long-term dehydroepiandrosterone treatment produced no PCOS features in mature mice. Our findings reveal that long-term DHT treatment replicated a breadth of ovarian, endocrine, and metabolic features of human PCOS and provides the best mouse model for experimental studies of PCOS pathogenesis.

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