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

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.

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Faculty Opinions recommendation of High-fat diet induces significant metabolic disorders in a mouse model of polycystic ovary syndrome.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718523489.793499307 ◽

2014 ◽

Author(s):

Virendra Mahesh

Keyword(s):

Polycystic Ovary Syndrome ◽

Mouse Model ◽

High Fat Diet ◽

Metabolic Disorders ◽

Polycystic Ovary ◽

High Fat ◽

Ovary Syndrome

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Polycystic ovary syndrome mouse model by prenatal exposure to high anti-Müllerian hormone

STAR Protocols ◽

10.1016/j.xpro.2021.100684 ◽

2021 ◽

Vol 2 (3) ◽

pp. 100684

Author(s):

Nour El Houda Mimouni ◽

Paolo Giacobini

Keyword(s):

Polycystic Ovary Syndrome ◽

Mouse Model ◽

Prenatal Exposure ◽

Polycystic Ovary ◽

Ovary Syndrome

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Myo‐inositol and D‐chiro‐inositol (40:1) reverse histological and functional features of polycystic ovary syndrome in a mouse model

Journal of Cellular Physiology ◽

10.1002/jcp.27623 ◽

2018 ◽

Vol 234 (6) ◽

pp. 9387-9398 ◽

Cited By ~ 20

Author(s):

Arturo Bevilacqua ◽

Jessica Dragotto ◽

Alessandro Giuliani ◽

Mariano Bizzarri

Keyword(s):

Polycystic Ovary Syndrome ◽

Mouse Model ◽

Polycystic Ovary ◽

Ovary Syndrome ◽

Functional Features

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Tissue-specific dysregulation of 11β-hydroxysteroid dehydrogenase type 1 in overweight/obese women with polycystic ovary syndrome compared with weight-matched controls

Acta Endocrinologica ◽

10.1530/eje-13-1030 ◽

2014 ◽

Vol 171 (1) ◽

pp. 47-57 ◽

Cited By ~ 16

Author(s):

Alessandra Gambineri ◽

Flaminia Fanelli ◽

Federica Tomassoni ◽

Alessandra Munarini ◽

Uberto Pagotto ◽

...

Keyword(s):

Polycystic Ovary Syndrome ◽

Polycystic Ovary ◽

Hydroxysteroid Dehydrogenase ◽

Whole Body ◽

Mrna Levels ◽

Ovary Syndrome ◽

Tissue Specific ◽

Cortisol Metabolism ◽

Cortisol Metabolites

ContextAbnormal cortisol metabolism in polycystic ovary syndrome (PCOS) has been invoked as a cause of secondary activation of the hypothalamic–pituitary–adrenal axis and hence androgen excess. However, this is based on urinary excretion of cortisol metabolites, which cannot detect tissue-specific changes in metabolism and may be confounded by obesity.ObjectiveTo assess cortisol clearance and whole-body and tissue-specific activities of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1 (HSD11B1)) in PCOS.DesignCase–control study.SettingMedical center.PatientsA total of 20 overweight–obese unmedicated Caucasian women with PCOS, aged 18–45 years, and 20 Caucasian controls matched for age, BMI, body fat distribution, andHSD11B1genotypes (rs846910 and rs12086634).Main outcome measuresCortisol metabolites were measured in 24 h urine. During steady-state 9,11,12,12-[2H]4-cortisol infusion, cortisol clearance was calculated and whole-body HSD11B1 activity was assessed as the rate of appearance of 9,12,12-2H3-cortisol (d3-cortisol). Hepatic HSD11B1 activity was quantified as the generation of plasma cortisol following an oral dose of cortisone. Subcutaneous adipose HSD11B1 activity andHSD11B1mRNA were measured,ex vivo, in biopsies.ResultsUrinary cortisol metabolite excretion, deuterated cortisol clearance, and the rate of appearance of d3-cortisol did not differ between patients with PCOS and controls. However, hepatic HSD11B1 conversion of oral cortisone to cortisol was impaired (P<0.05), whereas subcutaneous abdominal adipose tissueHSD11B1mRNA levels and activity were increased (P<0.05) in women with PCOS when compared with controls.ConclusionsTissue-specific dysregulation of HSD11B1 is a feature of PCOS, over and above obesity, whereas increased clearance of cortisol may result from obesity rather than PCOS.

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