scholarly journals Pathogenesis of reproductive and metabolic PCOS traits in a mouse model

2021 ◽  
Author(s):  
Valentina Rodriguez Paris ◽  
Melissa C Edwards ◽  
Ali Aflatounian ◽  
Michael J Bertoldo ◽  
William L Ledger ◽  
...  
Keyword(s):  
Body Weight ◽  
Mouse Model ◽  
Hepatic Steatosis ◽  
Polycystic Ovary ◽  
Treatment Strategies ◽  
Antral Follicle ◽  
Glucose Levels ◽  
New Treatment ◽  
Early Features ◽  
Large Antral Follicle

Abstract Polycystic ovary syndrome (PCOS) is a common heterogeneous disorder, however the etiology and pathogenesis of PCOS are poorly understood and current management is symptom based. Defining the pathogenesis of PCOS traits is important for developing early PCOS detection markers and new treatment strategies. Hyperandrogenism is a defining characteristic of PCOS and studies support a role for androgen driven actions in the development of PCOS. Therefore, we aimed to determine the temporal pattern of development of PCOS features in a well characterized dihydrotestosterone (DHT)-induced PCOS mouse model after 2, 4 and 8 weeks of DHT exposure. Following 2 weeks of treatment, DHT induced the key PCOS reproductive features of acyclicity, anovulation and multi-follicular ovaries as well as a decrease in large antral follicle health. DHT treated mice displayed the metabolic PCOS characteristics of increased body weight and exhibited increased visceral adiposity after 8 weeks of DHT treatment. DHT treatment also led to an increase in circulating cholesterol after 2 weeks exposure and had an overall effect on fasting glucose levels, but not triglycerides, aspartate transaminase (AST) and alanine transaminase (ALT) levels or hepatic steatosis. These data reveal that in this experimental PCOS mouse model, acyclicity, anovulation and increased body weight are early features of a developing PCOS phenotype whereas adiposity, impaired glucose tolerance, dyslipidemia and hepatic steatosis are later developing features of PCOS. These findings provide insights into the likely sequence of PCOS trait development and support the addition of body weight criteria to the early diagnosis of PCOS.

scholarly journals Neurokinin 3 receptor antagonism ameliorates key metabolic features in a hyperandrogenic PCOS mouse model

Endocrinology ◽  
2021 ◽  
Author(s):  
Irene E Sucquart ◽  
Ruchi Nagarkar ◽  
Melissa C Edwards ◽  
Valentina Rodriguez Paris ◽  
Ali Aflatounian ◽  
...  
Keyword(s):  
Body Weight ◽  
Mouse Model ◽  
Polycystic Ovary ◽  
Serum Triglyceride ◽  
Total Body Weight ◽  
Neurokinin B ◽  
Glucose Levels ◽  
Neurokinin 3 Receptor ◽  
Total Body ◽  
Novel Therapeutic Strategies

Abstract Polycystic ovary syndrome (PCOS) is a prevalent endocrine condition characterised 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 signalling 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 iAUC. 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.

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 Hafnia alvei HA4597 Strain Reduces Food Intake and Body Weight Gain and Improves Body Composition, Glucose, and Lipid Metabolism in a Mouse Model of Hyperphagic Obesity

2019 ◽  
Vol 8 (1) ◽  
pp. 35 ◽  
Author(s):  
Nicolas Lucas ◽  
Romain Legrand ◽  
Camille Deroissart ◽  
Manon Dominique ◽  
Saïda Azhar ◽  
...  
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Food Intake ◽  
Mouse Model ◽  
Body Weight Gain ◽  
Treatment Strategies ◽  
Probiotic Strain ◽  
Metabolic Effects ◽  
Standard Diet ◽  
Hafnia Alvei

Use of new generation probiotics may become an integral part of the prevention and treatment strategies of obesity. The aim of the present study was to test the efficacy of a potential probiotic strain of lactic bacteria Hafnia alvei (H. alvei) HA4597™, in a mouse model of obesity characterized by both hyperphagia and diet-induced adiposity. For this purpose, 10-week-old high-fat-diet (HFD)-fed hyperphagic ob/ob male mice received a daily treatment with 1.4 × 1010 CFU of H. alvei for 38 days. Effects of H. alvei were compared to those of a lipase inhibitor orlistat (80 mg/kg daily) and a vehicle (NaCl 0.9%) in HFD-fed ob/ob mice. A control untreated group of ob/ob mice received the standard diet throughout the experiment. The vehicle-treated HFD group displayed increased food intake, worsening of adiposity, and glycemia. Treatment with H. alvei was accompanied by decreased body weight and fat-mass gain along with reduced food intake to the level of the standard-diet-fed mice. At the end of the experiment, the group treated with H. alvei showed a decrease of glycemia, plasma total cholesterol, and alanine aminotransferase. The orlistat-treated mice showed a lower rate of body weight gain but were hyperphagic and hyperglycemic. These results demonstrate the beneficial anti-obesity and metabolic effects of H. alvei HA4597™ in mice with obesity resulting from hyperphagia and diet-induced adiposity.

scholarly journals Metabolic PCOS Features Are Ameliorated by Mitochondrial Uncoupler BAM15 in a PCOS Mouse Model

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A769-A770
Author(s):  
Valentina Rodriguez Paris ◽  
Stephanie J Alexopoulos ◽  
Ying Hu ◽  
Divya P Shah ◽  
Ali Aflatounian ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Weight Loss ◽  
Mouse Model ◽  
Hepatic Steatosis ◽  
Animal Studies ◽  
Metabolic Diseases ◽  
Polycystic Ovary ◽  
Mesenteric Fat ◽  
Adipocyte Hypertrophy ◽  
Mitochondrial Uncoupler

Abstract Polycystic ovary syndrome (PCOS) is a prevalent endocrine condition characterized by endocrine, reproductive and metabolic dysfunction. At present, there is no cure for PCOS and current treatments are suboptimal. Obesity and adverse metabolic features are prevalent in women with PCOS, with weight loss having a beneficial effect on PCOS features. The use of dietary interventions aimed at weight loss have low long-term compliance in women suffering from PCOS. Recent data from animal studies has shown that a small molecule mitochondrial uncoupler, BAM15, is an effective method to pharmacologically treat obesity and metabolic diseases. Therefore, the aim of this study was to investigate the efficacy of BAM15 to ameliorate PCOS-traits in a hyperandrogenic PCOS mouse model. As expected, exposure of female mice to dihydrotestosterone (DHT) induced the PCOS metabolic features of increased body weight (P<0.05), lean mass (P<0.001), increased parametrial and mesenteric fat pad weights (both P<0.05) and adipocyte hypertrophy (P<0.05). Additionally, DHT-induced PCOS mice exhibited insulin resistance measured by HOMA-IR, increased cholesterol and fasting triglyceride levels and hepatic steatosis (all P<0.05). In contrast, DHT-induced PCOS females treated with BAM15 displayed body weights which were comparable with controls, a significant decrease in parametrial and mesenteric fat depot weights (P<0.05) and reduced adipocyte hypertrophy. Furthermore, BAM15 treatment decreased insulin resistance, cholesterol and fasting triglyceride levels, as well as the degree of hepatic steatosis observed in PCOS females, to levels comparable with controls. PCOS mice presented the reproductive PCOS traits of irregular cycles and ovulatory dysfunction, however BAM15 did not improve these PCOS traits. These findings demonstrate that the pharmacologic mitochondrial uncoupler BAM15 is able to ameliorate metabolic PCOS features in a hyperandrogenic PCOS mouse model. These data provide compelling evidence to support BAM15 as a potential innovative and viable therapeutic approach to manage metabolic traits associated with PCOS.

scholarly journals Formyl peptide receptor agonist Ac2-26 alleviates neuroinflammation in a mouse model of pneumococcal meningitis

2020 ◽  
Author(s):  
Marvin Rüger ◽  
Eugenia Kipp ◽  
Nadine Schubert ◽  
Nicole Schröder ◽  
Thomas Pufe ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Mouse Model ◽  
Treatment Strategies ◽  
Neutrophil Infiltration ◽  
Brain Regions ◽  
Formyl Peptide Receptor ◽  
Formyl Peptide ◽  
The Central Nervous System ◽  
New Treatment ◽  
Deficient Mice

Abstract BackgroundBacterial meningitis is, despite progress in research and the development of new treatment strategies, still a cause of severe neurological disability. The brain is protected from penetrating pathogens by the blood-brain barrier and the innate immune system. The invading pathogens are recognized by pattern recognition receptors including the G-protein coupled formyl peptide receptors (FPRs), which are expressed by immune cells of the central nervous system. FPRs show a broad spectrum of ligands including pro- and anti-inflammatory ones. Here, we investigated the effects of the AnnexinA1 mimetic peptide Ac2-26 in a mouse model of pneumococcal meningitis.MethodsWildtype (WT), Fpr1 and Fpr2-deficient mice were intrathecally infected with Streptococcus pneumoniae D39 (type 2). Subsequently, the different mice groups were treated by intraperitoneal injections of Ac2-26 (1 mg/kg body weight) 2, 8 and 24 hour after the infection. The extent of inflammation was analyzed in various brain regions by means of immunohistochemistry and real-time RT-PCR 30 h after infection.ResultsAc2-26 treated mice showed less severe neutrophil infiltration, paralleled by a reduced induction of pro-inflammatory glia cell responses. While meningitis was ameliorated in Ac2-26-treated Fpr1-deficient mice, this protective effect was not observed in Fpr2-deficient mice.ConclusionsEven with appropriate antimicrobial therapy, mortality during bacterial meningitis is high and so attention has recently focused on adjunctive therapies. Our results suggest that Ac2-26 might be a novel adjunctive therapy for Streptococcus pneumoniae-induced meningitis.* The two last authors contributed equally to this study.

scholarly journals Sexual dysfunction in polycystic ovary syndrome: a systematic review and meta-analysis

2019 ◽  
Author(s):  
Huai Heng Loh ◽  
Anne Yee ◽  
Huai Seng Loh ◽  
Sharmilla Kanagasundram ◽  
Benedict Francis ◽  
...  
Keyword(s):  
Sexual Dysfunction ◽  
Polycystic Ovary ◽  
Meta Analysis ◽  
Interpersonal Relationship ◽  
Treatment Strategies ◽  
Total Testosterone ◽  
Pain Subscale ◽  
Significant Difference ◽  
New Treatment ◽  
The Impact

Abstract Background Polycystic ovarian syndrome is a common disorder characterized by clinical or biochemical hyperandrogenism and ovulary dysfunction. Female sexual dysfunction can have adverse effects on quality of life and interpersonal relationship. Methods We conducted a meta-analysis to evaluate the prevalence and severity of sexual dysfunction in women with PCOS. Results Compared to women without PCOS, those with PCOS were younger (28.90±3.11 versus 31.42±3.37 years; p<0.0001) and had higher body mass index (27.76±3.79 versus 24.95±3.71 kg/m2; p=0.002), Ferriman-Gallwey score (9.90±3.37 versus 4.11±2.17; p<0.0001) and serum total testosterone level (2.26±0.59 versus 1.51±0.49 nmol/L; p<0.0001). There was no significant difference in mean total FSFI score (25.72±2.33 versus 26.62±3.38; p=0.608) in women with and without PCOS. For the FSFI subscales, women with PCOS had a lower score for the pain subscale than women without PCOS (4.60±0.71 versus 5.24±0.39; p<0.001). Other subscales were not significantly different between the two groups. Women with PCOS had a 1.39 higher odds (95% CI 1.13, 1.72; p=0.002, I2 11.9%) of having FSD than women without PCOS. Conclusion FSD is a prevalent and disabling condition in young women with PCOS. Sensitive probing into the intimate aspects of their sex lives is needed to further understand the struggles that afflict women with PCOS. Parallel efforts should be undertaken to investigate the impact of new treatment strategies.

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