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 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.

scholarly journals Aberrant Hepatic Expression of PPARγ2 Stimulates Hepatic Lipogenesis in a Mouse Model of Obesity, Insulin Resistance, Dyslipidemia, and Hepatic Steatosis

2006 ◽  
Vol 281 (49) ◽  
pp. 37603-37615 ◽  
Author(s):  
Yuan-Li Zhang ◽  
Antonio Hernandez-Ono ◽  
Patty Siri ◽  
Stuart Weisberg ◽  
Donna Conlon ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Mouse Model ◽  
Hepatic Steatosis ◽  
Hepatic Lipogenesis ◽  
Hepatic Expression

Therapeutic potential of curcumin in non-alcoholic steatohepatitis

2005 ◽  
Vol 18 (2) ◽  
pp. 212-221 ◽  
Author(s):  
Haim Shapiro ◽  
Rafael Bruck
Keyword(s):  
Insulin Resistance ◽  
Hepatic Steatosis ◽  
Animal Studies ◽  
Cell Activation ◽  
Therapeutic Potential ◽  
Stellate Cell ◽  
Indirect Evidence ◽  
Deficient Diet ◽  
Alcoholic Steatohepatitis ◽  
Ppar Γ

Non-alcoholic steatohepatitis (NASH) may be associated with a number of clinical conditions, but it occurs most commonly in patients with insulin resistance. There is as yet no established disease-modifying treatment, and a safe and broadly available agent that targets hepatic steatosis, insulin resistance, inflammation and fibrosis is necessary. The polyphenolic compound curcumin exhibits antioxidant and anti-inflammatory properties, inhibits NF-κB and activates PPAR-γ. In rodents, curcumin prevents dietary-induced hepatic steatosis, hepatic stellate cell activation and production of fibrotic proteins, and ameliorates steatohepatitis induced by the intake of alcohol or a methionine–choline-deficient diet. Indirect evidence suggests that curcumin may improve insulin sensitivity in diabetes and inflammatory states. The present paper reviews the numerous cellular and animal studies indicating that curcumin attenuates many of the pathophysiological processes involved in the development and progression of NASH. It is suggested that basic and clinical studies on curcumin in the development and progression of NASH are indicated.

scholarly journals Clinical parallels and experience of antivira l therapy in chronic hepatitis with polycystic ovary syndrome

2020 ◽  
Vol 174 (2) ◽  
pp. 71-79
Author(s):  
P. O. Bogomolov ◽  
A. O. Bueverov ◽  
E. A. Fedosina ◽  
V. E. Bakirova ◽  
S. V. Koblov
Keyword(s):  
Insulin Resistance ◽  
Chronic Hepatitis ◽  
Polycystic Ovary Syndrome ◽  
Antiviral Therapy ◽  
Sustained Virological Response ◽  
Hepatic Steatosis ◽  
Virological Response ◽  
Safety Profile ◽  
Polycystic Ovary ◽  
Ovary Syndrome

Background. Despite the progress made in the treatment of chronic hepatitis C (CHC), there remain many unsolved problems in the treatment of patients infected with the 3rd virus genotype. This fact is mainly associated with the presence of hepatocyte steatosis due to the formation of local insulin resistance. Another important medical and social problem is polycystic ovary syndrome (PCOS), patogenetically associated with insulin resistance. Application of metformin in females to reduce insulin resistance can improve the results of antiviral therapy.Material and methods. Overall 81 females with CHC and PCOS were included in original study. The 1st group (35 patients) received metformin in dose of 20 mg/kg of body weight per day as preliminary and concomitant treatment in addition to antiviral therapy. In 14 patients of this group steatosis was revealed. In another subgroup (21 patients) steatosis was not revealed. The 2nd group (46 patients) received antiviral therapy only. Patients of this group were divided into two subgroups by presence (17 patients) or absence (29 patients) of hepatic steatosis. Interferon-α2b in a standard dose of 3 million IU3 times per week in combination to ribavirin 13 mg/kg/day for 24 wks was applied as antiviral therapy. The period of the subsequent follow-up was 24 wks.Results. Patients with hepatic steatosis had higher biochemical and histological scores of activities. In the groups of patients receiving metformin a higher incidence of a sustained virological response was observed. Additional application of metformin did not aff ect the safety profile of antiviral therapy.Conclusions. Women with CHC with the 3rd genotype and PCOS, who took metformin, had a significantly higher frequency of sustained virological response with an equal safety profile.

Abstract 3203: The role of Neprilysin in the Development of Insulin Resistance, Type 2 Diabetes and Cardiovascular Disease

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Kristina F Standeven ◽  
Angela M Carter ◽  
Anthony J Balmforth ◽  
Stephen B Wheatcroft ◽  
Nigel M Hooper ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Vascular Function ◽  
Animal Studies ◽  
Obese Mice ◽  
Human Adipocytes ◽  
The Metabolic Syndrome ◽  
Mesenteric Fat ◽  
Order Of Magnitude ◽  
Average Gene

Neprilysin (NEP) cleaves several bioactive peptides involved in the regulation of vascular function. In human microvascular endothelial cells, fatty acids and glucose increase NEP activity, and inhibition of NEP in animal studies results in increased insulin sensitivity, suggesting that NEP may be related to the metabolic syndrome. We tested this hypothesis in cell, animal and human based models. Microarray analysis of mRNA expression in differentiated human adipocytes (Affymetrix Human Genome U133 Plus 2.0 arrays) showed NEP expression to be an order of magnitude higher than the average gene signal, suggesting that human adipocytes express high endogenous levels of NEP mRNA. Real time PCR confirmed high levels of NEP mRNA in preadipocytes which increased 28 fold during differentiation and reached levels equivalent to the endogenous control, GAPDH, by 14 days. We created a diet induced model of obesity by feeding male C57BL/6J mice a high-fat diet, which resulted in decreased glucose tolerance and insulin resistance in obese mice. Plasma NEP levels measured after 15 weeks of feeding were significantly higher in obese mice (1642 [± 529]) pg/μl) compared to lean mice (820 [± 487] pg/μl) (p < 0.01). NEP levels increased 4- and 9-fold in epididymal and mesenteric fat in obese, compared to lean, mice. In a study of 318 healthy white European males, plasma NEP measured by activity assay was significantly higher in subjects with the metabolic syndrome (MetS) and levels increased progressively with increasing number of MetS components, being ~8-fold higher in those with 5 MetS components compared with those with none. NEP correlated with insulin, HOMA and BMI in all subjects. In conclusion, we have generated cell, murine and human data which suggest that NEP may have an important role in cardio-metabolic risk associated with insulin resistance, with the adipocyte as a major source of NEP. These findings indicate that NEP is a novel adipokine that links insulin resistance to vascular risk.

scholarly journals Elevated Circulating Fetuin-B Levels Are Associated with Insulin Resistance and Reduced by GLP-1RA in Newly Diagnosed PCOS Women

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Mani Mokou ◽  
Shan Yang ◽  
Bin Zhan ◽  
Shan Geng ◽  
Kejia Li ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Blood Glucose ◽  
Glucose Tolerance ◽  
Metabolic Diseases ◽  
Polycystic Ovary ◽  
Fasting Blood Glucose ◽  
Resistance Index ◽  
Oral Glucose ◽  
Healthy Women ◽  
Tnf Α

Background. Previous studies have suggested that Fetuin-B seems to be a secreted adipokine related to metabolic diseases. However, the results have been inconsistent. Here, our objective is to investigate the changes in circulating Fetuin-B levels in women with polycystic ovary syndrome (PCOS) and analyze the association of Fetuin-B and insulin resistance (IR). Methods. The current study is comprised of a cross-sectional study and a series of interventional studies. Oral glucose tolerance test (OGTT) and euglycemic-hyperinsulinemic clamp (EHC) were engaged to assess glucose tolerance and insulin sensitivity. Serum Fetuin-B levels were determined by ELISA. Results. Serum Fetuin-B and TNF-α levels were markedly increased in women with PCOS compared to healthy women. Circulating Fetuin-B was positively associated with body mass index, waist-to-hip ratio, the percentage of body fat (FAT%), systolic blood pressure, triglyceride, low-density lipoprotein cholesterol, fasting blood glucose, 2 h blood glucose after glucose overload, fasting insulin, 2 h insulin after glucose overload, HOMA-insulin resistance index (HOMA-IR), the area under the curve for insulin (AUCi), AUCg, and TNF-α, while negatively associated with M value and follicular stimulating hormone (FSH). During the EHC, Fetuin-B levels were found to be significantly increased in PCOS women. After a glucose challenge, serum Fetuin-B levels in healthy women were significantly increased. Lipid infusion reduced serum Fetuin-B levels in 30 healthy subjects. After six months of glucagon-like peptide-1 receptor agonist (GLP-1RA) intervention, serum Fetuin-B concentrations in PCOS women markedly decreased following ameliorated IR. Conclusion. Our results indicate that Fetuin-B may be a biomarker of IR in individuals with PCOS. This trial is registered with ChiCTR-IIR-16007901.

scholarly journals Disrupting phosphatase SHP2 in macrophages protects mice from high-fat diet-induced hepatic steatosis and insulin resistance by elevating IL-18 levels

2020 ◽  
Vol 295 (31) ◽  
pp. 10842-10856 ◽  
Author(s):  
Wen Liu ◽  
Ye Yin ◽  
Meijing Wang ◽  
Ting Fan ◽  
Yuyu Zhu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Hepatic Steatosis ◽  
High Fat Diet ◽  
Metabolic Disorders ◽  
Metabolic Diseases ◽  
Low Grade ◽  
High Fat ◽  
Caspase 1

Chronic low-grade inflammation plays an important role in the pathogenesis of type 2 diabetes. Src homology 2 domain-containing tyrosine phosphatase-2 (SHP2) has been reported to play diverse roles in different tissues during the development of metabolic disorders. We previously reported that SHP2 inhibition in macrophages results in increased cytokine production. Here, we investigated the association between SHP2 inhibition in macrophages and the development of metabolic diseases. Unexpectedly, we found that mice with a conditional SHP2 knockout in macrophages (cSHP2-KO) have ameliorated metabolic disorders. cSHP2-KO mice fed a high-fat diet (HFD) gained less body weight and exhibited decreased hepatic steatosis, as well as improved glucose intolerance and insulin sensitivity, compared with HFD-fed WT littermates. Further experiments revealed that SHP2 deficiency leads to hyperactivation of caspase-1 and subsequent elevation of interleukin 18 (IL-18) levels, both in vivo and in vitro. Of note, IL-18 neutralization and caspase-1 knockout reversed the amelioration of hepatic steatosis and insulin resistance observed in the cSHP2-KO mice. Administration of two specific SHP2 inhibitors, SHP099 and Phps1, improved HFD-induced hepatic steatosis and insulin resistance. Our findings provide detailed insights into the role of macrophagic SHP2 in metabolic disorders. We conclude that pharmacological inhibition of SHP2 may represent a therapeutic strategy for the management of type 2 diabetes.

Understanding bariatric surgery to support patients in primary care

2019 ◽  
Vol 30 (10) ◽  
pp. 482-490
Author(s):  
Jenny Abraham ◽  
Neha Shah ◽  
Fridi Levine ◽  
Yitka Graham
Keyword(s):  
Bariatric Surgery ◽  
Weight Loss ◽  
Metabolic Diseases ◽  
Polycystic Ovary ◽  
Signs And Symptoms ◽  
World Health ◽  
Alcoholic Fatty Liver ◽  
Practice Nurses ◽  
Excess Skin ◽  
Nutritional Monitoring

The relatively new field of bariatric surgery is increasingly used as an option to address issues linked to obesity. Practice nurses must understand how they can manage patients who have undergone these procedures Obesity is steadily rising, with 64% of adults in England in 2017 being classified as overweight or obese. Obesity is strongly linked to metabolic diseases such as cardiovascular disease, type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), musculoskeletal and respiratory disorders, cancer as well as psychological illness ( World Health Organization (WHO), 2018 ). Therefore every opportunity should be taken to support patients to lose weight and maintain weight loss. Practice nurses are in a unique and pivotal position to guide patients in a variety of options to assist in their weight loss. Bariatric surgery in England is relatively new, with its usage having increased dramatically in the last 10 years. Practice nurses require knowledge of bariatric surgery to undertake their role effectively. This article provides information to assist practice nurses in providing care and support to patients who have had a surgical intervention. This paper also highlights signs and symptoms of physical and psychological complications including pregnancy and excess skin and recommended action and advice including nutritional monitoring and supplementation.

scholarly journals A review of therapeutic options for managing the metabolic aspects of polycystic ovary syndrome

2020 ◽  
Vol 11 ◽  
pp. 204201882093830 ◽  
Author(s):  
Mohammed Altigani Abdalla ◽  
Harshal Deshmukh ◽  
Stephen Atkin ◽  
Thozhukat Sathyapalan
Keyword(s):  
Insulin Resistance ◽  
Weight Loss ◽  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Therapeutic Options ◽  
Reproductive Age ◽  
Obese Women ◽  
Cardiovascular Risk Reduction ◽  
Ovary Syndrome ◽  
Incretin Mimetics

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age. Metabolic sequelae associated with PCOS range from insulin resistance to type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). Insulin resistance plays a significant role in the pathophysiology of PCOS and it is a reliable marker for cardiometabolic risk. Although insulin sensitising agents such as metformin have been traditionally used for managing metabolic aspects of PCOS, their efficacy is low in terms of weight reduction and cardiovascular risk reduction compared with newer agents such as incretin mimetics and SGLT2 inhibitors. With current pharmaceutical advances, potential therapeutic options have increased, giving patients and clinicians more choices. Incretin mimetics are a promising therapy with a unique metabolic target that could be used widely in the management of PCOS. Likewise, bariatric procedures have become less invasive and result in effective weight loss and the reversal of metabolic morbidities in some patients. Therefore, surgical treatment targeting weight loss becomes increasingly common in the management of obese women with PCOS. Newer emerging therapies, including twincretins, triple GLP-1 agonists, glucagon receptor antagonists and imeglemin, are promising therapeutic options for treating T2DM. Given the similarity of metabolic and pathological features between PCOS and T2DM and the variety of therapeutic options, there is the potential to widen our strategy for treating metabolic disorders in PCOS in parallel with current therapeutic advances. The review was conducted in line with the recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome 2018.

scholarly journals A comprehensive insight into effects of green tea extract in polycystic ovary syndrome: a systematic review

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Vahid Maleki ◽  
Ehsaneh Taheri ◽  
Parisa Varshosaz ◽  
Fatemeh Pourteymour Fard Tabrizi ◽  
Jalal Moludi ◽  
...  
Keyword(s):  
Systematic Review ◽  
Weight Loss ◽  
Polycystic Ovary Syndrome ◽  
Green Tea ◽  
Animal Studies ◽  
Polycystic Ovary ◽  
Green Tea Extract ◽  
Therapeutic Effects ◽  
Ovary Syndrome ◽  
Tea Extract

Abstract Background Polycystic ovary syndrome (PCOS), as the most common endocrine disorder in reproductive-aged women, is characterized by oxidative stress and ovarian tissue inflammation. Green tea extract (GTE) potentially possesses therapeutic effects for PCOS because of the antioxidant and anti-inflammatory compounds. This systematic review evaluates the potential roles of GTE on metabolic variables, hormone levels, and ovarian function in PCOS. Methods A systematic review was conducted of published studies reporting the effects of GTE on PCOS. Several major databases, including PubMed, SCOPUS, and Google Scholar, were searched up from inception to April 2021. Clinical trials and animal studies that assessed the effects of GTE on PCOS were eligible for inclusion. Results Of 314 articles found in the search, four human studies and four animal studies were included. All studies in humans showed the effects of GTE on weight loss. GTE’s effect on decreasing testosterone levels in humans and LH levels in animals were also reported. In addition, increases in FSH and progesterone levels in animal models were observed. Although GTE improved fasting blood sugar and insulin levels, the effect of GTE on inflammatory parameters, such as TNF-alpha and IL-6 and antioxidant status, was limited to animal studies. Conclusion Therefore, this review suggests that GTE could be considered a potential agent to attenuate PCOS complications mainly due to its effect on weight loss and glycemic levels. However, more studies are needed to formulate conclusions about the effects and mechanisms of GTE in PCOS.

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