Vaspin, a novel adipokine in woman granulosa cells physiology and PCOS pathogenesis?

2021 ◽  
Author(s):  
Alice Bongrani ◽  
Namya Mellouk ◽  
Christelle Ramé ◽  
Marion Cornuau ◽  
Fabrice Guerif ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Granulosa Cells ◽  
Follicular Fluid ◽  
Polycystic Ovary ◽  
Normal Weight ◽  
Human Reproduction ◽  
In Vitro Fertilisation ◽  
Obese Women ◽  
Human Ovary

Vaspin is a novel adipokine mainly expressed in visceral adipose tissue and closely related to obesity and insulin-resistance. Currently, data about its ovarian expression are limited to animal models and its role in human reproduction is largely unexplored. Our study’s aims were thento characterise vaspin expression in the human ovary and to study in vitro its effects on granulosa cells physiology. Secondly, we assessed vaspin and its receptor GRP78 variations in granulosa cells and follicular fluid of a cohort of 112 infertile women undergoing an in vitro fertilisation procedure and allocated to 3 groups, each including normal-weight and obese subjects: 34 PCOS patients, 33 women with isolated polycystic ovary morphology (ECHO group) and 45 controls. Vaspin and GRP78 expression in the ovary was assessed by immunohistochemistry, RT-qPCR and Western blot. Granulosa cells and follicular fluid were analysed by RT-qPCR and ELISA, respectively. In vitro, granulosa cells metabolism was studied after stimulation with recombinant human vaspin, with and without a small interfering RNA directed against GRP78. Vaspin was highly expressed in the human ovary and concentration-dependently enhanced granulosa cells steroidogenesis, proliferation and viability through GRP78 (p<0.0001). Vaspin levels in both granulosa cells and follicular fluid were significantly higher in obese women (p<0.0001) and in the normal-weight ECHO group (p<0.001), which also had the highest expression rates of GRP78 (p<0.05).Although further investigation is needed, vaspin appears as a novel modulator of human granulosa cells physiology and possibly plays a role in PCOS pathogenesis, notably protecting from insulin-resistance induced complications.

scholarly journals Serum Testosterone to Androstenedione Ratio Predicts Metabolic Health in Normal-Weight Polycystic Ovary Syndrome Women

2021 ◽  
Author(s):  
Daniel A Dumesic ◽  
Ayli Tulberg ◽  
Megan McNamara ◽  
Tristan R Grogan ◽  
David H Abbott ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Elevated Serum ◽  
Normal Weight ◽  
Model Assessment ◽  
Metabolic Function ◽  
Ovary Syndrome ◽  
Intravenous Glucose

Abstract Context Increased aldo-keto reductase 1C3 (AKR1C3)-mediated conversion of androstenedione (A4) to testosterone (T) promotes lipid storage in subcutaneous (SC) abdominal adipose in overweight/obese polycystic ovary syndrome (PCOS) women. Objective To examine whether an elevated serum T/A4 ratio, as a marker of enhanced AKR1C3 activity in SC abdominal adipose, predicts metabolic function in normal-weight PCOS women. Design Prospective cohort study. Setting Academic center. Patients Nineteen normal-weight PCOS women; 21 age- and body mass index-matched controls. Intervention(s) Circulating hormone/metabolic determinations, intravenous glucose tolerance testing, total body dual-energy x-ray absorptiometry, SC abdominal fat biopsy. Main Outcome Measure(s) Serum T/A4 ratios, hormone/metabolic measures and AKR1C3 expression of adipocytes matured in vitro were compared between female types; serum T/A4 ratios were correlated with serum lipids, adipose insulin resistance (adipose-IR), homeostatic model assessment of insulin resistance (HOMA-IR) and insulin sensitivity (Si). Results Increased serum T/A4 ratios (P=0.040) and log adipose-IR values (P=0.002) in PCOS women versus controls were accompanied by AKR1C3 mRNA overexpression of PCOS adipocytes matured in vitro (P=0.016). Serum T/A4 ratios in PCOS women, but not controls, negatively correlated with log triglycerides (TG: R=-0.65, P=0.002) and the TG index (R=-0.57, P=0.011). Adjusting for serum free T, serum T/A4 ratios in PCOS women remained negatively correlated with log TG (R=-0.57, P=0.013) and TG index (R=-0.50, P=0.036), respectively, without significant relationships with other metabolic measures. Conclusion An elevated serum T/A4 ratio, as a marker of enhanced AKR1C3 activity in SC abdominal adipose, predicts healthy metabolic function in normal-weight PCOS women.

scholarly journals Insulin Resistance and Polycystic ovary Syndrome: A Review

2019 ◽  
Vol 9 (1-s) ◽  
pp. 433-436 ◽  
Author(s):  
Mudasir Maqbool ◽  
Mohmad Amin Dar ◽  
Imran Gani ◽  
Mohammad Ishaq Geer
Keyword(s):  
Insulin Resistance ◽  
Polycystic Ovary Syndrome ◽  
Cell Function ◽  
Polycystic Ovary ◽  
Hepatic Clearance ◽  
Normal Weight ◽  
Obese Women ◽  
Primary Defect ◽  
Ovary Syndrome ◽  
Insulin Metabolism

Polycystic Ovary Syndrome (PCOS) is the most common, yet complex, endocrine disorder affecting women in their reproductive years and is a leading cause of infertility. This disease appears to be multifactorial and polygenic in nature involving multisystem dysfunction, namely reproduction, endocrine and metabolic. Hyperandrogenism and insulin resistance appear to be central cause to the pathophysiology of the disease. The glucose and insulin metabolism pathways have been studied and debated to understand whether Insulin Resistance is due to a defect in insulin action or a primary defect in β-cell function or decreased hepatic clearance of insulin, or a combination of all these factors. Numerous studies have demonstrated that obese, normal weight and thin women with PCOS have a form of insulin resistance that is unique and intrinsic to the disorder. Moreover obese women with PCOS possess an additional burden of insulin resistance resulting from their excess adiposity. Hyperinsulinemia leads to increase in androgen production directly by acting as a co-gonadotropin, augmenting Luteinizing Hormone activity within the ovary, and indirectly by increasing serum LH pulse amplitude. Whereas Androgens may in turn contribute at least partially to the insulin resistance state linked with PCOS.  In this review, we will briefly study the role of insulin resistance in polycystic ovary syndrome. Keywords: Polycystic ovary syndrome, insulin resistance, Hyperandrogenism.

scholarly journals LRH-1 High Expression in the Ovarian Granulosa Cells of PCOS Patients

2021 ◽  
Author(s):  
Xiao Yang ◽  
Qiumin Wang ◽  
Ying Wang ◽  
Tian Song ◽  
Yanjun Zheng ◽  
...  
Keyword(s):  
Granulosa Cells ◽  
Follicular Fluid ◽  
Polycystic Ovary ◽  
Pearson Correlation ◽  
Statistical Significance ◽  
Control Group ◽  
Vitro Fertilization ◽  
Real Time Quantitative Pcr ◽  
Ovarian Granulosa Cells

Abstract Purpose: Polycystic ovary syndrome (PCOS) is considered as one of the most common endocrine disorder with heterogeneity. There are also reports that liver receptor homolog 1 [LRH-1 or nuclear receptor subfamily 5 group A member 2 (NR5A2)] plays an important role in the reproductive system. But up to now, there are no reports related to the link with PCOS and LRH-1. In this study, we aimed to detect the LRH-1 expression in the ovarian granulosa cell of PCOS patients and explore the potential relationship between LRH-1 and PCOS. Methods: 146 follicular fluid sample were collected in this study, including 72 from PCOS patients and 74 from control patients who underwent intracytoplasmic sperm injection (ICSI) or in vitro fertilization-embryo transfer (IVF-ET). The ovarian granulosa cells were extracted from the patient's follicular fluid by magnetic-activated cell sorting (MACS) method, and the real-time quantitative PCR (qRT-PCR) was used to measure the expression of LRH-1 in ovarian granulosa cells. Then we analyzed the correlation between the expression level of LRH-1 and the clinical characteristics of patient by using Pearson Correlation analysis. Results: The expression of LRH-1 was significantly higher in PCOS patients ovarian granulosa cells than that in the control patients [vs(1.38±0.47)vs(1.03±0.32), t=5.327, p<0.0001], and it was positively correlated with antral follicles counting (AFC) (r=0.3607, p<0.0001)and the serum AMH(r=0.2662, p=0.0012)\LH(r=0.2518, p=0.0022)\T(r=0.2516, p=0.0022) in all patients. No statistical significance between LRH-1 and BMI, FSH, HOMA-IR, DHE-S, progesterone. Conclusions: Compared with the control group, we found that LRH-1 was highly expressed in the ovarian granulosa cells of PCOS patients. Our study has revealed the relationship between the LRH-1 expression and PCOS, which suggested that LRH-1 may play an important role in ovulation disorders. While this finding provided new ideas for the study of the pathogenesis, it also provided a theoretical basis for the clinical diagnosis and treatment for PCOS.

scholarly journals TRIB3 Regulates FSHR Expression in Human Granulosa Cells Under High Levels of Free Fatty Acids

2021 ◽  
Author(s):  
Nan Wang ◽  
Chenchen Si ◽  
Lan Xia ◽  
Xian Wu ◽  
Sheng Zhao ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Free Fatty Acids ◽  
Signaling Pathway ◽  
Oocyte Maturation ◽  
Granulosa Cells ◽  
Follicular Fluid ◽  
Glycogen Synthase ◽  
Obese Women ◽  
Expression Levels

Abstract Background: Granulosa cells (GCs) in cumulus oophorus highly express follicle stimulating hormone receptor (FSHR), which is the most important mediator of both estradiol synthesis and oocyte maturation. Obese women have elevated free fatty acids (FFAs) levels in their follicular fluids and decreased FSHR expression in GCs, which is related to an altered protein kinase B/glycogen synthase kinase 3β (Akt/GSK3β) signaling pathway. Such FFA increases accompany 3-fold rises in pseudokinase 3 (TRIB3) expression and reduce the Akt phosphorylation status in both the human liver and in insulinoma cell lines. Therefore, in a high FFA environment, we determined if TRIB3 mediates regulation of FSHR via the Akt/GSK3β signaling pathway in human GCs. Methods: GCs from women undergoing in vitro fertilization were collected and designated as high and low FFAs cohorts based on their follicular fluid FFA content. GCs with low FFA levels and a human granulosa-like tumor (KGN) cell line were exposed to palmitic acid (PA), which is a dominate FFA follicular fluid constituent. The effects were assessed of this substitution on the Akt/GSK3β signaling pathway activity as well as the expressions of TRIB3 and FSHR at both the gene and protein levels by qPCR, Western blot and immunofluorescence staining analyses. Meanwhile, the individual effects of TRIB3 knockdown in KGN cells and p-AKT inhibitors were compared to determine the mechanisms of FFA-induced FSHR downregulation.Results: The average FSH dose consuming per oocyte (FSH dose/oocyte) was elevated and Top embryo quality ratio was decreased in women with high levels of FFAs in their follicular fluid. In these women, the GC TRIB3 and ATF4 protein expression levels were upregulated which was accompanied by FSHR downregulation. Such upregulation was confirmed based on corresponding increases in their gene expression levels. On the other hand, the levels of p-Akt decreased while p-GSK3β increased in the GCs. Moreover, TRIB3 knockdown reversed declines in FSHR expression and estradiol (E2) production in KGN cells treated with PA, which also resulted in increased p-Akt levels and declines in the p-GSK3β level. In contrast, treatment of TRIB3-knockdown cells with an inhibitor of p-Akt (Ser473) resulted in rises in the levels of both p-GSK3β as well as FSHR expression whereas E2 synthesis fell. Conclusions: During exposure to a high FFA content, TRIB3 can reduce FSHR expression through stimulation of the Akt/GSK3β pathway in human GCs. This response may contribute to inducing oocyte maturation.

scholarly journals Elevated levels of arachidonic acid metabolites in follicular fluid of PCOS patients

Reproduction ◽  
2020 ◽  
Vol 159 (2) ◽  
pp. 159-169 ◽  
Author(s):  
Shengxian Li ◽  
Jia Qi ◽  
Yongzhen Tao ◽  
Qinling Zhu ◽  
Rong Huang ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Follicular Fluid ◽  
Polycystic Ovary ◽  
Reproductive Age ◽  
Pathophysiological Mechanism ◽  
Obese Women ◽  
Liquid Chromatography Mass Spectrometry ◽  
Acid Metabolites ◽  
Cox 2

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-age women usually accompanied by lipid metabolic disorders. However, it remains unknown whether arachidonic acid (AA) and its metabolites in follicular fluid (FF) were altered in PCOS patients. This study was intended to measure the levels of AA and its metabolites in the FF of non-obese PCOS patients that underwent in vitro fertilization (IVF) and to explore the possible causes of the alterations. Thirty-nine non-obese women with PCOS and 30 non-obese women without PCOS were enrolled. AA and its metabolites were measured by liquid chromatography-mass spectrometry. The levels of AA metabolites generated via cyclooxygenase-2 (COX-2) pathway and cytochrome P450 epoxygenase pathway but not lipoxygenase (LOX) pathway were significantly higher in the FF of PCOS patients. The metabolites generated via COX-2 pathway were significantly correlated with levels of testosterone and fasting insulin in serum. The in vitro study further demonstrated that insulin but not testosterone could promote the IL-1β and hCG-induced COX-2 expression and prostaglandin E2 (PGE2) secretion in primary human granulosa cells. In conclusion, there was an elevation in AA metabolites in FF of PCOS patients. Insulin played a pivotal role in the increased AA metabolites generated via COX-2, which could be interpreted as another novel molecular pathophysiological mechanism of PCOS.

scholarly journals TRIB3 regulates FSHR expression in human granulosa cells under high levels of free fatty acids

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Nan Wang ◽  
Chenchen Si ◽  
Lan Xia ◽  
Xian Wu ◽  
Sheng Zhao ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Free Fatty Acids ◽  
Signaling Pathway ◽  
Oocyte Maturation ◽  
Granulosa Cells ◽  
Follicular Fluid ◽  
Glycogen Synthase ◽  
Obese Women ◽  
Expression Levels

Abstract Background Granulosa cells (GCs) in cumulus oophorus highly express follicle stimulating hormone receptor (FSHR), which is the most important mediator of both estradiol synthesis and oocyte maturation. Obese women have elevated free fatty acids (FFAs) levels in their follicular fluids and decreased FSHR expression in GCs, which is related to an altered protein kinase B/glycogen synthase kinase 3β (Akt/GSK3β) signaling pathway. Such FFA increases accompany 3-fold rises in pseudokinase 3 (TRIB3) expression and reduce the Akt phosphorylation status in both the human liver and in insulinoma cell lines. Therefore, in a high FFA environment, we determined if TRIB3 mediates regulation of FSHR via the Akt/GSK3β signaling pathway in human GCs. Methods GCs from women undergoing in vitro fertilization were collected and designated as high and low FFAs cohorts based on their follicular fluid FFA content. GCs with low FFA levels and a human granulosa-like tumor (KGN) cell line were exposed to palmitic acid (PA), which is a dominate FFA follicular fluid constituent. The effects were assessed of this substitution on the Akt/GSK3β signaling pathway activity as well as the expressions of TRIB3 and FSHR at both the gene and protein levels by qPCR, Western blot and immunofluorescence staining analyses. Meanwhile, the individual effects of TRIB3 knockdown in KGN cells and p-AKT inhibitors were compared to determine the mechanisms of FFA-induced FSHR downregulation. Results The average FSH dose consuming per oocyte (FSH dose/oocyte) was elevated and Top embryo quality ratio was decreased in women with high levels of FFAs in their follicular fluid. In these women, the GC TRIB3 and ATF4 protein expression levels were upregulated which was accompanied by FSHR downregulation. Such upregulation was confirmed based on corresponding increases in their gene expression levels. On the other hand, the levels of p-Akt decreased while p-GSK3β increased in the GCs. Moreover, TRIB3 knockdown reversed declines in FSHR expression and estradiol (E2) production in KGN cells treated with PA, which also resulted in increased p-Akt levels and declines in the p-GSK3β level. In contrast, treatment of TRIB3-knockdown cells with an inhibitor of p-Akt (Ser473) resulted in rises in the levels of both p-GSK3β as well as FSHR expression whereas E2 synthesis fell. Conclusions During exposure to a high FFA content, TRIB3 can reduce FSHR expression through stimulation of the Akt/GSK3β pathway in human GCs. This response may contribute to inducing oocyte maturation.

scholarly journals Involvement of Serum Amyloid A1 in the Pathogenesis of Insulin Resistance in Ovarian Granulosa Cells in Polycystic Ovary Syndrome

2021 ◽  
Author(s):  
Qinling Zhu ◽  
Yue Yao ◽  
Lizhen Xu ◽  
Hasiximuke Wu ◽  
Wangsheng Wang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Granulosa Cells ◽  
Follicular Fluid ◽  
Glucose Transporter ◽  
Polycystic Ovary ◽  
Serum Amyloid ◽  
Peripheral Tissues ◽  
Akt Phosphorylation ◽  
Ovarian Granulosa Cells ◽  
Serum Amyloid A1

Abstract Background: Insulin resistance (IR) contributes to ovarian dysfunctions in PCOS patients. Serum amyloid A1 (SAA1) is an acute phase protein produced primarily by the liver in response to inflammation. In addition to its role in inflammation, SAA1 may participate in IR development in peripheral tissues. Yet, expressional regulation of SAA1 in the ovary and its role in the pathogenesis of ovarian IR in PCOS remain elusive. Methods: Follicular fluid and granulosa cells were collected from PCOS and non-PCOS patients with and without IR to measure SAA1 abundance for analysis of its correlation with IR status. The effects of SAA1 on its own expression and insulin signaling pathway were investigated in cultured primary granulosa cells. Results: Ovarian granulosa cells were capable of producing SAA1, which could be induced by SAA1 per se. Moreover, the abundance of SAA1 significantly increased in granulosa cells and follicular fluid in PCOS patients with IR. SAA1 treatment significantly attenuated insulin-stimulated membrane translocation of glucose transporter 4 and glucose uptake in granulosa cells through induction of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression with subsequent inhibition of Akt phosphorylation. These effects of SAA1 could be blocked by inhibitors for toll-like receptors 2/4 (TLR 2/4) and nuclear factor kappa light chain enhancer of activated B (NF-κB). Conclusions: Human granulosa cells are capable of feedforward production of SAA1, which significantly increased in PCOS patients with IR. Excessive SAA1 reduces insulin sensitivity in granulosa cells via induction of PTEN and subsequent inhibition of Akt phosphorylation upon activation of TLR2/4 and NF-κB pathway. These findings highlight that local excessive synthesis of SAA1 is associated with IR development in granulosa cells of PCOS patients.

scholarly journals Novel mechanisms underlying anti-polycystic ovary like syndrome effects of electroacupuncture in rats: suppressing SREBP1 to mitigate insulin resistance, mitochondrial dysfunction and oxidative stress

2020 ◽  
Vol 53 (1) ◽  
Author(s):  
Yan Peng ◽  
Xinming Yang ◽  
Xi Luo ◽  
Chunhong Liu ◽  
Xia Cao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Mitochondrial Dysfunction ◽  
Granulosa Cells ◽  
Polycystic Ovary ◽  
Regulatory Element ◽  
Acupuncture Points ◽  
Hypodermic Injection ◽  
And Oxidative Stress

Abstract Background Acupuncture, a therapy of traditional Chinese medicine, is confirmed to exert the therapeutic action on polycystic ovary syndrome (PCOS). However, the detailed therapeutic mechanisms of acupuncture in PCOS remain ambiguous. In this study, we further investigated whether electroacupuncture (EA) alleviated PCOS-like symptoms in rats via regulating a metabolic regulator, sterol regulatory element binding protein-1 (SREBP1). Methods The PCOS-like rat model was built by hypodermic injection with dehydroepiandrosterone (DHEA). The rats were subjected to EA intervention (ST29 and SP6 acupuncture points) for 5 weeks. Primary granulosa cells were isolated from control and PCOS-like rats for evaluating insulin resistance, mitochondrial dysfunction and oxidative stress in vitro. Results The expression of SREBP1 was increased in PCOS-like rats, which was suppressed by EA treatment. In addition, lentivirus-mediated overexpression of SREBP1 restrained EA treatment-induced improvement in pathological changes, serum hormone levels and insulin resistance in rats. In addition, overexpression of SREBP1 repressed insulin-stimulated phosphorylation of insulin receptor β (IR) and AKT in primary granulosa cells. Moreover, upregulation of SREBP1 further exacerbated mitochondrial dysfunction and oxidative stress in granulosa cells isolated from PCOS-like rats. Mechanically, EA treatment suppressed SREBP1 expression through inducing the activation of AMP-activated protein kinase (AMPK) signaling pathway in PCOS-like rats. Conclusion EA intervention alleviated PCOS-like symptoms in rats via improving IR, mitochondrial dysfunction and oxidative stress through regulating SREBP1, a lipid metabolism regulator. Our findings illuminate the novel protective mechanisms of EA in the treatment of PCOS.

scholarly journals Associations Between Insulin Resistance, Free Fatty Acids, and Oocyte Quality in Polycystic Ovary Syndrome During In Vitro Fertilization

2014 ◽  
Vol 99 (11) ◽  
pp. E2269-E2276 ◽  
Author(s):  
Zhihong Niu ◽  
Nan Lin ◽  
Ruihuan Gu ◽  
Yijuan Sun ◽  
Yun Feng
Keyword(s):  
Insulin Resistance ◽  
Body Mass Index ◽  
Fatty Acids ◽  
In Vitro Fertilization ◽  
Follicular Fluid ◽  
Polycystic Ovary ◽  
Oocyte Quality ◽  
Ovary Syndrome ◽  
Vitro Fertilization

Context: Both polycystic ovary syndrome (PCOS) and obesity are associated with specific reproductive health complications, including lower oocyte quality and clinical pregnancy rates in assisted conception cycles, which may be a result of metabolism-induced changes in the oocyte through the microenvironment of follicular fluid. Free fatty acids (FFAs) are important biomedical indicators of abnormal lipid metabolism and have pronounced effects on cells, leading to changes in metabolism, cell growth, and differentiation Objective: Our objective was to determine the effect of FFA metabolism in plasma and follicular fluid on oocyte quality in the women with PCOS undergoing in vitro fertilization. Design and Setting: Ninety-three women undergoing in vitro fertilization treatment, including 55 with PCOS and 38 age-matched controls, were recruited. PCOS patients were divided into obese and nonobese subgroups on the basis of their body mass index. Main Outcome Measures: Embryo quality was morphologically assessed, and serum sex hormone and insulin levels were measured. FFAs in plasma and follicular fluid were measured using gas chromatography-mass spectrometry. Results: PCOS was found to be associated with significantly higher LH/FSH, total T, free androgen index (FAI), and lower SHBG levels, independent of obesity(P &lt; .05). Obese women with PCOS had a significantly higher total T level, FAI, fasting insulin, insulin resistance index as determined by homeostasis model assessment for insulin resistance, and lower SHBG levels than the nonobese women with PCOS (P &lt; .05). The embryo fragmentation score was significantly positively correlated with the oleic acid concentration in all PCOS patients (r = 0.22, P = .04, for nonobese patients and r = 0.25, P = .03, for obese patients). Conclusions: Our findings clearly demonstrated that PCOS is associated with significantly higher FAI and insulin resistance levels and decreased plasma SHBG levels, independent of body mass index. Obese PCOS patients had higher palmitoleic acid and oleic acid levels in both the plasma and follicular fluid than did the control subject and nonobese PCOS patients. Our results indicated that developmental competence is associated with oleic and stearic acid concentrations, which may contribute to the poor pregnancy outcomes in patients with PCOS.

scholarly journals Elevated SAA1 promotes the development of insulin resistance in ovarian granulosa cells in polycystic ovary syndrome

2022 ◽  
Vol 20 (1) ◽  
Author(s):  
Qinling Zhu ◽  
Yue Yao ◽  
Lizhen Xu ◽  
Hasiximuke Wu ◽  
Wangsheng Wang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Granulosa Cells ◽  
Follicular Fluid ◽  
Glucose Transporter ◽  
Polycystic Ovary ◽  
Venous Blood ◽  
Peripheral Tissues ◽  
Akt Phosphorylation ◽  
Ovarian Granulosa Cells ◽  
Tensin Homolog

Abstract Background Insulin resistance (IR) contributes to ovarian dysfunctions in polycystic ovarian syndrome (PCOS) patients. Serum amyloid A1 (SAA1) is an acute phase protein produced primarily by the liver in response to inflammation. In addition to its role in inflammation, SAA1 may participate in IR development in peripheral tissues. Yet, expressional regulation of SAA1 in the ovary and its role in the pathogenesis of ovarian IR in PCOS remain elusive. Methods Follicular fluid, granulosa cells and peripheral venous blood were collected from PCOS and non-PCOS patients with and without IR to measure SAA1 abundance for analysis of its correlation with IR status. The effects of SAA1 on its own expression and insulin signaling pathway were investigated in cultured primary granulosa cells. Results Ovarian granulosa cells were capable of producing SAA1, which could be induced by SAA1 per se. Moreover, the abundance of SAA1 significantly increased in granulosa cells and follicular fluid in PCOS patients with IR. SAA1 treatment significantly attenuated insulin-stimulated membrane translocation of glucose transporter 4 and glucose uptake in granulosa cells through induction of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression with subsequent inhibition of Akt phosphorylation. These effects of SAA1 could be blocked by inhibitors for toll-like receptors 2/4 (TLR 2/4) and nuclear factor kappa light chain enhancer of activated B (NF-κB). Conclusions Human granulosa cells are capable of feedforward production of SAA1, which significantly increased in PCOS patients with IR. Excessive SAA1 reduces insulin sensitivity in granulosa cells via induction of PTEN and subsequent inhibition of Akt phosphorylation upon activation of TLR2/4 and NF-κB pathway. These findings highlight that elevation of SAA1 in the ovary promotes the development of IR in granulosa cells of PCOS patients.

Sign in / Sign up

Export Citation Format

Share Document