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adiponectin, C1Q and collagen domain containing OKDB#: 2616
 Symbols: ADIPOQ Species: human
 Synonyms: ACDC, ADPN, APM1, APM-1, GBP28, ACRP30, ADIPQTL1  Locus: 3q27.3 in Homo sapiens


For retrieval of Nucleotide and Amino Acid sequences please go to: OMIM Entrez Gene
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General Comment Adiponectin is a 244-amino-acid-long polypeptide (protein). There are four distinct regions of adiponectin. The first is a short signal sequence that targets the hormone for secretion outside the cell; next is a short region that varies between species; the third is a 65-amino acid region with similarity to collagenous proteins; the last is a globular domain. Overall this protein shows similarity to the complement 1Q factors (C1Q). However, when the 3-dimensional structure of the globular region was determined, a striking similarity to TNFα was observed, despite unrelated protein sequences. Adiponectin is a protein hormone that modulates a number of metabolic processes, including glucose regulation and fatty acid oxidation. Adiponectin is secreted from adipose tissue (and also from the placenta in pregnancy) /////////Brown adipose tissue transplantation ameliorates polycystic ovary syndrome. Yuan X et al. (2016) Polycystic ovary syndrome (PCOS), which is characterized by anovulation, hyperandrogenism, and polycystic ovaries, is a complex endocrinopathy. Because the cause of PCOS at the molecular level is largely unknown, there is no cure or specific treatment for PCOS. Here, we show that transplantation of brown adipose tissue (BAT) reversed anovulation, hyperandrogenism, and polycystic ovaries in a dehydroepiandrosterone (DHEA)-induced PCOS rat. BAT transplantation into a PCOS rat significantly stabilized menstrual irregularity and improved systemic insulin sensitivity up to a normal level, which was not shown in a sham-operated or muscle-transplanted PCOS rat. Moreover, BAT transplantation, not sham operation or muscle transplantation, surprisingly improved fertility in PCOS rats. Interestingly, BAT transplantation activated endogenous BAT and thereby increased the circulating level of adiponectin, which plays a prominent role in whole-body energy metabolism and ovarian physiology. Consistent with BAT transplantation, administration of adiponectin protein dramatically rescued DHEA-induced PCOS phenotypes. These results highlight that endogenous BAT activity is closely related to the development of PCOS phenotypes and that BAT activation might be a promising therapeutic option for the treatment of PCOS.////////////////// Brown adipose tissue activation by rutin ameliorates polycystic ovary syndrome in rat. Hu T et al. (2017) Polycystic ovary syndrome (PCOS) is a complex endocrinopathy that is characterized by anovulation, hyperandrogenism and polycystic ovary. However, there is a lack of effective treatment for PCOS at present because the pathologic cause of PCOS has not been elucidated. Although it has been known that brown adipose tissue transplantation ameliorates PCOS by activating endogenous BAT, BAT transplantation is not applicable in clinic. Therefore, BAT activation with natural compound could be an effective treatment strategy for PCOS patients. Here, we found that 3 weeks of rutin (a novel compound for BAT activation) treatment increased BAT activation, thereby it improved thermogenesis and systemic insulin sensitivity in dehydroepiandrosterone (DHEA)-induced PCOS rat. In addition, the expression levels of ovarian steroidogenic enzymes such as P450C17, aromatase, 3β-HSD, 17β-HSD and STAR were up-regulated in rutin-treated PCOS rat. Furthermore, acyclicity and the serum level of luteinizing hormone were normalized, and a large number of mature ovulated follicle with a reduction of cystic formation were observed in PCOS rat after rutin treatment. Finally, rutin treatment surprisingly improved fertility and birth defect in PCOS rat. Collectively, our results indicate that rutin treatment significantly improves systemic insulin resistance and ovarian malfunction in PCOS, and our findings in this study provide a novel therapeutic option for the treatment of PCOS by activating BAT with rutin.//////////////////

NCBI Summary: This gene is expressed in adipose tissue exclusively. It encodes a protein with similarity to collagens X and VIII and complement factor C1q. The encoded protein circulates in the plasma and is involved with metabolic and hormonal processes. Mutations in this gene are associated with adiponectin deficiency. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Apr 2010]
General function Ligand, Hormone
Comment High-Molecular-Weight Adiponectin Is Selectively Reduced in Women with Polycystic Ovary Syndrome Independent of Body Mass Index and Severity of Insulin Resistance. O'Connor A et al. Context: High-molecular-weight (HMW) adiponectin contributes to insulin resistance (IR), which is closely associated with the pathophysiology of polycystic ovary syndrome (PCOS). Abnormalities in adipocyte function have been identified in PCOS and potentially contribute to lower adiponectin concentrations. Objective: Our objective was to determine which variables in plasma and adipose tissue influence HMW adiponectin in a well characterized cohort of women with PCOS. Design: This was a cross-sectional study. Settings and Participants: A teaching hospital. Women with PCOS (n = 98) and body mass index (BMI)-matched controls (n = 103) (including 68 age-, BMI-, and IR-matched pairs). Interventions: A standard 75-g oral glucose tolerance test was performed for each participant. Subcutaneous adipose tissue samples were taken by needle biopsy for a subset of PCOS women (n = 9) and controls (n = 8). Main Outcome Measures: Serum levels of HMW adiponectin and their relation to indices of insulin sensitivity, body composition, and circulating androgens as well as adipose tissue expression levels of ADIPOQ, TNFalpha, PPARgamma, and AR were assessed. Results: HMW adiponectin was significantly lower in women with PCOS compared with both BMI- and BMI- and IR-matched controls (P = 0.009 and P = 0.027, respectively). Although BMI and IR were the main predictors of HMW adiponectin, an interaction between waist to hip ratio and plasma testosterone contributed to its variance (P = 0.026). Adipose tissue gene expression analysis demonstrated that AR and TNFalpha (P = 0.008 and P = 0.035, respectively) but not ADIPOQ mRNA levels were increased in PCOS compared with controls. Conclusions: HMW adiponectin is selectively reduced in women with PCOS, independent of BMI and IR. Gene expression analysis suggests that posttranscriptional/translational modification contributes to reduced HMW adiponectin in PCOS.
Cellular localization Secreted
Comment Family123///////////Adropin levels and its associations as a fat-burning hormone in patients with polycystic ovary syndrome: a correlational meta-analysis. Varikasuvu SR et al. (2021) Adropin is a peptide hormone with potential implications in patients with polycystic ovary syndrome (PCOS). The aim of this meta-analysis was to compare the circulating (serum/plasma) and follicular fluid adropin levels between human PCOS patients and non-PCOS controls. Relevant studies were retrieved by online database and manual searching. The standardized mean differences (SMDs) with 95% confidence intervals (CIs) were obtained by a random-effects meta-analysis. Meta-analysis of correlations was performed for the associations of adropin with anthropometric, lipid, insulin resistance and hormonal covariates. The funnel plot analysis with Begg's and Egger's tests was used for publication bias. A total of 9 studies were included in this meta-analysis. The results indicated that the adropin levels were significantly decreased in PCOS patients as compared to non-PCOS controls (SMD = -1.87, 95% CI = -2.55 to -1.18, p < .0001). This decrease was more evident in overweight PCOS patients than their normoweight counterparts (SMD = -0.55, 95% CI = -0.80 to -0.30, p < .0001). A one-study leave-out sensitivity analysis indicated that no single study had a significant influence on the overall outcome, suggesting the robustness of this meta-analysis. There were significant associations of decreased adropin levels with the body mass index, dyslipidemia and insulin resistance in PCOS. Adropin levels are significantly reduced in PCOS patients compared to controls, and this decrease was more evident in overweight PCOS patients.//////////////////
Ovarian function Antral follicle growth, Steroid metabolism, Oocyte maturation, Early embryo development
Comment Effect of adiponectin on estradiol and progesterone secretion from human luteinized granulosa cells in vitro. Messini CI et al. (2021) Ιnformation on the role of adiponectin in human ovarian steroidogenesis is limited. The present study aimed to investigate the effect of different doses of adiponectin on the secretion of estradiol and progesterone by human luteinized granulosa cells in culture. Granulosa cells, obtained from women undergoing in vitro fertilization (IVF) treatment, were pre-incubated for 24 h and then cultured for 48 h. Adiponectin was used in 3 doses, i.e., 5, 10, and 100 μg/ml alone and in combinations with FSH (10 and 100 ng/ml). Estradiol and progesterone were measured by radioimmunoassays in culture supernatants at 24 h and 48 h. Adiponectin after 48 h of culture stimulated the secretion of estradiol and, to a lesser extent, progesterone in a dose-dependent manner. FSH showed a variable effect on steroidogenesis. However, when the low dose FSH was combined with adiponectin, estradiol, and progesterone secretion were increased disproportionally to the dose of adiponectin. With the high dose FSH, the positive effect of adiponectin on FSH-induced estradiol secretion was less pronounced, while the effect on progesterone secretion was negligible. This study shows for the first time a stimulatory effect of adiponectin on the secretion of estradiol and progesterone by human luteinized granulosa cells in vitro. It is suggested that adiponectin plays a paracrine role in human ovarian steroidogenesis by sensitizing the granulosa cells to FSH.//////////////////The adiponectin agonist, AdipoRon, inhibits steroidogenesis and cell proliferation in human luteinized granulosa cells. Grandhaye J et al. (2020) During obesity, excess body weight is not only associated with an increased risk of type 2-diabetes, but also several other pathological processes, such as infertility. Adipose tissue is the largest endocrine organ of the body that produces adipokines, including adiponectin. Adiponectin has been reported to control fertility through the hypothalamic-pituitary-gonadal axis, and folliculogenesis in the ovaries. In this study, we focused on a recent adiponectin-like synthetic agonist called AdipoRon, and its action in human luteinized granulosa cells. We demonstrated that AdipoRon activated the adenosine monophosphate-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor alpha (PPAR) signalling pathways in human luteinized granulosa cells. A 25 μM AdipoRon stimulation reduced granulosa cell proliferation by inducing cell cycle arrest in G1, associated with PTEN and p53 pathway activation. In addition, AdipoRon perturbed cell metabolism by decreasing mitochondrial activity and ATP production. In human luteinized granulosa cells, AdipoRon increased phosphodiesterase activity, leading to a drop in cyclic adenosine monophosphate (cAMP) production, aromatase expression and oestrogens secretion. In conclusion, AdipoRon impacted folliculogenesis by altering human luteinized granulosa cell function, via steroid production and cell proliferation. This agonist may have applications for improving ovarian function in metabolic disorders or granulosa cancers.////////////////// Systemic adiponectin treatment reverses polycystic ovary syndrome-like features in an animal model. Singh A et al. (2017) The present study examined the efficacy of adiponectin for regulating the reproductive, metabolic and fertility status of mice with polycystic ovary syndrome (PCOS). PCOS was induced in prepubertal (21- to 22-day-old) mice using dehydroepiandrosterone (6mg 100g-1day-1 for 25days), after which mice were administered either a low or high dose of adiponectin (5 or 15µgmL-1, s.c., respectively). PCOS mice exhibited typical features, including the presence of numerous cystic follicles, increased circulating androgens, increased body mass, altered steroidogenesis, decreased insulin receptor expression and increased serum triglycerides, serum glucose, Toll-like receptor (TLR)-4 (a marker of inflammation) and vascular endothelial growth factor (VEGF; a marker of angiogenesis). These parameters were significantly correlated with a reduction in adiponectin in PCOS mice compared with vehicle-treated control mice. Exogenous adiponectin treatment of PCOS mice restored body mass and circulating androgen, triglyceride and glucose levels. Adiponectin also restored ovarian expression of steroidogenic markers (LH receptors, steroidogenic acute regulatory protein and 3β-hydroxysteroid dehydrogenase), insulin receptor, TLR-4 and VEGF levels in control mice. Adiponectin restored ovulation in PCOS mice, as indicated by the presence of a corpus luteum and attainment of pregnancy. These findings suggest that adiponectin effectively facilitates fertility in anovulatory PCOS. We hypothesise that systemic adiponectin treatment may be a promising therapeutic strategy for the management of PCOS.////////////////// Expression of adiponectin and its receptors (AdipoR1 and AdipoR2) in goat ovary and its effect on oocyte nuclear maturation in vitro. Oliveira BSP et al. (2017) Adiponectin is an adipokine secreted primarily by adipocytes and is involved in the control of male and female reproductive functions. Circulating levels of adiponectin are inversely correlated with body fat mass, and its biological effects are predominantly mediated through two receptors, AdipoR1 and AdipoR2. The aim of the present study was to verify the expression of the adiponectin system (adiponectin and its receptors, AdipoR1 and AdipoR2) in goat ovary using qPCR and immunohistochemistry analyses and further investigate the in vitro effects of recombinant adiponectin (5 μg/mL and 10 μg/mL) on goat oocyte nuclear maturation. We demonstrated that the mRNA and proteins of the adiponectin system are present in goat ovary. Gene and protein expression of AdipoR1 and AdipoR2 was detected in follicular cells (oocyte, cumulus, granulosa and theca) of small and large antral follicles, while adiponectin mRNA was not detected in oocytes from small and large follicles or in large follicle cumulus cells. Finally, addition of various concentrations of adiponectin in maturation medium affected the number of oocytes that reached metaphase II. In conclusion, in the present study, we detected expression of adiponectin and its receptors AdipoR1 and AdipoR2 in goat ovarian follicles. Furthermore, we demonstrated that recombinant adiponectin increases nuclear maturation of goat oocytes in vitro.////////////////// A potential determinant role of adiponectin and receptors for the early embryo development in PCOS patients with obesity hinted by quantitative profiling. Zhang N et al. (2016) To identify the quantitative profiling of adiponectin and its receptors (AdipoR1, AdipoR2, and T-cadherin) in cumulus cells (CCs) and to evaluate their roles in the early embryo development of polycystic ovary syndrome (PCOS) patients, in part, with obesity. Fifty-five subjects were divided into two groups according to the body mass index. Oocytes were further inseminated and only mature and normal fertilized oocytes (2PN) were included in this research. Real-time PCR and western blot were performed to identify adiponectin and its receptors in CCs. Adiponectin and receptors were ubiquitously expressed in CCs of PCOS and non-PCOS patients. The level of AdipoR2 in CCs from the oocytes yielding blastocyst after 5/6 days in vitro culture was markedly higher than in those from oocytes could not develop to blastocyst stage after Day 6, for non-obese or obese PCOS patients (0.1647 ± 0.0161 versus 0.0783 ± 0.0385, 0.1948 ± 0.0307 versus 0.1057 ± 0.0236, respectively, p < 0.05). In addition, only in patients with PCOS and concurrent obesity the AdipoR1 in CCs was considerably increased in CC-B(+) compared with CC-B(-) subgroup (0.5162 ± 0.0371 versus 0.2448 ± 0.0333, p < 0.01). The development of early embryo was associated with the up-regulation of AdipoR1 and AdipoR2 in PCOS patients. Our results suggested that adiponectin could positively modulate embryo development in humans. Further investigations should be carried out to unlock the crucial role that adiponectin plays in embryo development.////////////////// Ovarian adipocytokines are associated with early in vitro human embryo development independent of the action of ovarian insulin. Li L et al. PURPOSE: We aimed to characterize the association between levels of serum and follicular fluid (FF) adipocytokines, reflected by the leptin to adiponectin ratio (L:A ratio), and oocyte quality and in vitro embryo development in women undergoing assisted reproduction. We also aimed to assess whether follicular hormonal pathways mediate this interaction. METHODS: We prospectively collected FF from up to four individual preovulatory follicles (n?=?76) and fasting sera from women (n?=?31) without endocrinopathies undergoing in vitro fertilization (IVF) at a university-based center for assisted reproduction. Leptin, total adiponectin, insulin, insulin-like growth factor 1 (IGF-1), and ovarian steriods were measured using enzyme immunoassay. Oocyte maturity, fertilization, and embryo development were assessed. RESULTS: FF leptin was similar to serum levels while FF adiponectin was lower. FF leptin (27.10???4.05?ng/mL) and the L:A ratio (11.48E-3???2.57E-3) were related to FF insulin (R (2)?=?0.370 and 0.419, p?95%CI 0.97-3.37]) more likely to undergo successful cleavage and 117?% (RR 2.17 [95?% CI 1.06-4.44]) more likely to obtain viable cleavage morphology compared to a low FF L:A ratio environment, even when adjusted for FF insulin, an independent predictor of cleavage. CONCLUSIONS: Certain adipocytokines, particularly the L:A ratio in the FF of the preovulatory follicle, are related to successful in vitro embryo development. This action may be independent of FF insulin. Effect of adiponectin on bovine granulosa cell steroidogenesis, oocyte maturation and embryo development. [Maillard V et al. ABSTRACT: BACKGROUND: Adiponectin is an adipokine, mainly produced by adipose tissue. It regulates several reproductive processes. The protein expression of the adiponectin system (adiponectin, its receptors, AdipoR1 and AdipoR2 and the APPL1 adaptor) in bovine ovary and its role on ovarian cells and embryo, remain however to be determined. METHODS: Here, we identified the adiponectin system in bovine ovarian cells and embryo using RT-PCR, immunoblotting and immunohistochemistry. Furthermore, we investigated in vitro the effects of recombinant human adiponectin (10 micro g/mL) on proliferation of granulosa cells (GC) measured by 3Hthymidine incorporation, progesterone and estradiol secretions measured by radioimmunoassay in the culture medium of GC, nuclear oocyte maturation and early embryo development. RESULTS: We show that the mRNAs and proteins for the adiponectin system are present in bovine ovary (small and large follicles and corpus luteum) and embryo. Adiponectin, AdipoR1 and AdipoR2 were more precisely localized in oocyte, GC and theca cells. Adiponectin increased IGF-1 10(-8) M-induced GC proliferation (P < 0.01) but not basal or insulin 10(-8) M-induced proliferation. Additionally, adiponectin decreased insulin 10(-8) M-induced, but not basal or IGF-1 10(-8) M-induced secretions of progesterone (P < 0.01) and estradiol (P < 0.05) by GC. This decrease in insulin-induced steroidogenesis was associated with a decrease in ERK1/2 MAPK phosphorylation in GC pre-treated with adiponectin. Finally, addition of adiponectin during in vitro maturation affected neither the percentage of oocyte in metaphase-II nor 48-h cleavage and blastocyst day 8 rates. CONCLUSIONS: In bovine species, adiponectin decreased insulin-induced steroidogenesis and increased IGF-1-induced proliferation of cultured GC through a potential involvement of ERK1/2 MAPK pathway, whereas it did not modify oocyte maturation and embryo development in vitro. Effect of Adiponectin Gene Polymorphisms on Circulating Adiponectin and Insulin Resistance Indexes in Women with Polycystic Ovary Syndrome. Xita N, et al . BACKGROUND: We examined the possible association of adiponectin gene polymorphisms with polycystic ovary syndrome (PCOS) and their influence on serum adiponectin and insulin resistance indexes in Greek women with PCOS. METHODS: We genotyped samples from 100 women with PCOS characterized with respect to body mass index (BMI), glucose and insulin concentrations during an oral glucose tolerance test (OGTT), lipid profile, and serum adiponectin concentrations and from 140 healthy controls for the 45T>G and 276G>T polymorphisms in the adiponectin gene. RESULTS: The distribution of genotypes and alleles of both polymorphisms was no different in women with PCOS and controls, indicating that the individual polymorphisms are not associated with increased risk for PCOS. However, the two polymorphisms were found to be associated with insulin resistance indexes among women with PCOS and to influence adiponectin production. In particular, carriers of the TG genotype at position +45 had greater hyperinsulinemia, as estimated by the area under the curve for insulin (AUCinsulin) during the OGTT, than those with the TT genotype (P <0.05), and this was independent of age and BMI. In addition, women with PCOS with the GG or GT genotypes at position +276 had a higher BMI (P = 0.01) and greater AUCinsulin (P = 0.01) than carriers of the TT genotype. The latter genotype was found less frequently among overweight/obese women with PCOS than in normal-weight individuals (P = 0.002). In addition, the presence of the GG or GT genotype was associated with lower serum adiponectin than the TT genotype, independent of age, BMI, and insulin concentrations (P = 0.03). Serum adiponectin was negatively correlated with serum triglycerides and insulin resistance indexes and positively with HDL-cholesterol. CONCLUSIONS: Adiponectin gene polymorphisms at positions +45 and +276 are not associated with PCOS. However, these genomic variants may influence production of adiponectin and the metabolic variables related to insulin resistance/metabolic syndrome in patients with PCOS.
Expression regulated by Growth Factors/ cytokines
Comment Role of adiponectin in regulating ovarian theca and granulosa cell function. Lagaly DV et al. Adiponectin is an adipokine that has been implicated in insulin resistance, a condition associated with polycystic ovarian syndrome in humans, but whether adiponectin can directly affect ovarian theca or granulosa cell function is unknown. Therefore, to determine the effects of adiponectin on proliferation, steroidogenesis and gene expression of large-follicle theca and granulosa cells, experiments were conducted using bovine ovarian cell cultures. RT-PCR was used to elucidate the effects of adiponectin on gene expression of CYP11A1 and LH receptor (LHR) in large-follicle theca and granulosa cells, as well as expression of CYP17A1 in theca cells and CYP19A1 in granulosa cells. Adiponectin decreased (P<0.05) insulin-induced progesterone and androstenedione production as well as attenuated IGF-I-induced LHR, CYP11A1, and CYP17A1 gene expression in theca cells. In contrast, adiponectin decreased (P<0.05) LHR mRNA abundance in granulosa cells but did not affect steroidogenic enzyme gene expression in granulosa cells. Adiponectin had no effect (P>0.10) on proliferation of large-follicle theca cells. RT-PCR also revealed that abundance of mRNA for the adiponectin receptor (ADIPOR2) was greater (P<0.05) in large-follicle than in small-follicle theca cells and did not significantly differ between small- and large-follicle granulosa cells. In cultured theca cells, LH increased (P<0.05) and IGF-I decreased (P<0.05) ADIPOR2 mRNA abundance. These results indicate that the inhibitory effects of adiponectin on steroidogenesis are primarily localized to theca cells and that the response of theca cells to adiponectin (i.e., ADIPOR2) may be regulated by LH and IGF-I.
Ovarian localization Oocyte, Cumulus, Granulosa, Theca, Luteal cells
Comment Ovarian HMW adiponectin is associated with folliculogenesis in women with polycystic ovary syndrome. Tao T 2013 et al. BACKGROUND Adiponectin may regulate ovarian steroidogenesis, folliculogenesis and ovulation. The alterations in the distribution of adiponectin multimers in follicular fluid (FF) and the relationship between adiponectin multimers and folliculogenesis in women with polycystic ovary syndrome (PCOS ) remain unclear. In this study, we aimed to investigate the association between the levels of total and high molecular weight (HMW) adiponectin in serum and FF and folliculogenesis in women undergoing in vitro fertilisation (IVF). METHODS This prospective study included ten Chinese women with PCOS and ten controls undergoing IVF. The levels of the total and HMW adiponectin in serum and FF were determined by ELISA. Insulin resistance (IR) was estimated using the homeostasis model assessment insulin resistance index (HOMA-IR). RESULTS After controlling for the body mass index (BMI), the levels of the total, and the HMW adiponectin in the serum and FF were significantly lower in the women with PCOS compared with the normovulatory women undergoing IVF (P < 0.05). The levels of the HMW adiponectin were significantly lower in the FF than in the serum (P < 0.01).No significant differences were found in the total adiponectin levels in the serum and in the FF (P > 0.05). Decreased HMW adiponectin in the FF was associated with an increased number of follicles and decreased follicular diameters in the normovulatory and PCOS women, and this association was independent of the overall adiposity. A strong positive linear correlation was observed between the number of the follicles and the IR resistance estimated by HOMA-IR (r = 0.784, P < 0.0001). We found that the larger follicular diameters had a negative relationship with the IR estimated by HOMA-IR (r = -0.445, P < 0.05). A strong negative linear correlation was observed between HOMA-IR and the HMW adiponectin levels(r = -0.726, P < 0.001) and the total adiponectin levels (r = -0.759, P < 0.001) in the FF. CONCLUSIONS The levels of the total adiponectin and the HMW adiponectin in the FF and serum were decreased in the Chinese women with PCOS compared with the normovulatory women undergoing IVF, and the differences persisted after controlling for the BMI. Ovarian HMW adiponectin is negatively correlated to folliculogenesis. ///////////////////////// Adiponectin Expression in the Porcine Ovary during the Oestrous Cycle and Its Effect on Ovarian Steroidogenesis. Maleszka A 2014 et al. Adiponectin is an adipose-secreted hormone that regulates energy homeostasis and is also involved in the control of the reproductive system. The goal of the present study was to investigate changes in adiponectin gene and protein expression in porcine ovarian structures during the oestrous cycle and to examine the effects of in vitro administration of adiponectin on basal and gonadotrophin- and/or insulin-induced secretion of ovarian steroid hormones. Both gene and protein expression of adiponectin were enhanced during the luteal phase of the cycle. Adiponectin affected basal secretion of progesterone by luteal cells, oestradiol by granulosa cells, and testosterone by theca interna cells. The gonadotrophin/insulin-induced release of progesterone from granulosa and theca interna cells and the release of oestradiol and androstenedione from theca cells was also modified by adiponectin. In conclusion, the presence of adiponectin mRNA and protein in the porcine ovary coupled with our previous results indicating adiponectin receptors expression suggest that adiponectin may locally affect ovarian functions. The changes in adiponectin expression throughout the oestrous cycle seem to be dependent on the hormonal status of pigs related to the stage of the oestrous cycle. The effect of adiponectin on ovarian steroidogenesis suggests that this adipokine influences reproductive functions in pigs. ///////////////////////// Adiponectin and its receptors modulate granulosa cell and cumulus cell functions, fertility, and early embryo development in the mouse and human. Richards JS et al. OBJECTIVE: To study the expression and function of adiponectin and its receptors in mouse and human follicle cells and in early embryo development. DESIGN: Whole ovaries, granulosa cells, and cumulus-oocyte complexes isolated from immature mice before and during hormone-induced ovulation were used to analyze the expression of adiponectin, its receptors, and ovulation-related genes; human cumulus cells and granulosa cells were isolated from patients undergoing in?vitro fertilization (IVF) procedures. SETTING: Multicenter. PATIENT(S): Women in IVF programs in Japan and the United States. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Expression of adiponectin receptors and fertility. RESULT(S): Adiponectin expression is absent/low in mouse and human granulosa cells and cumulus cells. Adiponectin receptors are hormonally regulated in mouse granulosa and cumulus cells in?vivo and in culture. Adiponectin differentially alters the expression of Adipor1/Adipor2 as well as genes related to steroidogenesis, ovulation, and apoptosis in cumulus cells versus granulosa cells. Adiponectin enhances oocyte maturation and early embryo development in mouse and human IVF procedures. CONCLUSION(S): Adiponectin can modulate not only follicle growth but also embryo development in mice and humans. Changes in the gene expression of adiponectin and adiponectin receptors (AdipoR1 and AdipoR2) in ovarian follicular cells of dairy cow at different stages of development. Tabandeh MR et al. Adiponectin is one of the most important, recently discovered adipocytokines that acts at various levels to control male and female fertility through central effects on the hypothalamus-pituitary axis or through peripheral effects on the ovary, uterus, and embryo. We studied simultaneous changes in the gene expression pattern of adiponectin and adiponectin receptors 1 and 2 (AdipoR1 and AdipoR2) in granulosa and theca cells, cumulus-oocyte complex, and in corpus luteum in healthy bovine (Bos tarus) follicles at different stages of development. The expression levels of adiponectin, AdipoR1, and AdipoR2 mRNA were lower (P<0.05) in granulosa and cumulus cells in comparison with that in theca cells and oocyte. In contrast with the oocyte, AdipoR1 in granulosa, theca, and luteal cells was expressed (P<0.05) more than AdipoR2. Adiponectin expression increased (P<0.05) in granulosa cells and in cumulus-oocyte complex during follicular development from small to large follicles. Opposite results were observed in theca cells. Expression of adiponectin was highest in the late stages of corpus luteum (CL) regression, whereas lower expression was recorded in active CL (P<0.05). AdipoR1 and AdipoR2 expression increased during the terminal follicular growth in granulosa and theca cells (P<0.05) and during the luteal phase progress in CL. There was positive correlation between adiponectin mRNA level in granulosa cells from large follicles and follicular fluid estradiol concentration (r=0.48, P<0.05) and negative correlation between adiponectin mRNA abundance in theca cells and follicular fluid progesterone concentration (r=-0.44, P<0.05). In conclusion, we found that the physiologic status of the ovary has significant effects on the natural expression patterns of adiponectin and its receptors in follicular and luteal cells of bovine ovary. Effects of high levels of glucose on the steroidogenesis and the expression of adiponectin receptors in rat ovarian cells. Chabrolle C et al. ABSTRACT: BACKGROUND: Reproductive dysfunction in the diabetic female rat is associated with altered folliculogenesis and steroidogenesis. However, the molecular mechanisms involved in the reduction of steroid production have not been described. Adiponectin is an adipocytokine that has insulin-sensitizing actions including stimulation of glucose uptake in muscle and suppression of glucose production in liver. Adiponectin acts via two receptor isoforms --AdipoR1 and AdipoR2-- that are regulated by hyperglycaemia and hyperinsulinaemia in liver and muscle. We have recently identified AdipoR1 and AdipoR2 in rat ovary. However, their regulation in ovaries of diabetic female rat remains to be elucidated. METHODS: We incubated rat primary granulosa cells in vitro with high concentrations of glucose (5 or 10g/l) + or - FSH (10-8M) or IGF-1 (10-8M), and we studied the ovaries of streptozotocin-induced diabetic rats (STZ) in vivo. The levels of oestradiol and progesterone in culture medium and serum were measured by RIA. We used immunoblotting to assay key steroidogenesis factors (3beta HSD, p450scc, p450 aromatase, StAR), and adiponectin receptors and various elements of signalling pathways (MAPK ERK1/2 and AMPK) in vivo and in vitro. We also determined cell proliferation by [3H] thymidine incorporation. RESULTS: Glucose (5 or 10g/l) impaired the in vitro production in rat granulosa cells of both progesterone and oestradiol in the basal state and in response to FSH and IGF-1 without affecting cell proliferation and viability. This was associated with substantial reductions in the amounts of 3beta HSD, p450scc, p450 aromatase and StAR proteins and MAPK ERK1/2 phosphorylation. In contrast, glucose did not affect the abundance of AdipoR1 or AdipoR2 proteins. In vivo, as expected, STZ treatment of rats caused hyperglycaemia and insulin, adiponectin and resistin deficiencies. Plasma progesterone and oestradiol levels were also reduced in STZ rats. However, the amounts of 3beta HSD and p450 aromatase were the same in STZ rat ovary and controls, and the amounts of StAR and p450scc were higher. Streptozotocin treatment did not affect adiponectin receptors in rat ovary but it increased AMPK phosphorylation without affecting MAPK ERK1/2 phosphorylation. CONCLUSIONS: High levels of glucose decrease progesterone and oestradiol production in primary rat granulosa cells and in STZ-treated rats. However, the mechanism that leads to reduced ovarian steroid production seems to be different. Furthermore, adiponectin receptors in ovarian cells are not regulated by glucose.
Follicle stages Corpus luteum
Comment Adiponectin levels in women with polycystic ovary syndrome: a systematic review and a meta-analysis. Toulis KA et al. BACKGROUND Conflicting results regarding adiponectin levels in women with polycystic ovary syndrome (PCOS) have been reported. To evaluate adiponectin levels in PCOS, a systematic review of all studies comparing adiponectin levels in women with PCOS with healthy controls and a meta-analysis of those involving women with similar body mass index (BMI) were performed. The influence of possible effect modifiers, such as insulin resistance (IR) and testosterone, was investigated. The influence of obesity was investigated through a 'nested' meta-analysis after within-study BMI stratification and appropriate pooling. METHODS Literature search was conducted through MEDLINE, EMBASE, Cochrane CENTRAL (through June 2008), references from relevant studies and personal contact with the authors. Thirty-one studies, reporting data on 3469 subjects, were reviewed and 16 included in the main meta-analysis. RESULTS Women with PCOS demonstrated significantly lower adiponectin values [weighted mean difference (95% confidence interval) -1.71 (-2.82 to -0.6), P < 10(-4)], yet with significant between-study heterogeneity. Lower adiponectin levels are associated with the IR observed in women with PCOS, compared with controls. IR, but not total testosterone, was found significant among biological parameters explored in the meta-regression model. Hypoadiponectinaemia was present in both lean and obese women with PCOS when compared with non-PCOS counterparts. Data on high molecular weight (HMW) adiponectin are limited (three studies). CONCLUSIONS After controlling for BMI-related effects, adiponectin levels seem to be lower in women with PCOS compared with non-PCOS controls. Low levels of adiponectin in PCOS are probably related to IR but not to testosterone. Total adiponectin should not be used as a biomarker of PCOS severity. Further investigation is needed for HMW adiponectin levels in PCOS.
Phenotypes PCO (polycystic ovarian syndrome)
Mutations 9 mutations

Species: human
Mutation name: None
type: naturally occurring
fertility: subfertile
Comment: Association of single nucleotide polymorphisms in adiponectin and its receptor genes with polycystic ovary syndrome. Yoshihara K et al. OBJECTIVE: To examine the possible association of adiponectin (ADIPOQ), adiponectin receptor (ADIPOR1/2) gene polymorphisms with polycystic ovary syndrome (PCOS) and their influence on insulin resistance in Japanese women with PCOS. STUDY DESIGN: Six single nucleotide polymorphisms (SNPs) in ADIPOQ and ADIPOR1/2 were genotyped in 59 infertile Japanese women with PCOS and 97 healthy Japanese controls. In addition, the association between the genotype and allele frequencies of these SNPs and the clinical phenotypes was analyzed in PCOS patients. RESULTS: There was no significant difference in the genotype and allele frequencies of the 6 SNPs between PCOS patients and controls. In the PCOS group, women with the GG genotype of 45T > G of ADIPOQ had a significantly higher score in the homeostasis model assessment for insulin resistance, fasting blood sugar and insulin level than those with other genotypes. Furthermore, a statistically significant difference in the genotype frequency of 45T > G polymorphism was observed between PCOS subjects with insulin resistance (n = 38) and controls (p = 0.011). CONCLUSION: The 6 SNPs of ADIPOQ and ADIPOR1/2 were not associated with a risk of PCOS. However, the 45T > G SNP in the ADIPOQ may be related to insulin resistance in Japanese women with PCOS.

Species: human
Mutation name: None
type: naturally occurring
fertility: subfertile
Comment: Frequency of adiponectin gene polymorphisms in polycystic ovary syndrome and the association with serum adiponectin, androgen levels, insulin resistance and clinical parameters. Demirci H et al. AIM: Although the association between adiponectin gene polymorphisms and insulin resistance has been investigated in many studies, there are only a few studies, which have investigated adiponectin gene polymorphisms in patients with polycystic ovary syndrome (PCOS). The objectives of this study were to determine the frequency of T45G polymorphisms localised in exon 2 of the adiponectin gene in a Turkish population with PCOS and to determine the association of T45G polymorphisms with insulin resistance and serum adiponectin levels in PCOS. MATERIALS AND METHODS: Ninety-six patients with PCOS and 93 healthy control subjects were included in the study. Insulin resistance was estimated via HOMA-IR. Serum adiponectin levels were measured by ELISA. For determination of adiponectin gene polymorphisms, PCR was performed with appropriate primers after genomic DNA was obtained from the peripheral blood of the patients and control subjects. RESULTS: Adiponectin levels were low in patients with PCOS than control subjects. There was no significant statistical difference between the PCOS and control groups with respect to the frequency of polymorphisms and the genotype distribution. Adiponectin gene polymorphisms were not associated with the anthropometric parameters, hyperandrogenism and adiponectin levels in PCOS. However, the fasting insulin level and insulin resistance were significantly higher and more frequent, respectively, in the polymorphic group compared to the other genotypes among patients with PCOS. CONCLUSION: The risk of PCOS, hyperandrogenism in patients with PCOS and low serum adiponectin levels cannot be directly attributed to T45G adiponectin gene polymorphisms in exon 2, rather these polymorphisms may be associated with insulin resistance and hyperinsulinemia in PCOS.

Species: human
Mutation name: None
type: naturally occurring
fertility: subfertile
Comment: Association of +45G15G(T/G) and +276(G/T) polymorphisms in the ADIPOQ gene with polycystic ovary syndrome among Han Chinese women. Zhang N et al. Polycystic ovary syndrome (PCOS) is frequently associated with insulin resistance (IR) and consequently with increased risk of metabolic disorders. Adiponectin is the most abundant adipocytokine and may play a role in the regulation of insulin sensitivity and IR in PCOS. The aim of the present study was to evaluate the genetic influence of the adiponectin (ADIPOQ) gene polymorphisms in the development of PCOS among Han Chinese women.///////////// Haplotype TGTG from SNPs 45T/G and 276G/T of the adiponectin gene contributes to risk of polycystic ovary syndrome. Radavelli-Bagatini S et al. Background: Haplotypes of adiponectin gene single nucleotide polymorphisms (SNPs) might be related to metabolic disorders. Aim: To assess whether the prevalence of SNPs 45T/G and 276G/T of the adiponectin gene and their haplotypes differ between PCOS and non-hirsute cycling controls and to investigate the relationship between these haplotypes and risk factors for cardiovascular disease. Subjects and Methods: In this case-control study, 80 women with PCOS and 1,500 non-hirsute controls with regular cycles underwent clinical and laboratory measurements. Genotype distribution was analyzed by conventional polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: Compared to controls, PCOS women had greater body mass index (BMI) (31.0?7.9 kg/m? vs. 23.4?4.6 kg/m?; p<0.001), waist circumference (92.2?18.8 cm vs. 74.5?10.2 cm;p<0.001), and systolic and diastolic blood pressure (124.6?19.9 vs. 111.5?13.0 mmHg and 79.2?12.5 vs. 71.8?10.6 mmHg;p<0.025), as well as a worse lipid profile (p<0.007), even after adjustment for age and BMI. Genotype distribution was similar in PCOS and controls (45T/G:p=0.399; 276G/T:p=0.135). Six haplotypes were inferred and their frequencies differed significantly between the groups (p=0.001). The TGTG haplotype was more frequent in PCOS than controls (41.3 vs. 18.9%). In PCOS, the GG genotype for SNP 276 (p=0.031) and the TGTG haplotype (p=0.023) were associated with higher systolic blood pressure vs. other genotypes and haplotypes. Body composition, glucose, insulin and lipid profile were similar across genotypes and haplotypes in both groups. Conclusions: Haplotype TGTG from adiponectin gene variants 45T/G and 276G/T is related to susceptibility to PCOS, and might be associated with increased blood pressure in PCOS.

Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: Effects of ADIPOQ polymorphisms on PCOS risk: a meta-analysis. Liu Z et al. (2018) Whether adiponectin (ADIPOQ) polymorphisms are associated with the risk of polycystic ovary syndrome (PCOS) remain controversial. Therefore, we performed this study to better explore correlations between ADIPOQ polymorphisms and PCOS risk. Literature retrieve was conducted in PubMed, Medline and Embase. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Eighteen studies were enrolled for analyses. Pooled overall analyses showed that rs1501299 polymorphism was significantly associated with PCOS risk (recessive model: p = 0.02, OR = 0.77, 95%CI 0.62-0.95; allele model: p = 0.001, OR = 1.15, 95%CI 1.06-1.26). Further subgroup analyses according to ethnicity of participants revealed that rs1501299 and rs2241766 polymorphisms were both significantly correlated with PCOS risk in Caucasians. In addition, rs1501299 polymorphism was also significantly correlated with PCOS risk in East Asians. Our findings indicated that rs1501299 and rs2241766 polymorphisms might serve as genetic biomarkers of PCOS in certain ethnicities.////////////////// Associations between two single nucleotide polymorphismsin the adiponectin gene and polycystic ovary syndromeHeinonen S, et al . In the present study we determined whether genetic variability in the gene encoding adiponectin is associated with polycystic ovary syndrome (PCOS). Altogether 143 Caucasian women with PCOS and 245 healthy controls were genotyped for two single nucleotide polymorphisms (SNPs) in exon 2 and intron 2 in the adiponectin gene. Single-point analysis was expanded to pair-of-loci haplotype analysis to examine the estimated haplotype frequencies of the two SNPs, of unknown phase, in the PCOS and control groups. Estimated haplotype frequencies were assessed using the maximum-likelihood method, employing an expectation-maximization algorithm. A significantly different allele distribution in intron 2 SNP was observed between the groups, with the T allele being significantly reduced in the PCOS group (25.9%) compared with the control group (32.7%) ( p = 0.047), at an odds ratio of 0.72 (95% confidence interval 0.52-0.99). Otherwise, the allele and genotype distributions in either SNP were not statistically different between the groups. In haplotype estimation analysis, there was a lower frequency of the haplotype T-T in the PCOS group (25.9%) than in the control group (32.7%) ( p = 0.058). We conclude that polymorphisms of the adiponectin gene may be implicated in individual susceptibility to PCOS. Evaluating reported candidate gene associations with polycystic ovary syndrome. Pau C et al. OBJECTIVE: To replicate variants in candidate genes associated with polycystic ovary syndrome (PCOS) in a population of European women with PCOS and control subjects. DESIGN: Case-control association analysis and meta-analysis. SETTING: Major academic hospital. PATIENT(S): Women of European ancestry with PCOS (n = 525) and controls (n = 472), aged 18-45 years. INTERVENTION(S): Variants previously associated with PCOS in candidate gene studies were genotyped (n = 39). Metabolic, reproductive, and anthropomorphic parameters were examined as a function of the candidate variants. All genetic association analyses were adjusted for age, body mass index, and ancestry and were reported after correction for multiple testing. MAIN OUTCOME MEASURE(S): Association of candidate gene variants with PCOS. RESULT(S): Three variants, rs3797179 (SRD5A1), rs12473543 (POMC), and rs1501299 (ADIPOQ), were nominally associated with PCOS. However, they did not remain significant after correction for multiple testing, and none of the variants replicated in a sufficiently powered meta-analysis. Variants in the FBN3 gene (rs17202517 and rs73503752) were associated with smaller waist circumferences, and variant rs727428 in the SHBG gene was associated with lower sex hormone-binding globulin levels. CONCLUSION(S): Previously identified variants in candidate genes do not seem to be associated with PCOS risk. CLINICAL TRIAL REGISTRATION NUMBER: NCT00166569.

Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: Family-Based Association Study of rs17300539 and rs12495941 Polymorphism in Adiponectin Gene and Polycystic Ovary Syndrome in a Chinese Population. Sun X et al. (2017) BACKGROUND Polycystic ovary syndrome (PCOS) is a complex disease that has both genetic and environmental components. Adiponectin plays an important role in the regulation of insulin sensitivity and insulin resistance (IR) in PCOS. The aim of this study was to determine 2 single-nucleotide polymorphisms (SNPs) variants (rs12495941 and rs17300539) of the adiponectin gene (ADIPOQ) in polycystic ovary syndrome (PCOS) families. MATERIAL AND METHODS We recruited 197 PCOS probands, their biological parents, and 192 controls. Anthropometric variables, including hip circumference (HC) and waist circumference (WC), were measured in all subjects during their first visit to the outpatient department. Serum T, FBG, FINS, TC, TG, LDL, and HDL levels were measured. PCOS patients were divided into 2 groups based on BMI: group A (BMI <25 kg/m²) and group B (BMI ≥25 kg/m²). Parents of PCOS were accordingly categorized into group C and group D (fathers), and group E and group F (mothers). The associations among ADIPOQ rs12495941, rs17300539, and PCOS were analyzed using the transmission disequilibrium test (TDT). RESULTS A significant association was found between SNP rs17300539 and PCOS in our Chinese population. The levels of TG and FINS and the genotype frequencies of rs17300539 are significantly different between overweight and lean PCOS. No significant association was detected for rs12495941. CONCLUSIONS TDT confirms that rs17300539 of ADIPOQ is strongly associated with the risk of PCOS in a Chinese Han population, but rs12495941 of ADIPOQ is not associated with the occurrence of PCOS.////////////////// Family-based analysis of adiponectin gene polymorphisms in Chinese Han polycystic ovary syndrome. Zhang W 2014 et al. OBJECTIVE To study the association between two single-nucleotide polymorphisms (SNPs) variants (rs2241766 and rs1501299) of the adiponectin gene (ADIPOQ) and polycystic ovary syndrome (PCOS) in PCOS family trios. DESIGN Family-based study. SETTING University hospital. PATIENT(S) A total of 224 unrelated PCOS probands, their biologic parents, and 204 control subjects. INTERVENTION(S) Anthropometric, hormonal, and metabolic assessment; genotype detection. MAIN OUTCOME MEASURE(S) Basic endocrine, serum fasting glucose (FG), fasting insulin (FINS), total cholesterol (TC), triglycerides (TG), and low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels were measured. The transmission disequilibrium test (TDT) was used to analyze the association between two SNPs of ADIPOQ and PCOS. RESULT(S) A significant positive association was detected between SNP rs1501299 and PCOS. Compared with AA genotype, AC and CC genotypes had increased risk for PCOS, and the difference remained significant after adjustment for age, body mass index, and testosterone (T). The levels of T, TG, HDL cholesterol, and FINS were significantly higher in obese PCOS patients. However, we failed to find significant overtransmission of the other SNP, rs2241766, from parents to PCOS offspring. The genotype frequencies of rs2241766 and rs1501299 were not different in obese and lean PCOS patients and their parents. CONCLUSION(S) TDT confirms that SNP rs1501299 in the ADIPOQ is significantly associated with the risk of PCOS in the Chinese Han population. The present data may provide a basis for further studies of the role of the ADIPOQ in the etiology of PCOS. ///////////////////////// Association of the T45G and G276T polymorphisms in the adiponectin gene with PCOS: a meta-analysis. Gao L et al. Adiponectin is the most abundant adipocytokine in human body and may play a role in the pathogenesis of polycystic ovary syndrome (PCOS). To clarify the conflicting data in the literature concerning the association between PCOS and two polymorphisms of the adiponectin gene, T45G and G276T, a meta-analysis was performed in this study. Literature search was conducted through PubMed, EMBASE and other relevant studies. Pooled odds ratios (OR) were estimated using fixed-effects (FE) models in codominant, recessive and dominant models. Sensitive analysis was performed by excluding invalid studies. Eight articles investigated the T45G polymorphism in PCOS, and five publications are associated with the G276T polymorphism in PCOS. Significant associations of adiponectin T45G polymorphism with PCOS were found in codominant (FEM: OR?=?1.36, 95% CI: 1.12?1.65), recessive (FEM: OR?=?2.02, 95% CI: 1.17?3.47) or dominant models (FEM: OR?=?1.33, 95% CI: 1.06?1.67). For adiponectin G276T polymorphism, the OR and 95% CI are 0.81(0.68, 0.98), 0.74(0.51, 1.09) and 0.78 (0.61, 0.99) in codominant, dominant and recessive models, respectively. This study provides positive evidence for a causal relationship between the adiponectin gene and PCOS which needs to be further confirmed by further studies.

Species: mouse
Mutation name:
type: null mutation
fertility: subfertile
Comment: Adiponectin Deficiency Leads to Female Subfertility and Ovarian Dysfunctions in Mice. Cheng L et al. (2016) Adipose tissue plays an important role in regulating female fertility, owing to not only its energy stores but also the endocrine actions of secreted adipokines. As one of the adipokines, adiponectin is almost exclusively secreted from the fat, and its circulating concentration is paradoxically reduced in obesity. Although recent studies implied a purported positive role of adiponectin in ovarian functions, definitive in vivo evidence has been sorely lacking. We have consistently observed subfertility in female adiponectin null mice and therefore postulated a protective role of adiponectin in ovarian functions. Female adiponectin null mice displayed impaired fertility, reduced retrieval of oocytes, disrupted estrous cycle, elevated number of atretic follicles, and impaired late folliculogenesis. Analysis of their sera revealed a significant decrease in estradiol and FSH but an increase in LH and testosterone at proestrus. In addition, we found marked reduction of progesterone levels at diestrus, a significant decrease in LH receptor expression as well as in the number of GnRH immunoreactive neurons. Adiponectin deficiency also altered the peak concentrations of LH surge and led to lower expression of Cytochrome P450 family 11 subfamily A member 1 (P450scc), an enzyme critical for progesterone synthesis, as well as an increase in BCL2 associated X, apoptosis regulator and Insulin like growth factor binding protein 4 in atretic follicles. These physiological and molecular events were independent of insulin sensitivity. Thus, we have revealed a novel mechanism linking adiponectin and female fertility that entails regulation of reproductive hormone balance and ovarian follicle development.//////////////////

Species: mouse
Mutation name:
type: null mutation
fertility: None
Comment: Adiponectin protects against development of metabolic disturbances in a PCOS mouse model. Benrick A et al. (2017) Adiponectin, together with adipocyte size, is the strongest factor associated with insulin resistance in women with polycystic ovary syndrome (PCOS). This study investigates the causal relationship between adiponectin levels and metabolic and reproductive functions in PCOS. Prepubertal mice overexpressing adiponectin from adipose tissue (APNtg), adiponectin knockouts (APNko), and their wild-type (WT) littermate mice were continuously exposed to placebo or dihydrotestosterone (DHT) to induce PCOS-like traits. As expected, DHT exposure led to reproductive dysfunction, as judged by continuous anestrus, smaller ovaries with a decreased number of corpus luteum, and an increased number of cystic/atretic follicles. A two-way between-groups analysis showed that there was a significant main effect for DHT exposure, but not for genotype, indicating adiponectin does not influence follicle development. Adiponectin had, however, some protective effects on ovarian function. Similar to in many women with PCOS, DHT exposure led to reduced adiponectin levels, larger adipocyte size, and reduced insulin sensitivity in WTs. APNtg mice remained metabolically healthy despite DHT exposure, while APNko-DHT mice were even more insulin resistant than their DHT-exposed littermate WTs. DHT exposure also reduced the mRNA expression of genes involved in metabolic pathways in gonadal adipose tissue of WT and APNko, but this effect of DHT was not observed in APNtg mice. Moreover, APNtg-DHT mice displayed increased pancreatic mRNA levels of insulin receptors, Pdx1 and Igf1R, suggesting adiponectin stimulates beta cell viability/hyperplasia in the context of PCOS. In conclusion, adiponectin improves metabolic health but has only minor effects on reproductive functions in this PCOS-like mouse model.//////////////////

Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: The preliminary association study of ADIPOQ, RBP4, and BCMO1 variants with polycystic ovary syndrome and with biochemical characteristics in a cohort of Polish women. Czeczuga-Semeniuk E et al. (2018) We aimed to elucidate the frequency of the SNPs in the ADIPOQ, RBP4 and BCMO1genes in a population of Caucasian Polish women with polycystic ovary syndrome (PCOS), and to evaluate the possible associations between these variants and the susceptibility to PCOS. Additionally, the relationship of these polymorphisms to a clinical phenotype of this syndrome, and the concentrations of adipokines, were determined. Clinical and biochemical profiles, DNA isolation and genotyping, and adipokine assays were performed in 294 PCOS women and 78 controls. In a cohort of Polish women, for the genotype distribution and allele frequencies (minor allele frequency - MAF) proved that only the SNP rs1501299 in the gene ADIPOQ (P = 0.0010, OR = 0.41, 95% C.I.:0.24-0.70) and rs7501331 in the gene BCMO1 (P = 0.0106, OR = 0.24, 95% C.I.:0.21-0.71), are significantly associated (the latter marginally significant) with the decrease of the risk of the disease. Also for this SNPs there were significant differences in the genotypic frequencies in the study population. There was a link between rs12934922 of BCMO1 gen and serum concentration of RBP4 (P = 0.034) and adiponectin (P = 0.038) in the study group but not in the control group. The elevated mean serum concentration of cholesterol (P = 0.020) and LDL cholesterol (P = 0.005) was observed for GG rs1501299 genotype and triglycerides (P = 0.028) for TT rs2241766 genotype. The results of the present study revealed that the genes variants RBP4 is not associated with PCO. It seems that rs1501299 of ADIPOQ gene influences the occurrence of PCO and lipids profile in those patients.//////////////////

Species: human
Mutation name:
type: None
fertility: None
Comment: High-molecular-weight adiponectin is inversely associated with sympathetic activity in polycystic ovary syndrome. Shorakae S et al. (2018) To examine the role of high-molecular-weight (HMW) adiponectin and its relationship to sympathetic activity in women with polycystic ovary syndrome (PCOS). Cross sectional study using biobanked samples. Not applicable. Premenopausal women with PCOS (n = 46, Rotterdam diagnostic criteria) and without PCOS (n = 22). None. High-molecular-weight adiponectin levels with secondary outcomes of sympathetic activity and leptin levels. The high-molecular-weight adiponectin level was lower in women with PCOS (median 2.2 interquartile range (IQR)2.3] μg/mL) than in controls (median 3 [IQR2.5] μg/mL) (age and BMI adjusted), and it correlated inversely with the values measured for homeostatic model of assessment of insulin resistance (HOMA-IR), fasting insulin, triglycerides, and free androgen index and positively with sex hormone-binding globulin (SHBG) and high-density lipoprotein cholesterol in all participants and in the PCOS group. In the PCOS group, sympathetic activity (burst frequency) was statistically significantly higher than in controls (median 26 [IQR11] vs. median 22 [IQR14], respectively) and correlated inversely with HMW adiponectin (r = -0.230). The leptin levels were similar between the women with PCOS and controls and did not statistically significantly correlate with HMW adiponectin or sympathetic activity. On multiple regression analysis, burst frequency and SHBG explained 40% of the HMW adiponectin variability (B = -0.7; 95% CI -1.2 to -0.2; and B = 0.01; 95% CI 0.004-0.01) in PCOS. Alongside insulin resistance, increased sympathetic activity is associated with and may modulate HMW adiponectin levels in women with PCOS.////////////////// Downregulation of adiponectin system in granulosa cells and low levels of HMW adiponectin in PCOS. [Artimani T et al. (2015) The purpose of the study was to investigate changes in adiponectin system expression in granulosa cells (GCs) and high molecular weight adiponectin levels in serum and follicular fluid (FF) of 40 women with polycystic ovary syndrome (PCOS) compared to those in 40 women with normal ovary function. Adiponectin (Adipo), adiponectin receptor 1 (AdipoR1), and adiponectin receptor 2 (AdipoR2) messenger RNA (mRNA) expression levels were measured using quantitative real-time polymerase chain reaction (qRT-PCR). High molecular weight (HMW) adiponectin protein concentration was evaluated by ELISA method. Data were analyzed using Student's t test and one-way ANOVA in SPSS 21 software. At oocyte retrieval, FF was aspirated and GCs were obtained from a pooled collection of FF per each patient. PCR results showed expression of adiponectin, AdipoR1, AdipoR2, follicle-stimulating hormone receptor (FSHR), and luteinizing hormone receptor (LHR) in GCs. After controlling body mass index (BMI) values, qRT-PCR demonstrated a decreased expression of adiponectin system in GCs of PCOS patients compared to those in controls (p = 0.001). There was a strong positive correlation among AdipoR1 and AdipoR2 expression and also among FSH and LH receptor expression. (Both r = 0.8, p = 0.001). There were low levels of high molecular weight adiponectin in the serum of PCOS patients with controlled ovarian hyperstimulation (30.19 ± 4.3 ng/ml) compared to the controls (48.47 ± 5.9 ng/ml) and in the FF of PCOS patients with controlled ovarian hyperstimulation (7.86 ± 1.44 ng/ml) compared to the controls (14.22 ± 2.01 ng/ml; p = 0.02). Lower expression of adiponectin and its receptors in GCs might be an important manifestation in gonadotropin-stimulated PCOS patients which could influence the physiologic adiponectin roles such as interaction with insulin and LH in induction of GC gene expression.//////////////////

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