Retraction of
Visfatin: a protein secreted by visceral fat that mimics the effects of insulin. Science. 2005] . Retraction. [Fukuhara A et al. (2007)/////////////////
NCBI Summary:
This gene encodes a protein that catalyzes the condensation of nicotinamide with 5-phosphoribosyl-1-pyrophosphate to yield nicotinamide mononucleotide, one step in the biosynthesis of nicotinamide adenine dinucleotide. The protein belongs to the nicotinic acid phosphoribosyltransferase (NAPRTase) family and is thought to be involved in many important biological processes, including metabolism, stress response and aging. This gene has a pseudogene on chromosome 10. [provided by RefSeq, Feb 2011]
General function
Ligand, Cytokine
Comment
Plasma Visfatin Levels in Adolescents with Polycystic Ovary Syndrome: A Prospective Case-Control Study. Gümüş Ü et al. (2015) We evaluated the plasma visfatin levels in hirsute female adolescents with polycystic ovary syndrome. This prospective case-control study included 87 female patients who were seen in our adolescence department. Demographic characteristics and hormonal and biochemical parameters were evaluated between patients with and without polycystic ovary syndrome. Next, we divided the patients with polycystic ovary syndrome into the following subgroups: overweight or obese (body mass index ≥ 25 kg/m(2)) vs normal weight (BMI < 25 kg/m(2)) and hirsute vs nonhirsute. There were statistically significant differences in the BMI, serum androgen levels, homeostasis model assessment-insulin resistance (HOMA-IR) levels, and insulin levels between patients with and without polycystic ovary syndrome (P < .05). The mean visfatin levels showed no statistically significant difference between these 2 groups (P > .05). The serum visfatin levels were similar between the 2 subgroups classified by BMI (P > .05). However, there were statistically significant differences in the total and free testosterone levels, 17-hydroxylase progesterone level, HOMA-IR level, and visfatin level between the 2 subgroups classified by hirsutism (P < .05). The plasma visfatin level was higher in hirsute PCOS than in nonhirsute PCOS patients. Significantly higher visfatin levels were found in hirsute than in nonhirsute adolescents with PCOS. According to these results, plasma visfatin levels may be a useful marker in hirsute adolescents with PCOS.//////////////////
Correlation of visfatin levels and lipoprotein lipid profiles in women with polycystic ovary syndrome undergoing ovarian stimulation. Tsouma I 2014 et al.
Abstract The aim of this study was to determine serum and follicular fluid (FF) visfatin levels in age and weight-matched women with polycystic ovary syndrome (PCOS) and normally ovulating subjects undergoing controlled ovarian stimulation and correlate them with their lipid and lipoprotein levels. We included 80 PCOS women (40 lean and 40 overweight) and 80 age- and weight-matched controls, enrolled in the IVF program. In PCOS women, we determined significantly increased serum and FF visfatin as well as serum levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, apolipoprotein B, lipoprotein(a) and homocysteine, while high-density lipoprotein cholesterol and apolipoprotein A1 were significantly lower compared to controls. Serum visfatin levels positively correlated with total cholesterol, LDL cholesterol, triglycerides, lipoprotein(a) and homocysteine levels and negatively with apolipoprotein A1. FF visfatin levels positively correlated with triglycerides and homocysteine and negatively with apolipoprotein A1. Dyslipidemia is common in reproductive age women with PCOS exposing them to risk for cardiovascular diseases. However, the detailed role of visfatin on lipoprotein lipid profile awaits further clarification through future investigation.
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Cellular localization
Secreted
Comment
Evidence for visfatin as an independent predictor of endothelial dysfunction in polycystic ovary syndrome. Pepene CE et al. (2012) Emerging evidence links adipocyte-secreted hormones, in particular adiponectin and visfatin, to cardiovascular pathology. Although adipocytokines dysregulation is common in polycystic ovary syndrome (PCOS) within the context of obesity and insulin resistance, their participation in the process of vascular injury remains elusive. This prospective, case-control study enrolled 102 young women (69 patients with PCOS and 33 eumenorrheic age-matched controls); serum adiponectin, resistin and visfatin, testosterone, SHBG, lipids, glucose, insulin, the homeostasis model assessment of insulin resistance (HOMA-IR) and high-sensitivity C-reactive protein (hs-CRP) were simultaneously measured in all participants. Body composition analysis was performed using dual X-ray absorptiometry. Endothelium impairment was assessed by carotid artery intimae-media thickness (CIMT) and brachial artery flow-mediated vasodilatation (FMD), respectively. In PCOS, both univariate and multivariate analyses evidenced that circulating visfatin was significantly related to free testosterone (P = 0·024) and brachial artery FMD (P = 0·008; P < 0·01 in multivariate analyses). By every visfatin tertile, a stepwise decrease in FMD was observed in all and PCOS only (P = 0·036), not confounded by age, body mass index, total body fat mass, testosterone, SHBG or HOMA-IR. Multiple regression analysis retained visfatin and free testosterone as independent predictors of FMD, explaining about 20% of FMD variability. Adiponectin correlated with CIMT and hs-CRP, but the association was driven by age, body mass and body fat. No relationship between resistin and endothelial markers was found. Visfatin may be a candidate to play a role in the pathogenesis of endothelial dysfunction in PCOS, independently of additional risk factors.//////////////////
Ovarian function
Ovulation, Steroid metabolism, Oocyte maturation
Comment
Nampt affects mitochondrial function in aged oocytes by mediating the downstream effector FoxO3a. Zhuan Q et al. (2021) Maternal aging can impair the quality and decrease the developmental competence of ovulated oocytes. In this study, compromised germinal vesicle breakdown (GVBD) was found in aged mice oocytes. Furthermore, we observed increased reactive oxygen species (ROS) and mitochondrial Ca2+ levels, along with reduced mitochondrial temperature in aged oocytes. Maternal aging also changed the crotonylation level in oocytes. Forkhead box O3 (FoxO3a), a member of the forkhead protein family involved in the regulation of cell survival and life span reached a peak level in the metaphase II stage. Compared with a younger group, FoxO3a expression increased in aged oocytes. Intracellular localization of FoxO3a changed from the cytoplasm to chromatin in response to aging. The expression of the upstream regulator nicotinamide-phosphoribosyltransferase (Nampt) peaked in the GVBD stage. Moreover, Nampt expression was increased in aged oocytes, and more intense staining of Nampt was found in aged mice ovary. To further study the role of Nampt in mitochondrial function, specific agonist P7C3 and inhibitor FK866 were applied to aged oocytes, and FK866 significantly decreased adenosine triphosphate and mitochondrial membrane potential. In conclusion, mitochondrial dysfunction in aged oocytes was associated with elevated FoxO3a, and suppression of Nampt could further impair mitochondrial function.//////////////////Inhibition of visfatin/NAMPT affects ovarian proliferation, apoptosis, and steroidogenesis in pre-pubertal mice ovary. Annie L et al. (2020) Pubertal ovarian function might be dependent on the factors present in the pre-pubertal stages. Visfatin regulates ovarian steroidogenesis in adult. To date, no study has investigated the role of visfatin either in pre-pubertal or pubertal mice ovary. Thus, we investigated the role of visfatin in pre-pubertal mice ovary in relation to steroidogenesis and proliferation and apoptosis in vitro by inhibiting the endogenous visfatin by a specific inhibitor, FK866. Inhibition of visfatin increased the estrogen secretion and also up-regulated the expression of CYP11A1, 17βHSD and CYP19A1 in mice ovary. Furthermore, active caspase3 was up-regulated along with the down-regulation of BAX and BCL2 in the pre-pubertal ovary after visfatin inhibition. The expression of GCNA, PCNA, and BrdU labeling was also decreased by FK866 treatment. These results suggest that visfatin inhibits steroidogenesis, increases proliferation, and suppresses apoptosis in the pre-pubertal mice ovary. So, visfatin is a new regulator of ovary function in pre-pubertal mice.////////////////// Nampt-mediated spindle sizing secures a post-anaphase increase in spindle speed required for extreme asymmetry. Wei Z et al. (2020) Meiotic divisions in oocytes are extremely asymmetric and require pre- and post-anaphase-onset phases of spindle migration. The latter induces membrane protrusion that is moulded around the spindle thereby reducing cytoplasmic loss. Here, we find that depleting the NAD biosynthetic enzyme, nicotinamide phosphoribosyl-transferase (Nampt), in mouse oocytes results in markedly longer spindles and compromises asymmetry. By analysing spindle speed in live oocytes, we identify a striking and transient acceleration after anaphase-onset that is severely blunted following Nampt-depletion. Slow-moving midzones of elongated spindles induce cortical furrowing deep within the oocyte before protrusions can form, altogether resulting in larger oocyte fragments being cleaved off. Additionally, we find that Nampt-depletion lowers NAD and ATP levels and that reducing NAD using small molecule Nampt inhibitors also compromises asymmetry. These data show that rapid midzone displacement is critical for extreme asymmetry by delaying furrowing to enable protrusions to form and link metabolic status to asymmetric division.//////////////////
Role of Visfatin in Restoration of Ovarian Aging and Fertility in the Mouse Aged 18 Months. Park BK et al. (2020) The activation of dormant primordial follicles and ovarian angiogenesis has been attempted as a new treatment strategy for age-related ovarian aging. This study examined whether visfatin rescues age-related fertility decline in female mice aged 18 months, and whether this effect relates to the mTOR/PI3K signaling pathways for activation of primordial follicles and ovarian angiogenesis. Female mice were intraperitoneally injected with 0.1 ml of 500 ng/ml or 1000 ng/ml of visfatin three times at intervals of 2 days, and both ovaries were provided for H&E staining. In another experiment, the mice were superovulated with pregnant mare's serum gonadotropin and human chorionic gonadotropin, and were mated with males. After 18 h, zygotes were collected and cultured for 4 days, and numbers and embryo developmental competency of zygotes retrieved were evaluated. The expression of mTOR/PI3K signaling pathway regulated genes (4EBP1, S6K1, and RPS6) and angiogenic factors (VEGF, visfatin, and SDF-1α) in the ovary were examined. As well, visfatin-treated mice were mated with male mice for 2 weeks, and the pregnancy outcome was monitored up to 3 weeks. Visfatin significantly increased the total numbers of follicles compared with control. Numbers of zygotes retrieved, blastocyst formation rate, and pregnancy rate were significantly increased at 500 ng/ml of visfatin (2.83%, 40.0%, and 80%, respectively) compared with control (0, 0, and no pregnancy). Ovarian expressions of S6K1, RPS6, VEGF, visfatin, and SDF-1α were significantly stimulated at 500 ng/ml of visfatin. These results show that visfatin treatment of an optimal dose rescues age-related decline in fertility, possibly by stimulating mTOR/PI3K signaling.//////////////////
VISFATIN (NAMPT) Improves In Vitro IGF1-Induced Steroidogenesis and IGF1 Receptor Signaling Through SIRT1 in Bovine Granulosa Cells. Reverchon M et al. (2016) VISFATIN is a novel adipokine, also known as a Nicotinamide phosphorybosyltransferase (NAMPT) that is able to modulate different processes including lipid and glucose metabolism, oxidative stress, inflammation and insulin resistance. Recent data suggest that it also plays a role in reproductive function in rats, humans and chickens Here we identified VISFATIN in the bovine ovary and investigated the in vitro effects of this hormone on granulosa cell steroidogenesis and proliferation and oocyte maturation. By RT-PCR, immunoblotting and immunohistochemistry, we found VISFATIN in various ovarian cells, including granulosa and theca cells, corpus luteum, and oocytes. In cultured bovine granulosa cells, we showed that IGF1 (10(-8)M) and VISFATIN (10 and 100 ng/ml) but not FSH (10(-8)M) increased mRNA expression levels of NAMPT after 48h of stimulation. Moreover, we observed that human recombinant VISFATIN (hVisf, 10 ng/ml, 48h) increased the release of progesterone and estradiol secretion and this was associated with an increase in the protein level of STAR, the HSD3B activity and the phosphorylation levels of IGF1R and MAPK ERK1/2 in the presence or absence of IGF1 (10(-8) M). All these effects were abolished when NAMPT was knocked down and when the sirtuin pharmacological inhibitors, CHIC-35 (60 nM) and EX-527 (0.5 M) were pre-incubated in bovine granulosa cells. Thus, in cultured bovine granulosa cells, VISFATIN improves basal and IGF1-induced steroidogenesis and IGF1 receptor signaling through SIRT1.//////////////////
Expression and effect of NAMPT (visfatin) on progesterone secretion in hen granulosa cells. Diot M et al. (2015) In mammals, NAMPT is an adipokine mainly produced by adipose tissue and exists in intracellular and extracellular compartments. The intracellular form of NAMPT is a nicotina-mide phosphoribosyltransferase whereas the extracellular form is considered as an adipokine. In human, NAMPT regulates metabolism but also reproduction and more precisely ovarian functions. In hens, no study has yet identified and investigated the role of NAMPT in ovary. Here, we investigated the presence of NAMPT in hen ovarian follicles and its role in granu-losa cells. By RT-PCR, Western-Blot and immunocytochemistry, we found mRNA transcript and protein of NAMPT in theca and granulosa cells from preovulatory follicles. By RT-qPCR, we observed that mRNA NAMPT levels were higher in granulosa than in theca cells and they decreased during follicle development in theca cells where it remained unchanged in granulosa cells. NAMPT protein quantities were significantly higher in theca as compared to granulosa cells and were unchanged during follicular development. Plasma NAMPT levels, determined by ELISA and immunoblot, were significantly reduced in adult as compared to young hen. In vitro, treatment with human recombinant NAMPT (100 ng/ml, 48h) halved basal and IGF1-induced progesterone secretion and this was associated with a reduction in STAR and HSD3B protein levels and MAPK3/1 phosphorylation levels by granulosa cells. These effects were abolished by the addition of FK866, a specific inhibitor of NAMPT enzy-matic activity. Moreover, NAMPT had no effects on granulosa cell proliferation. In conclu-sion, NAMPT is present in chicken ovarian cells and inhibits progesterone production in granulosa cells.//////////////////
Administration of visfatin during superovulation improves developmental competency of oocytes and fertility potential in aged female mice. Choi KH et al. OBJECTIVE: To examine whether visfatin administration during superovulation improves ovarian response, developmental competence of oocytes, and fertility in aged female mice. DESIGN: Controlled experimental study. SETTING: University hospital. ANIMAL(S): Two groups of differently aged C57BL female mice (6-11 and 26-31 weeks). INTERVENTION(S): Female mice were coinjected intraperitoneally with 5 IU pregnant mare's serum gonadotropin (PMSG) and visfatin of various doses (0-500 ng/mL), followed by 5 IU human chorionic gonadotropin (hCG) injection 48 hours later. Then the mice were immediately mated with an individual male. After 18 hours zygotes were cultured, and expression of ovarian visfatin and vascular endothelial growth factor (VEGF) was examined. Potential pregnancies of visfatin-administered aged female mice were monitored for delivery of offspring. MAIN OUTCOME MEASURE(S): Number of zygotes retrieved, embryo developmental competency, fertility potential, ovarian visfatin and VEGF expression. RESULT(S): Ovarian visfatin expression was significantly decreased in the aged mice group compared with the young. Visfatin administration significantly increased embryo developmental rate and ovarian visfatin and VEGF expressions in the aged mice. Visfatin-administered aged mice delivered significantly higher numbers of offspring than controls. CONCLUSION(S): This study suggests that visfatin administration during superovulation plays an important role in regulating oocyte quality and can improve oocyte quality and fertility of aged female mice.
Expression regulated by
LH, Eicosanoids, PGE2
Comment
The midcycle luteinizing hormone (LH) surge stimulates a rise in follicular fluid prostaglandin E2 (PGE2), which is necessary for normal ovulation. To examine PGE2-regulated processes in primate follicles, monkey granulosa cells were cultured with human chorionic gonadotropin (hCG) alone or with hCG and PGE2, and the resulting total RNA was subjected to microarray analysis. Twenty PGE2-regulated mRNAs were identified Seachord CL,et al .
Ovarian localization
Granulosa, Theca, Luteal cells, Follicular Fluid
Comment
Changes in the localization of ovarian visfatin protein and its possible role during estrous cycle of mice. Annie L et al. (2020) Visfatin is a crucial adipokine, which also regulates ovarian functions in many animals. Mice estrous cycle is characterized by a dynamic complex physiological process in the reproductive system. Expression of various factors changes during the estrous cycle in the ovary. To the best of our knowledge, no previous study has been conducted on the expression of visfatin in mice ovaries during the estrous cycle. Therefore, we investigated the localization and expression of visfatin protein in the ovary of mice during the estrous cycle. Western blot analysis showed the elevated expression of visfatin in proestrus and lowest in diestrus. Immunohistochemical localization of visfatin showed intense staining in the corpus luteum of proestrus and diestrus ovaries. Thecal cells, granulosa cells, and oocytes also showed the presence of visfatin. Expression of ovarian visfatin was correlated to BCL2 and active caspase3 expression and exhibited a significant positive correlation. Furthermore, in vivo inhibition of visfatin by FK866 in the proestrus ovary down-regulated active caspase3 and PCNA expression, and up-regulated the BCL2 expression. These results suggest the role of visfatin in the proliferation and apoptosis of the follicles and specific localization of visfatin in the corpus luteum also indicate its role in corpus luteum function, which may be in progesterone biosynthesis and regression of old corpus luteum. However, further study is required to support these findings. In conclusion, visfatin may also be regulating follicular growth during the estrous cycle by regulating proliferation and apoptosis.////////////////// The concentrations of visfatin in the follicular fluids of women undergoing controlled ovarian stimulation are correlated to the number of oocytes retrieved. Shen CJ et al. (2010) To compare the concentrations of visfatin in the plasma with those in follicular fluid of women undergoing controlled ovarian stimulation and to discover their correlation to the number of oocytes retrieved. Further, to examine whether FSH or hCG affects the expression of visfatin and whether visfatin affects COX-2 expression in cultured granulosa luteal (GL) cells. A clinical and in vitro study. University hospital. Women subjected to IVF procedures were enrolled in the study. Plasma and follicular fluid visfatin levels were analyzed using ELISA. HCG, FSH, PGE2 and visfatin were added to cultured GL cells. Enzyme immunoassay and RT-PCR were performed. There was no correlation between follicular fluid and plasma visfatin levels (r = 0.443). The number of oocytes retrieved was significantly correlated to follicular visfatin levels in multiple linear regression analysis (r = 0.891, r(2) = 0.794). In vitro experiments on GL cells revealed that hCG and PGE(2) considerably increased visfatin mRNA expression. FSH did not affect visfatin mRNA expression. Treatment with visfatin caused an induction of COX-2 mRNA. The follicular fluid visfatin concentrations are correlated to the number of oocytes retrieved. Human GL cells produce visfatin, and visfatin synthesis is increased by hCG and PGE2 treatment. Visfatin can induce expression of COX-2 mRNA in GL cells.//////////////////
Plasma visfatin level in women with polycystic ovary syndrome. Dıkmen E et al. (2011) The aim of this study is to compare the serum level of visfatin between patients with polycystic ovary syndrome (PCOS) and control subjects matched for age and body mass index (BMI) and to assess the possible correlations of visfatin to the hormonal and metabolic parameters of the syndrome. Fifty-five patients with PCOS diagnosis composed of 25 obese, 13 overweight, 17 normal weight subjects and 49 women without concomitant disease matched for age and BMI were included in this study. Serum visfatin levels were similar in normal weight PCOS and control group. Visfatin levels in obese and overweight patients with PCOS were higher than that found in control women with similar BMI, and visfatin had positive linear correlation with BMI, waist circumference and HOMA-IR. Obese women with PCOS had also significantly higher visfatin levels than normal weight women with PCOS. Visfatin levels in obese and overweight patients with PCOS were higher than that found in females without concomitant disease with similar BMI, and visfatin had positive linear correlation with BMI, waist circumference and HOMA-IR.//////////////////
Alterations of circadian clockworks during differentiation and apoptosis of rat ovarian cells. Chu G et al. (2011) Ovarian development is related to cell proliferation, differentiation, and apoptosis of granulosa cells and luteal cells under the control of various modulators, including follicle-stimulating hormone (FSH), luteinizing hormone (LH), and growth factors. In the present study, the expression of clock genes and the related regulation mechanism were analyzed in different ovarian cell types during differentiation and apoptosis. The authors focused on the circadian expression of Per2 as a core clock gene for the maintenance of circadian rhythms. By using a real-time monitoring system of the Per2 promoter activity, the circadian oscillation was analyzed in the granulosa and luteal cells from preantral follicles, antral follicles, and corpora lutea of immature Per2 promoter-destabilized luciferase transgenic rats that were primed with diethylstilbestrol, equine chorionic gonadotropin (eCG), and/or human CG. In addition, transcript levels of Per2, Bmal1, Clock, and Nampt were quantified by quantitative polymerase chain reaction (qPCR). Immunohistochemical studies revealed strong circadian rhythmicity of PER2 protein in the luteal cells, but apparently little rhythmicity in granulosa cells of both preantral and antral follicles. In vitro monitoring of promoter activity showed generation of several oscillations in luteal cells after exposure to dexamethasone (DXM), whereas oscillatory amplitudes of immature and mature granulosa cells were rapidly attenuating. The circadian rhythm of the Bmal1 transcript levels, but not the Per2 transcript, was very weak in the granulosa cells, as compared with that in luteal cells. Granulosa cells gained a strong circadian rhythm ability of the Per2 promoter activity after stimulation with FSH for 3 days. In contrast, LH had little effect on the circadian rhythm before stimulation of granulosa cells with FSH, probably owing to lack of LH receptor. In luteal cells, induction of apoptosis by inhibiting progesterone synthesis resulted in deregulation of Per2 circadian oscillation. Transcript levels of Bmal1 and Clock, but not Per2 and Nampt, were significantly decreased in apoptotic luteal cells. The Bmal1 transcript level was particularly reduced. Consequently, these results strongly suggest the circadian clockwork alters in ovarian cells during follicular development, luteinization, and apoptosis, and expression of Bmal1 may be related to the switch-on and switch-off of the circadian oscillation.//////////////////
Visfatin is expressed in human granulosa cells: regulation by metformin through AMPK/SIRT1 pathways and its role in steroidogenesis. Reverchon M et al. (2013) Visfatin is a cytokine hormone and an enzyme involved in metabolic (obesity, type II diabetes) and immune disorders. Some data suggest a role of visfatin in ovarian function. Here, we identified visfatin in human follicles and investigated the molecular mechanisms involved in the regulation of its expression in response to insulin sensitizers, metformin (MetF) and rosiglitazone, in primary human granulosa cells (hGCs) and in a human ovarian granulosa-like tumour cell line (KGN). We also studied the effects of human recombinant visfatin (RhVisf) on steroid production and on the activation of various signalling pathways. By RT-PCR, immunoblotting and immunohistochemistry, we showed that visfatin is expressed not only in hGCs and KGN cells, but also in human cumulus cells and oocytes. In hGCs and KGN cells, MetF increased visfatin mRNA in a dose-dependent manner (0.1, 1 and 10 mM), and rosiglitazone increased visfatin mRNA expression (only at 10 μM) after treatments for 24 h, whereas both reduced it after 48 h of incubation. This regulation was confirmed at the protein level for the MetF treatment only. Using the compound C and Aicar, inhibitor and activator of AMP-activated protein kinase (AMPK), respectively, and Sirtinol, an inhibitor of sirtuin-1 (SIRT1), we observed that these MetF effects on visfatin expression were mediated through the AMPK/SIRT1 signalling pathways. RhVisf (10 ng/ml) significantly increased insulin-like growth factor-1 (IGF-1) (10 nM)- but not FSH (10 nM)-induced secretion of progesterone and estradiol as determined by radioimmunoassay and IGF-1-induced thymidine incorporation in hGCs and KGN cells. Finally, rhVisf rapidly activates the mitogen-activated protein kinase pathway via ERK1/2, P38 and Akt phosphorylation under basal conditions in primary hGC cells. In conclusion, visfatin is present in ovarian human follicles, and in hGCs and KGN cells, visfatin increases IGF-1-induced steroidogenesis and cell proliferation and MetF regulates visfatin expression through the AMPK/SIRT1 signalling pathway.//////////////////
Expression and Regulation of INTELECTIN1 (ITLN1) in Human Granulosa-Lutein Cells: Role in IGF1-Induced Steroidogenesis Through NAMPT. Cloix L 2014 et al.
INTELECTIN (ITLN) is an adipokine involved in the regulation of insulin sensitivity, inflammatory and immunity response. Serum ITLN levels are lower in obese, diabetic and polycystic ovary syndrome women as compared to control subjects. ITLN has never been studied in ovarian cells. Here, we identified ITLN1 in human ovarian follicles and investigated the molecular mechanisms involved in the regulation of its expression in response to insulin sensitizers, metformin and rosiglitazone, in the human granulosa-lutein cells (hLGCs) and in a human ovarian granulosa like tumor cell line (KGN). We also studied the effects of human recombinant ITLN1 (hRom1) on steroid production and on the activation of various signaling pathways. By RT-PCR, immunoblotting and immunohistochemistry, we found that INTL1 is present in human follicular cells. By ELISA, we showed that INTL levels are similar in plasma and follicular fluid (FF) in control patients whereas they are higher in FF than plasma in PCOS patients. In KGN and hLGCs, INSULIN (10(-8)M), IGF1 (10(-8)M) and metformin (10(-2)M or 10(-3)M) increase INTL1 expression (mRNA and protein) after 12 and 24 h of stimulation. For metformin this effect is mediated by PRKA (Adenosine Monophosphate-activated kinase). Furthermore, hRom increases NAMPT expression in KGN and hLGCs. We also showed that hRom1 increases IGF1-induced progesterone and estradiol secretion and this was associated with an increase in STAR and CYP19A1 protein levels and an increase in IGF1R signaling. Furthermore all these data were abolished when NAMPT was knocked down in KGN cells suggesting that INTL1 improves IGF1-induced steroidogenesis through induction of NAMPT in human granulosa-lutein cells.
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Follicle stages
Comment
Visfatin and retinol-binding protein 4 concentrations in lean, glucose-tolerant women with PCOS. Yildiz BO et al. (2010) Since insulin resistance is accepted to be a common feature of polycystic ovary syndrome (PCOS), the exact molecular mechanism(s) involved in glucose and lipid metabolism have been under investigation in the syndrome. Recently, two novel adipokines, namely visfatin and retinol-binding protein 4 (RBP4), have been suggested to play a role in insulin resistance and diabetes. This study sought to determine whether plasma concentrations of visfatin and RBP4 are altered in PCOS by comparing a total of 27 lean, normal glucose-tolerant PCOS patients with 19 age- and body mass index-matched healthy controls. The mean plasma visfatin concentrations were higher in PCOS patients than those in healthy subjects (37.9+/-18.2 versus 19.8+/-17.5, P<0.01), while RBP4 concentrations were similar between the two. Both adipokines were correlated with each other in the whole (r=0.50, P<0.01) and in PCOS (r=0.52, P<0.01) groups but not in controls. The results suggest that lean, glucose-tolerant women with PCOS have increased circulating visfatin and unaltered RBP4 concentrations compared with healthy lean women. In order to clarify overlapping effects and their potential contribution to the pathophysiology of PCOS, further studies are needed.//////////////////
Phenotypes
PCO (polycystic ovarian syndrome)
Mutations
1 mutations
Species: mouse
Mutation name: type: null mutation fertility: embryonic lethal Comment: Deletion of Nampt in Projection Neurons of Adult Mice Leads to Motor Dysfunction, Neurodegeneration, and Death. Wang X et al. (2018) Intracellular nicotinamide phosphoribosyltransferase (iNAMPT) is the rate-limiting enzyme of the mammalian NAD+ biosynthesis salvage pathway. Using inducible and conditional knockout (cKO) mice, we show that Nampt gene deletion in adult projection neurons leads to a progressive loss of body weight, hypothermia, motor neuron (MN) degeneration, motor function deficits, paralysis, and death. Nampt deletion causes mitochondrial dysfunction, muscle fiber type conversion, and atrophy, as well as defective synaptic function at neuromuscular junctions (NMJs). When treated with nicotinamide mononucleotide (NMN), Nampt cKO mice exhibit reduced motor function deficits and prolonged lifespan. iNAMPT protein levels are significantly reduced in the spinal cord of amyotrophic lateral sclerosis (ALS) patients, indicating the involvement of NAMPT in ALS pathology. Our findings reveal that neuronal NAMPT plays an essential role in mitochondrial bioenergetics, motor function, and survival. Our study suggests that the NAMPT-mediated NAD+ biosynthesis pathway is a potential therapeutic target for degenerative MN diseases.//////////////////