| leptin receptor | OKDB#: 174 |
| Symbols: | LEPR | Species: | human | ||
| Synonyms: | OBR, OB-R, CD295, LEP-R, LEPRD | Locus: | 1p31.3 in Homo sapiens | HPMR |
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| General Comment |
The OB(obese) gene product, leptin, is an important circulating signal for the regulation of body weight. To identify high affinity leptin-binding sites, Tartaglia et al. (1995) generated a series of leptin-alkaline phosphatase fusion proteins, as well as (125I)-leptin. After a binding survey of cell lines and tissues, they identified leptin-binding sites in the mouse choroid plexus. A cDNA expression library was prepared from mouse choroid plexus and screened for a leptin-alkaline phosphatase fusion protein to identify a leptin receptor. The leptin receptor is a single membrane-spanning receptor most related to the gp130 signal-transducing component of the IL-6 receptor, the G-CSF receptor, and the LIF receptor.
NCBI Summary: The protein encoded by this gene belongs to the gp130 family of cytokine receptors that are known to stimulate gene transcription via activation of cytosolic STAT proteins. This protein is a receptor for leptin (an adipocyte-specific hormone that regulates body weight), and is involved in the regulation of fat metabolism, as well as in a novel hematopoietic pathway that is required for normal lymphopoiesis. Mutations in this gene have been associated with obesity and pituitary dysfunction. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. It is noteworthy that this gene and LEPROT gene (GeneID:54741) share the same promoter and the first 2 exons, however, encode distinct proteins (PMID:9207021).[provided by RefSeq, Nov 2010] |
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| General function | Receptor, Metabolism | ||||
| Comment | Decreased soluble leptin receptor levels in women with polycystic ovary syndrome Hahn S, et al . OBJECTIVE: Polycystic ovary syndrome (PCOS) is associated with insulin resistance and a high incidence of obesity. Leptin, the product of the ob gene, is involved in the regulation of energy balance and obesity and circulates in both free and bound forms. The soluble leptin receptor (sOB-R) is the most important leptin-binding protein, thus influencing the biologically active free leptin level. DESIGN: We assessed the correlation of metabolic and endocrine parameters with leptin and sOB-R levels in 122 PCOS women (aged 27 +/- 5.7 years) and 81 healthy controls (aged 25 +/- 4.0 years). METHODS: Leptin and sOB-R levels were measured using ELISA kits. In addition, anthropometric variables, body fat and endocrine parameters were evaluated and a glucose tolerance test performed to assess indices of insulin resistance and glucose metabolism. RESULTS: In PCOS patients, no correlation was found between leptin or sOB-R and parameters of hyper-androgenism. However, as expected, body mass index (BMI), body fat, waist circumference and indices of insulin resistance were significantly correlated with leptin in PCOS subjects and controls. In a subgroup analysis of lean, overweight and obese PCOS patients, significant differences were found in leptin (29.7 +/- 20.7 vs 45.4 +/- 25.0 vs 67.7 +/- 28.8 ng/ml, P < 0.0001) and sOB-R (8.0 +/- 3.4 vs 6.4 +/- 2.5 vs 5.7 +/- 2.3 ng/ml, P < 0.05). Compared with BMI-matched controls, lean PCOS patients had lower sOB-R levels (8.0 +/- 3.4 vs 12.7 +/- 4.7 ng/ml, P < 0.0001) and higher free leptin indices (4.5 +/- 3.9 vs 2.8 +/- 2.2, P = 0.0285). CONCLUSION: Taking into account that low sOB-R levels supposedly compensate diminished leptin action, PCOS per se might cause leptin resistance. | ||||
| Cellular localization | Plasma membrane | ||||
| Comment | candidate123 | ||||
| Ovarian function | Follicle development, Antral follicle growth, Ovulation, Steroid metabolism, Oogenesis, Oocyte maturation, Early embryo development | ||||
| Comment | Leptin and ObRa/MEK signalling in mouse oocyte maturation and preimplantation embryo development. Ye Y et al. Recent studies indicate that LH stimulates production of ovarian paracrine factors that induce meiosis of the oocyte. DNA microarray analyses of ovarian transcripts were performed in mice and major increases of a short isoform of leptin receptor, ObRa, were identified by the preovulatory LH/human chorionic gonadotrophin (HCG) surge. In oocytes, the level of ObRa transcripts was increased shortly after HCG stimulation, whereas the level of ObRb transcripts was not changed. Leptin was produced by cumulus, granulosa, theca and interstitial cells of ovaries and its transcript level was not regulated during gonadotrophin treatment. Treatment with leptin promoted germinal vesicle breakdown (GVBD) in oocytes within preovulatory follicles, and enhance first polar body extrusion in both cumulus-oocyte complexes and denuded oocytes. The leptin-promoted GVBD and first polar body extrusion were blocked by a mitogen-activated protein kinase extracellular signal regulated kinase kinases (MEK)1/2 inhibitor, U0126, but not its inactive analogue U0124. Furthermore, leptin promoted fertilization of oocytes and the in-vitro development of zygotes to preimplantation embryos. These findings suggest paracrine roles of leptin in the enhancement of nuclear maturation of oocytes through MEK1/2 signalling, and in the promotion of cytoplasmic maturation essential for successful oocyte development to the preimplantation embryos. Barkan et al. (1999) reported that leptin suppressed ovarian steroid synthesis costimulated by FSH and dexamethasone in primary rat granulosa cells and in rat and human granulosa cell lines. Production of pregnenolone, progesterone, and 20alpha-hydroxy-4-pregnen-3-one was inhibited by leptin. This inhibition was due at least in part to reduced expression of adrenodoxin, a component of the P450scc system enzyme. In addition, leptin induces c-Jun expression and attenuates the transcriptional activity of the glucocorticoid receptor in granulosa cells. Zachow et al. (1997) reported direct intraovarian effects of leptin, showing an impairment of the synergistic action of insulin-like growth factor-I on FSH-dependent estradiol-17 beta production by rat ovarian granulosa cells. Karlsson et al. (1997) reported that leptin inhibited LH-stimulated estradiol production. In contrast, leptin had no effect on estradiol production in the absence of LH. Zachow et al (1999) reported that leptin antagonizes the stimulatory effects of TGF-beta on FSH-dependent estrogen production in cultured rat granulosa cells by a mechanism involving the leptin-induced attenuation of P450(arom) activity and mRNA expression. In contrast, Kitawaki et al. (1999) reported that leptin stimulates estrogen production by human granulosa cells by increasing P450arom mRNA and P450arom protein expression and, consequently, aromatase activity through its direct action on the human luteinized granulosa cells. Agarwal et al. (1999) reported that, in cultured human theca cells, leptin did not alter androstenedione production, alone or in the presence of LH. Leptin caused a concentration-related inhibition of the IGF-I augmentation of LH-stimulated androstenedione production. Spicer et al. (1998) reported that leptin can directly attenuate insulin-induced steroidogenesis of thecal cells while stimulating proliferation of the same cell type.Duggal et al 2000 reported the in Vivo and in Vitro Effects of Exogenous Leptin on Ovulation in the Rat. Ip administration of leptin (30 ?g at 3 hourly intervals for 15 h) to immature gonadotropin-primed rats caused a decline in ovulation in vivo, from 15.9 ? 2.0 oocytes in the control animals to 5.3 ? 1.6 oocytes in the leptin-treated animals (P < 0.001). Plasma progesterone and estradiol levels were analyzed immediately before ovulation, and neither was altered significantly in animals receiving the leptin treatment. In vitro perfusion of FSH-primed whole ovaries showed that treatment with leptin in combination with LH significantly decreased ovulations from 5.7 ? 1.6 per ovary perfused with LH alone to 1.3 ? 0.6 in those with LH and 1 ?g/ml leptin (P < 0.05). Progesterone and estradiol levels in the samples taken during the perfusion period were unaffected by leptin treatment. Kikuchi N, et al 2001 reported te inhibitory action of leptin on early follicular growth differs in immature and adult female mice. In order to investigate the action of leptin on early follicular growth, preantral follicles, 95-115 &mgr;m in diameter were mechanically isolated from the ovaries of BDF1 hybrid immature (11-day-old) and adult (8-wk-old) mice, and cultured for 4 days in vitro. Follicular growth was assessed by daily changes in follicular diameter and by the amount of estradiol and immunoreactive (IR)-inhibin released into the culture medium at Day 4. Preantral follicles from immature mice showed a significant development in follicular growth as a result of stimulation by GH (1 mIU/ml), insulin-like growth factor (IGF)-I (100 ng/ml) + FSH (100 mIU/ml), and GH (1 mIU/ml) + FSH (100 mIU/ml). Although leptin at concentrations of 1-1000 ng/ml did not have any significant effect on follicular growth stimulated by IGF-I or GH, it significantly inhibited follicular growth in a dose-related manner when follicles were stimulated by IGF-I + FSH and GH + FSH, respectively, suggesting that leptin attenuated the additive effect of FSH. On the other hand, preantral follicles from adult mice were cultured in the presence of FSH, and FSH-dependent follicular growth was inhibited by leptin in a dose-related manner. Leptin Enhances Oocyte Nuclear and Cytoplasmic Maturation via the Mitogen-Activated Protein Kinase Pathway Craig J, et al . Recent studies have suggested that leptin has a central role in female reproduction, including ovarian function. The leptin receptor (Ob-R) has six isoforms and can signal through either the MAPK or the Janus-activated kinase/signal transducer and activator of transcription signal-transduction pathway, depending on the isoform. Expression of Ob-R has been reported in human and mouse oocytes; however, the physiological role of leptin during follicular development and oocyte maturation is largely unknown. In the current study, expression of Ob-R during oocyte growth and maturation was investigated in porcine oocytes from small, medium, and large follicles and in oocytes in the germinal vesicle (GV), GV breakdown, and metaphase II (MII) stages at both the mRNA and protein levels. The proportion of oocytes expressing Ob-R was maximal in oocytes from medium follicles and at the GV breakdown stage (P < 0.05), whereas the proportion of oocytes expressing the long isoform, Ob-Rb, was found to be consistently low throughout growth and maturation. When included in oocyte maturation medium, leptin significantly increased the proportion of oocytes reaching MII (P < 0.01), elevated cyclin B1 protein content in MII-stage oocytes (P < 0.05), and enhanced embryo developmental potential (P < 0.05), suggesting that leptin plays a role in both nuclear and cytoplasmic maturation. During oocyte maturation, leptin increased phosphorylated MAPK content by 2.8-fold (P < 0.05), and leptin-stimulated oocyte maturation was blocked when leptin-induced MAPK phosphorylation was suppressed by a specific MAPK activation inhibitor, U0126 (P < 0.01), demonstrating that leptin enhances nuclear maturation via activation of the MAPK pathway. Enhancement of Bovine oocyte maturation by leptin is accompanied by an upregulation in mRNA expression of leptin receptor isoforms in cumulus cells. van Tol HT et al. In this study, the mechanisms of supposed leptin action on oocyte maturation were examined. Expression of leptin mRNA, as determined with RT-PCR, was present in oocytes but not in cumulus cells. The long isoform of the leptin receptor (ObR-L) was expressed exclusively in cumulus cells after 7 and 23 hr of maturation. In oocytes the expression of the short receptor isoform (ObR-S) and all the receptor isoforms combined (ObR-T) did not change during maturation, as determined by quantitative RT-PCR, but in cumulus cells there was a significant increase in ObR-S transcripts after 7 hr of maturation. To determine if leptin plays a role in resumption of meiosis, oocytes meiotically arrested by the connection of the cumulus to a piece of granulosa layer were exposed to leptin. After 23 hr of culture, the proportion of oocytes that had resumed meiosis did not differ from the control. Exposure of COCs to leptin (1,000 ng/ml) resulted after 17 hr of maturation in a smaller proportion of oocytes that was still in metaphase-I stage (M-I) compared to the control group. Fertilization of oocytes after maturation in the presence of leptin resulted in a larger proportion of embryos that had developed to the 8-cell stage on Day 5 compared to the control group and in more blastocysts on Day 8 of culture. It is concluded that leptin enhances meiotic maturation of bovine oocytes, and that this effect is cumulus cell-mediated. Mol. Reprod. Dev. (c) 2007 Wiley-Liss, Inc. | ||||
| Expression regulated by | LH | ||||
| Comment | Leptin interferes with 3',5'-cyclic adenosine monophosphate (cAMP) signaling to inhibit steroidogenesis in human granulosa cells. Lin Q et al. BACKGROUND: Obesity has been linked to an increased risk of female infertility. Leptin, an adipocytokine which is elevated during obesity, may influence gonadal function through modulating steroidogenesis in granulosa cells. METHODS: The effect of leptin on progesterone production in simian virus 40 immortalized granulosa (SVOG) cells was examined by Enzyme linked immunosorbent assay (ELISA). The effect of leptin on the expression of the steroidogenic enzymes (StAR, P450scc, 3betaHSD) in SVOG cells was examined by real-time PCR and Western blotting. The mRNA expression of leptin receptor isoforms in SVOG cells were examined by using PCR. SVOG cells were co-treated with leptin and specific pharmacological inhibitors to identify the signaling pathways involved in leptin-reduced progesterone production. Silencing RNA against leptin receptor was used to determine that the inhibition of leptin on cAMP-induced steroidogenesis acts in a leptin receptor-dependent manner. RESULTS AND CONCLUSION: In the present study, we investigated the cellular mechanisms underlying leptin-regulated steroidogenesis in human granulosa cells. We show that leptin inhibits 8-bromo cAMP-stimulated progesterone production in a concentration-dependent manner. Furthermore, we show that leptin inhibits expression of the cAMP-stimulated steroidogenic acute regulatory (StAR) protein, the rate limiting de novo protein in progesterone synthesis. Leptin induces the activation of ERK1/2, p38 and JNK but only the ERK1/2 (PD98059) and p38 (SB203580) inhibitors attenuate the leptin-induced inhibition of cAMP-stimulated StAR protein expression and progesterone production. These data suggest that the leptin-induced MAPK signal transduction pathway interferes with cAMP/PKA-stimulated steroidogenesis in human granulosa cells. Moreover, siRNA mediated knock-down of the endogenous leptin receptor attenuates the effect of leptin on cAMP-induced StAR protein expression and progesterone production, suggesting that the effect of leptin on steroidogenesis in granulosa cells is receptor dependent. In summary, leptin acts through the MAPK pathway to downregulate cAMP-induced StAR protein expression and progesterone production in immortalized human granulosa cells. These results suggest a possible mechanism by which gonadal steroidogenesis could be suppressed in obese women. Ryan NK, et al reported Leptin and Leptin Receptor Expression in the Rat Ovary. Leptin is an important satiety hormone and reproductive regulator and is found, along with its receptors, throughout the ovary. To date, the changes in ovarian expression of both of these proteins throughout the estrous cycle has not been studied, and the examination of protein expression has not distinguished between different forms of the receptor. In this study, leptin mRNA expression in the immature gonadotropin-primed rat ovary increased 3-fold following hCG administration, followed by a dramatic increase in mRNA for both the short form (Ob-Ra) and long form (Ob-Rb) of the leptin receptor (approximately 8- and 7-fold respectively). A corresponding increase in mRNA expression of the receptor was not observed in isolated pre-ovulatory follicles. Using immunohistochemistry, we observed protein expression of the long form of the leptin receptor (Ob-Rb) in the ovary, with high intensities observed in oocytes and endothelial cells, as well as thecal cells and corpora lutea. These results suggest that ovarian expression of leptin and its receptor are regulated across the cycle by gonadotropins, with peak expression at ovulation, indicating a possible involvement in oocyte maturation, angiogenesis, follicle rupture or subsequent corpus luteum formation. | ||||
| Ovarian localization | Oocyte, Cumulus, Granulosa, Theca, Luteal cells | ||||
| Comment | Karlsson et al. (1997) analyzed the expression of leptin receptors in the human ovary. Transcripts encoding both the long and short isoforms of the leptin receptor were present in human granulosa cells and thecal cells. Immunoreactive leptin was present in follicular fluid at levels similar to those found in serum. OB gene expression, however, was undetectable in the ovary, as determined by reverse transcription-PCR, whereas it was easily detected in adipose tissue. Cioffi et al. (1997) also reported leptin expression at the mRNA and protein levels by human granulosa and cumulus cells, and the presence of leptin in mature human oocytes. Using reverse transcriptase-polymerase chain reaction (RT-PCR) and immunoblotting, Matsuoka et al. (1999) showed that mRNA and protein of leptin receptor were expressed in M2 stage oocytes. Leptin at 15 ng/ml, the concentration observed in follicular fluid, caused tyrosine phosphorylation of STAT3 in mouse M2 stage oocytes. Leptin receptor mRNA was present in porcine granulosa cells at isolation and increased in abundance as the cells luteinized over 96 hr in culture. Leptin eceptor protein was detectable after 12 hr of in vitro luteinization (Ruiz-Cortes et al.2000). | ||||
| Follicle stages | Antral, Preovulatory, Corpus luteum | ||||
| Comment | Long form of leptin receptor gene and protein expression in the porcine ovary during the estrous cycle and early pregnancy. Smolinska N et al. Leptin, a hormone secreted by adipocytes, plays an important role in the regulation of metabolism and reproduction. The effect of leptin is mediated mainly via the long isoform of the leptin receptor (OB-Rb). Expression of leptin and its receptor has been identified in the central nervous system (hypothalamus, pituitary) and reproductive tract (uterus, ovary and placenta) in prepubertal gilts. Therefore, in the present study, the porcine OB-Rb expression was examined by a semiquantitative reverse transcription polymerase chain reaction (RT-PCR), in situ hybridization and Western blotting in the corpus luteum (CL) and ovarian stroma (OS) during the luteal phase of the estrous cycle (days 10-12 and 14-16) and two stages of early pregnancy (days 14-16 and 30-32). The OB-Rb gene expression in both ovarian structures was higher during early pregnancy in comparison to the mid- and late-luteal phase of the estrous cycle. Significant differences in OB-Rb gene expression between the two periods of the pregnancy were observed only in OS. The results of in situ hybridization are generally supported by data of semiquantitative RT-PCR. The CL expression of leptin receptor protein was significantly lower during early pregnancy compared to the cycle. In OS, the OB-Rb protein content was higher during pregnancy compared to the late-luteal phase of the estrous cycle. In summary, the obtained results indicate that leptin may participate in the control of pig reproduction at the ovarian level and have a direct effect on the ovary during both, the luteal phase of the cycle and early pregnancy. Moreover, changes in OB-Rb gene and protein expression in ovarian structures strongly suggest that their sensitivity to leptin varies throughout the luteal phase of the cycle and early pregnancy. | ||||
| Phenotypes |
PCO (polycystic ovarian syndrome) |
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| Mutations |
4 mutations
Species: human
Species: mouse
Species: human
Species: rat
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| Genomic Region | show genomic region | ||||
| Phenotypes and GWAS | show phenotypes and GWAS | ||||
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| created: | Oct. 23, 1999, midnight | by: |
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| last update: | March 18, 2020, 3:41 p.m. | by: | hsueh email: |
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