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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of treatment with a 0.03% fatty acid (FA) cocktail on leptin-receptor-mediated STAT (signal transducers and activators of transcription) activation in the rat insulinoma cell line BRIN-BD11 was investigated. Leptin (10 nM) stimulated the tyrosine phosphorylation of STAT3 and STAT5b. Acute treatment with FAs prevented leptin-stimulated STAT3 tyrosine phosphorylation and significantly raised basal STAT5 phosphorylation. A chronic treatment (5 days) of BRIN-BD11 cells with FAs similarly attenuated leptin-stimulated STAT tyrosine phosphorylation. Chronic FA treatment also attenuated prolactin-stimulated STAT5b tyrosine phosphorylation but not interleukin-6-stimulated STAT3 tyrosine phosphorylation, suggesting that the effect is receptor/ligand specific. TaqMan analysis of gene expression following chronic FA treatment showed neither a decrease in the amount of leptin receptor (Ob-R) mRNA, nor an increase in the negative regulators of STAT signalling, SOCS3 (suppressors of cytokine signalling) or cytokine inducible sequence (CIS). These data demonstrate that FAs modulate leptin and prolactin signalling in beta-cells, implying that high levels of circulating FAs present in obese individuals affect the action of selective cytokines in beta-cell function.
J Mol Endocrinol 2001 Apr
PMID:Fatty acids inhibit leptin signalling in BRIN-BD11 insulinoma cells. 1124 Nov 66

Obesity is highly prevalent in industralized countries and is increasing worldwide. It is also a major risk factor for type 2 diabetes, hypertension, coronary artery disease and certain cancers. An understanding of the regulation of eating behavior is pertinent to obesity, as the latter results from an imbalance between food consumption and energy expenditure. Leptin and other hormones regulate feeding and energy balance by modulating the expression of neuropeptides in the brain. Major efforts are underway to determine whether the peripheral and central pathways involved in the regulation of feeding behavior and energy balance could be targeted for the treatment of obesity.
Trends Mol Med 2001 May
PMID:Molecular regulation of eating behavior: new insights and prospects for therapeutic strategies. 1132 32

Leptin is secreted primarily from white adipose tissue and stimulates long-form OB-Rb receptors in the hypothalamus to decrease food intake and increase energy expenditure. A variety of neuropeptides are involved in these responses, including neuropeptide Y, agouti-related protein, the prepro-melanocortin system and cocaine- and amphetamine-regulated transcript. OB-Rb receptors (and other receptor isoforms) are also found in peripheral tissues. Leptin is now known to have a wide range of peripheral actions and is involved in activating the immune system, haematopoiesis, angiogenesis and as a growth factor, as well as being a regulator of many cellular functions. The identification of leptin has led to reappraisal of the role of white adipose tissue from being an organ concerned primarily with energy storage as fat to an understanding that it is also a major endocrine and secretory organ. While the importance of the sympathetic nervous system in mobilising fatty acids from adipose tissue has long been known, it has become apparent that the sympathetic system is a key regulator of leptin production in white adipose tissue as well. Sympathomimetic amines and cold exposure or fasting (which lead to sympathetic stimulation of white fat), decrease leptin gene expression in the tissue and leptin production. On the other hand, sympathetic blockade often increases circulating leptin and leptin gene expression, and it is possible that the sympathetic system has a tonic inhibitory action on leptin synthesis. Apart from the few instances where leptin is absent, leptin levels are increased in obesity, while the sympathetic sensitivity of adipose tissue is reduced, consistent with the high leptin levels that are seen. The dysregulation of energy balance leading to obesity may partly involve a decrease in leptin sensitivity, or the leptin system may be set to have maximal effects at low leptin levels.
J Mol Med (Berl) 2001
PMID:Regulation of leptin production: sympathetic nervous system interactions. 1132 6

Leptin was originally believed to be an exclusively adipocyte-derived hormone regulating appetite and energy balance. It has recently become apparent that leptin is actively expressed in a number of other tissues including the CNS and pituitary, as well as brain- and pituitary-derived cell lines. However, the factors controlling leptin expression in cells of neuroectodermal origin are unknown. The mouse leptin gene 5'-flanking DNA contains multiple AP-1 and SRF-1 binding sites as well as a consensus CRE site at -491 to -482 bp. In addition, a number of potential PIT1 and Oct-1 binding sites may contribute to leptin gene transcription in pituitary and brain. We have used leptin promoter-luciferase reporter constructs to examine the regulation of the leptin promoter in 3T3-L1 preadipocytes, C6 glioma cells, and GH3 pituitary cells in response to serum and hormonal stimuli. Cells were transiently transfected with reporter constructs containing either the proximal 500 bp of the leptin promoter (-500-luc) or 6000 bp of the leptin gene 5' flanking region (-6000-luc). Functional analysis indicates that the leptin promoter is constitutively active in all 3 cell lines. Transcriptional activity was significantly higher with a -500 to +9 promoter than with a construct containing -6000 to +9 bp of 5' flanking DNA, indicating the presence of repressor elements which may contribute to the tissue-specific regulation of leptin expression. However, qualitatively similar results were observed with both constructs in response to serum and hormonal manipulation. Leptin promoter activity was significantly stimulated by serum in all cell lines, although to varying extents. In contrast, the response of the leptin promoter to insulin, IGF-1 and dibutyryl cAMP was cell-type specific and dependent on the presence or absence of FBS in the culture medium. Insulin, IGF-1 and dibutyryl cAMP each caused an approximately two-fold stimulation of leptin promoter activity in 3T3-L1 cells under serum-free conditions, but had no significant effect in the presence of 10% FBS. In contrast, dibutyryl cAMP markedly stimulated leptin promoter activity (5-8-fold) in C6 or GH3 cells in the presence or absence of FBS, whereas insulin or IGF-1 had minimal effects. These findings support our previous studies on the regulation of leptin steady state mRNA levels in C6 cells and demonstrate tissue-specific differences in the regulation of leptin gene transcription in adipose vs. neuroectodermal tissues.
Mol Cell Endocrinol 2001 May 15
PMID:Transcriptional regulation of the leptin gene promoter in rat GH3 pituitary and C6 glioma cells. 1136 43

Leptin is a potential regulator of conceptus development. We have previously suggested that in primate pregnancy, leptin biosynthesis is regulated by estrogen in a tissue-specific manner. Therefore, the objective of the current study was to determine the mechanism of estrogen action on LEP promoter activation in divergent cell types. The effects of estrogen were investigated in estrogen receptor (ER)-positive MCF-7 breast cancer cells and in ER-negative JEG-3 choriocarcinoma cells. Cells were transfected with a leptin-luciferase or an estrogen responsive element (ERE)-luciferase reporter construct, in conjunction with ERalpha, ERbeta, or empty vector expression plasmids. Cells were treated with estradiol and/or the specific estrogen antagonists, ICI-182,780 or 4-hydroxytamoxifen. In MCF-7 cells, estradiol stimulated (P<0.05) ERE-luciferase activity and was inhibited by ICI-182,780, but did not stimulate leptin-luciferase activity. However, leptin-luciferase was stimulated by estradiol (P<0.05) and inhibited by antiestrogens in JEG-3 cells that were co-transfected with ERalpha. Both antiestrogens stimulated leptin-luciferase activity (P<0.05) in JEG-3 cells co-transfected with ERbeta. Results suggested that LEP promoter activation may depend upon co-activators present in leptin-producing cells and may be inhibited by repressors present in non-leptin producing cells. Divergent effects of estrogen may be owed to differences in the type of ER (alpha or beta) expressed in target tissues.
Mol Cell Endocrinol 2001 May 15
PMID:Effects of estrogen on leptin gene promoter activation in MCF-7 breast cancer and JEG-3 choriocarcinoma cells: selective regulation via estrogen receptors alpha and beta. 1136 44

Leptin is secreted by adipocytes and regulates appetite through interaction with hypothalamic leptin receptors (OB-R). Leptin is involved in the stimulation of reproductive functions, and local expression of leptin and OB-R in the ovary, oocyte, embryo, and placenta might play a role in early development. The mRNA and protein of the long form leptin receptor (OB-R(L)) but not of leptin are expressed in the human endometrium and the abundance of OB-R mRNA expression varies during the menstrual cycle with a peak in the early secretory phase. We examined the steroidal regulation of OB-R(L) mRNA expression. Northern blot analyses showed that in organ-cultured proliferative endometrial specimens, oestradiol (10(-9) and 10(-8) mol/l) had no acute effect on the OB-R(L) mRNA expression, whereas oestradiol plus progesterone (10(-8), 10(-7) and 10(-6) mol/l) or medroxyprogesterone acetate (10(-8) and 10(-7) mol/l) suppressed the expression by approximately 50%. This progestin-induced suppression was blocked by a concomitant addition of mifepristone. Additionally, incubation of endometrial specimens in the presence of leptin resulted in the phosphorylation of its intracellular target, STAT3 (signal transducer and activator of transcription 3). These results indicate that, in the human endometrium, progestins act via the progesterone receptors to suppress functional OB-R(L) mRNA expression, and may thereby alter the sensitivity of the endometrium to leptin.
Mol Hum Reprod 2001 Jun
PMID:Progesterone inhibition of functional leptin receptor mRNA expression in human endometrium. 1138 12

Leptin, the product of ob gene, is an endocrine hormone that regulates adipose tissue mass. Recently, leptin has been found to generate a growth signal involving a tyrosine kinase-dependent intracellular pathway and promote angiogenic processes via activation of leptin receptor (Ob-R) in endothelial cells. However, it is not clear how leptin functions to promote multi-step processes involved in the neovascularization at the atherosclerotic plaque. We have examined the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) and Ob-R in human atherosclerotic lesions, leptin-mediated angiogenesis in vivo and in vitro. Immunohistochemical analysis of human atherosclerotic aorta revealed an increased expression of Ob-R in the intima of neorevascularized regions and of both MMPs and TIMPs predominantly in the endothelial lining of intimal neovessels and macrophages/foam cells. In the rat corneal angiogenesis assay, leptin elicited a comparable sensitivity of angiogenic activity to those of vascular endothelial growth factor (VEGF). The immunohistological analysis of the leptin-treated rat cornea showed definitive rises in Ob-R, MMPs and TIMPs expression as well as those of VEGF receptor (VEGFR-1). Leptin (10-40 ng/ml) induced proliferation of the human umbilical vein endothelial cells (HUVECs) and elevation of MMP-2, MMP-9, TIMP-1, and TIMP-2 expression in a dose-dependent manner. Leptin also induced increases of MMP-2, MMP-9, TIMP-1, and Up-regulated the human coronary artery smooth muscle cells (HCASMCs). These findings suggest that leptin, a hormone with pluralistic properties including a mitogenic activity on vascular endothelial cells, plays a role in matrix remodeling by regulating the expression of MMPs and TIMPs. Taken together, our findings further provide evidences for leptin's role as an angiogenesis inducer in the normal organ (rat cornea) and in aberrant vasculature under duress like atherosclerosis.
Exp Mol Med 2001 Jun 30
PMID:Potential role of leptin in angiogenesis: leptin induces endothelial cell proliferation and expression of matrix metalloproteinases in vivo and in vitro. 1146 Aug 88

Leptin has a powerful effect on fertility and the initiation of puberty in addition to its effect on obesity. It has been suggested that that in times of fasting, infertility induced by low leptin levels protect the female from the energy demands of pregnancy. Despite this there have been no studies of the potential role of LEP gene variants on the age of onset of menarche. We genotyped 183 non-Hispanic Caucasian adult females at the LEP D7S1875 dinucleotide repeat polymorphism. The alleles were placed into three genotypes, <208/<208 bp, heterozygotes, and > or =208/> or =208 bp. A hierarchical ANOVA was performed with age of menarche as the dependent variable and LEP(1875) genotypes and maternal age (age of the mothers at birth of the subject) as independent variables. There was a significant (P </= 0.006) interaction of LEP(1875) x maternal age but neither independent variable was significant by itself. This was due to an "association crossover effect" in which the LEP(1875) by age of menarche effects were in opposite directions for those with a maternal age of <30 years compared to those with a maternal age of > or =30 years. If maternal age effects prove to be generalized, failure to take them into consideration could provide a source of hidden stratification that could significantly alter the replication of association studies.
Mol Genet Metab 2001 Jul
PMID:The LEP gene and age of menarche: maternal age as a potential cause of hidden stratification in association studies. 1146 Nov 87

Leptin is a recently identified hormone produced by the adipocyte ob gene which acts as a negative feedback signal critical to the normal control of food intake and body weight. A number of proinflammatory cytokines, such as interleukin 6, tumor necrosis factor alpha, and interferon gamma, have been proposed as mediators of cancer cachexia; these data suggest that abnormalities in leptin production/release or in its feedback mechanism play a role in cancer patients. We therefore studied the relationship between serum leptin and serum cytokines interleukin 6 and tumor necrosis factor alpha levels in advanced-stage cancer patients. Twenty-nine advanced stage cancer patients (all but one stage IV) with tumors at various sites were included in the study. A direct correlation between body mass index and serum leptin levels was found both in cancer patients and in healthy individuals. The serum levels of interleukin 6 were significantly higher in cancer patients than in healthy individuals. In cancer patients an inverse correlation was found between serum levels of leptin and proinflammatory cytokines. There was an inverse correlation between the Eastern Cooperative Oncology Group performance status scale and serum levels of leptin. Regarding survival, patients with very high serum levels of proinflammatory cytokines and very low levels of leptin had very short survival. Although obtained in a cancer patient population not overtly cachectic, our results provide further evidence that a simple dysregulation of leptin production and/or release cannot be involved in cancer-associated pathophysiological changes leading to cachexia.
J Mol Med (Berl) 2001 Jul
PMID:Serum values of proinflammatory cytokines are inversely correlated with serum leptin levels in patients with advanced stage cancer at different sites. 1146 63

Leptin is small cytokine-like protein that is involved in appetite and body weight regulation. Due to increased interest in using leptin as an anti-obesity reagent, recombinant forms of leptin have been produced for several species, including humans, mice, rats, pigs, dogs, sheep etc. The biological activities of such recombinant proteins were determined using various in vitro or in vivo systems; however so far, no specific assay system for rat leptin is available. Since rats are representative animal models in obesity research, the establishment of a biological assay system for determining rat leptin activity has been eagerly awaited. This study describes the generation of such a system using chinese hamster ovary (CHO)-cells that were transfected with the long form of the rat leptin receptor isoform, OB-Rb, whereby a signal transduces and activators of transcription-sensitive luciferase reporter system is further employed to quantify the leptin-mediated signals. This system is the first rat-specific leptin bioassay system that has been reported. It is expected that this assay will be used to further quantify and determine leptin activity from various biological fluids and sources.
Mol Cells 2001 Aug 31
PMID:Determination of rat leptin activity in vitro using a novel luciferase reporter assay. 1156 23


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