Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Growth hormone secretion by the somatotroph cells depends upon the interaction between hypothalamic regulatory peptides, target gland hormones and a variety of growth factors acting in a paracrine or autocrine fashion. This review will be focused on recent data regarding the mechanism by which growth hormone-releasing hormone (GHRH) influences somatotroph cell function and the physiological role played by Ghrelin and leptin in the regulation of growth hormone (GH) secretion. It is well established that binding of GHRH to its receptor leads to activation of protein kinase A (PKA). More recently, it was found that GHRH can also activate mitogen-activated protein (MAP) kinase both in pituitary cells and in a cell line overexpressing the GHRH receptor. Whether somatotroph adenomas, either with or without a GS-alpha mutation, have alterations in some of the components of the activation of the MAP kinase pathway remains to be known. The recent isolation of Ghrelin, the endogenous ligand of the growth hormone secretagogue receptor, can be considered a landmark in the GH field, which opens up the possibility of gaining greater insight into our understanding of the mechanisms involved in the regulation of GH secretion and somatic growth. Indeed, preliminary evidences indicate that this peptide exerts a marked stimulatory effect on plasma GH levels in both rats and humans. Finally, it is well known that GH secretion is markedly influenced by nutritional status. Leptin has emerged as an important adipose tissue-generated signal that is involved in the regulation of GH secretion, thus providing an integrated regulatory system of growth and metabolism. Although the effects of leptin on GH secretion in humans remain to be clarified, indirect evidences indicate that it may play an inhibitory role.
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PMID:Hormonal control of growth hormone secretion. 1140 55

Leptin is a hormone believed to control appetite and regulate body weight via receptors in the hypothalamus. Much is known about the structure of the functional, or long, form of the leptin receptor, OB-Rb. However, the mechanism by which the receptor regulates leptin's biological action is unknown. Both the type and amount of dietary fat have been shown to affect factors involved in OB-Rb binding and signaling, as well as the morphology of hypothalamic cell membranes. Thus, the following review article examines possible mechanisms by which dietary fat may affect OB-Rb functioning at the hypothalamic level. Dietary fat can alter the fatty acid make-up of membranes, such as the polyunsaturated:saturated fat ratio, changing membrane fluidity and possibly leading to an enhancement or impairment of the structure and/or function of any membrane-associated receptor complexes. Dietary fat also interferes in biochemical pathways involving leptin, OB-Rb, and other neurons containing neuropeptides under OB-Rb's control, such as neuropeptide Y (NPY), proopiomelanocortin (POMC), and cocaine- and amphetamine-regulated transcript (CART). Increased monounsaturated fat increases cyclic adenosine monophosphate (cAMP) levels, possibly reducing mitogen-activated protein kinase (MAPK) activation and interrupting leptin signaling through Janus kinase/signal tranducers and activators of transcription (JAK/STAT) pathways. Dietary induced alterations in hypothalamic cell membranes, SNS activity, or other factors involved in OB-Rb function form a possible basis for the control of leptin's effects on body composition and appetite. Improving the biological activity of leptin by diet modification may exist as a practical strategy for the treatment of obesity and related disorders.
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PMID:A role for dietary fat in leptin receptor, OB-Rb, function. 1150 53

We have previously shown that murine recombinant leptin directly stimulates catecholamine synthesis through the long form of the leptin receptor (Ob-Rb) expressed in cultured porcine chromaffin cells. Additionally, we found that leptin activates IP3 production after PLC activation. It is well established that activation of PLC elicits IP3 production as well as an increase in diacylglycerol, a compound that stimulates PKC. Therefore, we investigated the involvement of PKC in leptin-induced catecholamine synthesis. Leptin was found to induce significant increases in PKC activity in a dose-dependent manner (1, 10, and 100 nM); chelation of extracellular Ca(2+) by EDTA abolished this PKC stimulatory activity. We also confirmed by Western blot analysis that leptin (at 100 nM) induced significant increases in Ca(2+)-dependent PKC alpha, -beta(I), and -gamma expression. The activity of the rate-limiting enzyme tyrosine hydroxylase (TH) in the biosynthesis of catecholamine is regulated at the transcriptional and posttranscriptional levels. TH enzyme activity and TH mRNA levels induced by 100 nM leptin were significantly inhibited by the PKC inhibitor Ro 32-0432 as well as by EDTA. In addition, increases in TH protein and intracellular catecholamine content stimulated by leptin were completely inhibited by Ro 32-0432. Leptin markedly activated ERKs and, to a lesser extent, JNK; these stimulatory effects on ERKs and JNK were completely inhibited by Ro 32-0432 as well as EDTA. In contrast, leptin did not activate P38 MAPK. Similar to leptin, PMA activated ERK and JNK. Nicardipine and omega-conotoxin GVIA, each at 1 microM, were effective at inhibiting leptin-induced TH enzyme activity, TH mRNA accumulation, PKC activity, and ERK activity. Leptin increased activating protein-1 DNA-binding activity, and this was diminished by Ro 32-0432 as well as EDTA, similar to the reduction of TH mRNA levels. In addition, using supershift analysis, we documented the involvement of c-Fos and, to a lesser extent, c-Jun in leptin-induced activating protein-1 activity. These results indicate that leptin stimulates Ca(2+)-dependent PKC isoform-dependent catecholamine synthesis in porcine chromaffin cells. Previously, we had shown that leptin stimulated cAMP. The present study also showed that H89 (a PKA inhibitor) moderately, but significantly, inhibited leptin-induced ERK and TH mRNA. Consistent with this finding, leptin is shown here to activate novel PKC epsilon, which is assumed to stimulate Raf, upstream of ERKs, via cAMP, supporting the suggestion that Ca(2+)-independent novel PKC may also play some physiological role in regulating catecholamine synthesis.
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PMID:Leptin stimulates catecholamine synthesis in a PKC-dependent manner in cultured porcine adrenal medullary chromaffin cells. 1160 54

The obese gene product leptin is an important signaling protein that regulates food intake and body weight via activation of the hypothalamic leptin receptor (Ob-Rb; Jacob et al., 1997). However, there is growing evidence that Ob-Rb is also expressed in CNS regions, not directly associated with energy homeostasis (Mercer et al., 1996; Hakansson et al., 1998). In the hippocampus, an area of the brain involved in learning and memory, we have found that leptin facilitates the induction of synaptic plasticity. Leptin converts short-term potentiation of synaptic transmission induced by primed burst stimulation of the Schaffer collateral commissural pathway into long-term potentiation. The mechanism underlying this effect involves facilitation of NMDA receptor function because leptin rapidly enhances NMDA-induced increases in intracellular Ca(2+) levels ([Ca(2+)](i)) and facilitates NMDA, but not AMPA, receptor-mediated synaptic transmission. The signaling mechanism underlying these effects involves activation of phosphoinositide 3-kinase, mitogen-activated protein kinase, and Src tyrosine kinases. These data indicate that a novel action of leptin in the CNS is to facilitate hippocampal synaptic plasticity via enhanced NMDA receptor-mediated Ca(2+) influx. Impairment of this process may contribute to the cognitive deficits associated with diabetes mellitus.
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PMID:Leptin enhances NMDA receptor function and modulates hippocampal synaptic plasticity. 1173 1

Leptin, the adipocyte-secreted hormone that centrally regulates weight control, is known to function as an immunomodulatory regulator. Thus, we have recently found that human leptin promotes stimulation and proliferation of human peripheral blood mononuclear cells. In the present work, we sought to study the mechanisms underlying these effects. First, we have assessed the presence of the long isoform of the human leptin receptor by RT-PCR. Next, we have studied tyrosine phosphorylation of cell proteins in response to leptin stimulation. We have found that leptin receptor, IRS-1 and the RNA-binding protein Sam68 are tyrosine phosphorylated upon leptin challenge in a dose-dependent manner. Moreover, tyrosine phosphorylation of IRS-1 and Sam68 promotes their association with p85, the regulatory subunit of PI3K, and this association leads to the stimulation of PI3K activity. On the other hand, the leptin-stimulated tyrosine phosphorylation of Sam68 mediates the dissociation from RNA as assessed by Sepharose-conjugated poly(U) binding. Finally, leptin receptor activation also triggers MAPK signaling pathway. Thus, leptin dose-dependently stimulates tyrosine and threonine phosphorylation of MAPK in mononuclear cells. In summary, the present work demonstrates the presence of the long isoform of the human leptin receptor in peripheral blood mononuclear cells and the activation of two signaling pathways, PI3K and MAPK. The effects on Sam68 phosphorylation may modulate its binding to RNA, although the physiological implications remain to be studied. These signal transduction pathways may mediate the described effects of human leptin on human peripheral blood mononuclear cells.
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PMID:Human leptin activates PI3K and MAPK pathways in human peripheral blood mononuclear cells: possible role of Sam68. 1174 24

Since the cloning of leptin by Friedman's laboratory in 1994, over 3000 papers have been published on leptin, making it one of the most active research areas in all of science. Leptin appears to be a pleiotrophic hormone affecting many different tissues in the body. This review focuses on the role of leptin in reproduction. Evidence is accumulating that leptin potentially has roles in the regulation of GnRH and LH secretion, puberty, pregnancy, and lactation. Reciprocal regulation of leptin and its receptors by gonadal hormones and the implications and controversies thereof are also discussed in the review. Signaling pathways utilized by leptin are starting to become more clear, particularly JAK/STAT, MAPK, and SOCS3 have been implicated as mediators/modulators of leptin effects at the cellular level. At the hypothalamic level, there is also evidence that CART (cocaine and amphetamine-related transcript) is involved as a downstream mediator of leptin effects, especially with regards to control of GnRH secretion. While leptin clearly has many effects upon the reproductive axis, defining its precise roles is not without controversies. This review presents both pro and con findings, thereby demarking controversial areas that undoubtedly will be fertile ground for future investigation.
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PMID:Leptin and reproduction. 1175 73

Leptin regulates cardiovascular function. Leptin levels are elevated in obesity and hypertension and may play a role in cardiovascular dysfunctions in these comorbidities. This study was designed to determine the influence of hypertension on the cardiac contractile response of leptin. Mechanical and intracellular Ca(2+) properties were evaluated using an IonOptix system in ventricular myocytes from spontaneously hypertensive (SHR) and age-matched Wistar Kyoto (WKY) rats. The contractile properties included peak shortening (PS), duration and maximal velocity of shortening/relengthening (TPS/TR(90), +/-dL/dt), and fura-fluorescence intensity change (DeltaFFI). NO and nitric oxide synthase (NOS) activity were assessed by the Griess and the (3)H-arginine/citrulline conversion assays, respectively. The leptin receptor (Ob-R) and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway were evaluated by Western blot analysis. SHR animals displayed significantly elevated blood pressure and plasma leptin levels. Leptin elicited a concentration-dependent inhibition of PS and DeltaFFI in WKY, but not in SHR myocytes. Leptin did not affect TPS, TR(90), or +/- dL/dt. The difference in leptin-induced contractile response between the WKY and the SHR groups was abolished by the NOS inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME), but not by elevated extracellular Ca(2+). Either the JAK2 inhibitor AG-490 or the mitogen-activated protein (MAP) kinase inhibitor SB203580 abrogated the leptin-induced response in the WKY myocytes, whereas AG-490 unmasked a negative response in PS in the SHR myocytes. SHR myocytes displayed similar Ob-R protein abundance and basal NO levels, a blunted leptin-induced increase in NOS activity as well as enhanced basal STAT3 levels compared with the WKY group. These data indicate that the leptin-induced cardiac contractile response is abolished by spontaneous hypertension, possibly because of mechanisms involving altered JAK/STAT, MAP kinase signaling, and NO response.
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PMID:Abrogated leptin-induced cardiac contractile response in ventricular myocytes under spontaneous hypertension: role of Jak/STAT pathway. 1179 81

Activation of the transcription factor signal transducer and activator of transcription 3 (STAT3) requires dimerization that is induced by phosphorylation of Tyr705, but its activity can be further modulated by phosphorylation at Ser727 in a manner that is dependent on cell context and the stimulus used. The role of STAT3 Ser727 phosphorylation in leptin signalling is currently not known. While cells transfected with the signalling-competent long form of the leptin receptor (ObRb) have been used to study leptin signalling, these are likely to be of limited use in studying STAT3 Ser727 phosphorylation due to the importance of cell background in determining the nature of the response. However, we have recently found that J774.2 macrophages endogenously express high levels of ObRb, and using these cells we find that leptin stimulates STAT3 phosphorylation on both Tyr705 and Ser727. The phosphorylation of Ser727 was not affected by rapamycin or the protein kinase C inhibitor H7 [1-(5-isoquinolinylsulphonyl)-2-methylpiperazine dihydrochloride]. While the MEK-1 [mitogen-activated protein kinase (MAP kinase)/extracellular-signal-related kinase (ERK) kinase-1] inhibitor PD98059 [(2-amino-3'-methoxyphenyl)oxanaphthalen-4-one] had no effect on leptin-stimulated phosphorylation of STAT3 Tyr705, it greatly attenuated leptin's effects on STAT3 Ser727 phosphorylation. Further, Ob's effect on the DNA binding activity of STAT3 was also greatly reduced at all time points by PD98059. Leptin-induced ERK activation in J774.2 cells shows a biphasic pattern, with an initial reduction in ERK phosphorylation for up to 10 min following leptin stimulation, while at later time points phosphorylation of ERK was increased above basal levels. The increase in ERK activity corresponded with an increase in both phosphorylation of Ser727 and STAT3 DNA binding activity. These data provide the first evidence that ERK-mediated phosphorylation of Ser727 is required for full stimulation of STAT3 by leptin.
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PMID:Biphasic regulation of extracellular-signal-regulated protein kinase by leptin in macrophages: role in regulating STAT3 Ser727 phosphorylation and DNA binding. 1204 54

Leptin, the Ob gene product, is an adipocyte hormone that centrally regulates weight control. In addition, other effects of leptin in peripheral tissues have been described. Thus, leptin has been found to regulate reproduction, haematopoiesis and immune function. We have found recently that leptin has a stimulatory effect on human peripheral blood mononuclear cells (PBMC). Monocytes are activated by leptin alone whereas T lymphocytes need a suboptimal stimulus of PHA or ConA before further activation by leptin. These effects are mediated by the long isoform of the leptin receptor, which has been shown to trigger signalling in PBMC. In fact, we have found that human leptin stimulates Janus kinase (JAK)-signal transducer and activator of transcription (STAT), phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways in PBMC. In order to assess possible regulation of the long isoform of the leptin receptor (Ob-R) in mononuclear cells upon activation, we have studied the expression of Ob-R by RT-PCR and Western blotting in PBMC activated in vitro by PHA or ConA and in vivo in HIV-infected patients. We have found that in vitro activation and in vivo HIV infection correlates with an increase in leptin receptor expression in PBMC. Moreover, the leptin receptor is tyrosine phosphorylated in PBMC from HIV-infected patients, suggesting that the leptin receptor is activated. These results are consistent with the suggested role of leptin in modulating the immune response.
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PMID:Leptin receptor (Ob-R) expression is induced in peripheral blood mononuclear cells by in vitro activation and in vivo in HIV-infected patients. 1210 31

Leptin, an adipocyte-derived hormone, regulates food intake and energy expenditure in the hypothalamus via its receptor, member of the class I cytokine receptor family. Leptin resistance has been observed in rodents and in humans. However, the mechanisms could not be explained in most cases of human obesity, except for rare cases with mutations in the leptin receptor. Recent reports demonstrated that ethanol inhibited the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway activated by some members of the class I cytokine receptor family. In this study, we examined the effects of ethanol on the leptin-induced JAK/STAT signaling pathway using human hepatoma cell lines transiently expressing long form of the leptin receptor. A 30 min pretreatment with ethanol dose-dependently inhibited the leptin-induced STAT3 phosphorylation. Furthermore, to determine the time course of ethanol inhibitory effects, the cells were incubated in 10 mM ethanol for various times. Partial inhibition of leptin-induced STAT3 activation was seen after 1 min of treatment with ethanol and completely inhibited after 30 min pretreatment. SB 202190, a p38 mitogen-activated protein kinase (MAPK) inhibitor, partly prevented this inhibition by ethanol of leptin-induced STAT3 activation. These findings suggest that ethanol time- and dose-dependently inhibits the leptin action, in part via p38 MAPK.
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PMID:Ethanol inhibits leptin-induced STAT3 activation in Huh7 cells. 1216 72


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