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)

Leptin, secreted by adipocytes, regulates satiety and energy expenditure. Several forms of leptin receptors produced by alternative mRNA splicing are found in many tissues, including the hypothalamus, liver, lung, kidney, hematopoietic cells, and gonads, suggesting that leptin exerts effects in these tissues. In accordance with the distribution of leptin receptors, there is accumulating evidence that leptin plays various roles in reproduction, hematopoiesis, and the immune systems in addition to the regulation of food intake and energy expenditure. In the present study, we examined the in vitro effects of leptin on proliferation of a mouse embryonic cell line, C3H10T1/2, and its mechanism of action. Leptin caused a dose- and time-dependent increase in mitogen-activated protein kinase (MAPK) activity that was accompanied by an increase in C3H10T1/2 cell number. The MAPK kinase-1-specific inhibitor PD98059 completely blocked the increases in both MAPK activity and cell proliferation caused by leptin. These findings indicate that leptin stimulates the proliferation of C3H10T1/2 cells via the MAPK cascade.
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PMID:Leptin induces mitogen-activated protein kinase-dependent proliferation of C3H10T1/2 cells. 914 92

Leptin receptors include a long form (OBRl) with 302 cytoplasmic residues that is presumed to mediate most or all of leptins signaling, and several short forms, including one (OBRs) that has 34 cytoplasmic residues, is widely expressed, and is presumed not to signal but to mediate transport or clearance of leptin. We studied the abilities of these two receptor isoforms to mediate signaling in transfected cells. In response to leptin, OBRl, but not OBRs, underwent tyrosine phosphorylation that was enhanced by co-expression with JAK2. In cells expressing receptors and JAK2, both OBRs and OBRl mediated leptin-dependent tyrosine phosphorylation of JAK2, and this was abolished with OBRs when the Box 1 motif was mutated. In cells expressing receptors, JAK2 and IRS-1, leptin induced tyrosine phosphorylation of IRS-1 through OBRs and OBRl. In COS cells expressing hemagglutinin-ERK1 and receptors, leptin increased ERK1 kinase activity through OBRl, with the magnitude increased by co-expression of JAK1 or JAK2, and to a lesser degree through OBRs, despite greater receptor expression. In stable Chinese hamster ovary cell lines expressing OBRs or OBRl, leptin stimulated endogenous ERK2 phosphorylation. Whereas leptin stimulated tyrosine phosphorylation of hemagglutinin-STAT3 and induction of a c-fos luciferase reporter plasmid through OBRl, OBRs was without effect in these assays. In conclusion, OBRl is capable of signaling to IRS-1 and mitogen-activated protein kinase via JAK, in addition to activating STAT pathways. Although substantially weaker than OBRl, OBRs is capable of mediating signal transduction via JAK, but these activities are of as yet unknown significance for leptin biology in vivo.
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PMID:Divergent signaling capacities of the long and short isoforms of the leptin receptor. 940 87

Leptin at 1-5 nM, the concentrations observed in obese subjects, caused an increase in the active form of mitogen-activated protein kinase (MAPK) that was accompanied by increased tyrosine phosphorylation of STAT-1 and STAT-3 in a mouse pancreatic beta cell line, MIN6. Leptin also increased DNA synthesis and cell viability in MIN6 cells based on the results of [3H]-thymidine incorporation and colorimetric MTT assay, respectively. The specific MAPK-inhibitor PD98059 blocked not only the MAPK activation but also the increment in DNA synthesis and cell viability caused by leptin. Thus, leptin stimulates both the MAPK and the Janus kinase (JAK)-STAT cascade as well as inducing proliferation through the MAPK cascade in MIN6 cells. This mechanism might account, at least in part, for obesity-induced pancreatic islet hypertrophy.
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PMID:Leptin induces proliferation of pancreatic beta cell line MIN6 through activation of mitogen-activated protein kinase. 943 83

Leptin has been shown to activate multiple signaling molecules in cultured cells, including Janus kinase-2, STAT (signal transducer and activator of transcription) proteins, and mitogen-activated protein kinase, and to stimulate the DNA-binding activity of STAT3 in mouse hypothalamus. In this study, the activation of candidate leptin signaling molecules in the hypothalamus of normal rats in vivo was investigated. Fasted male Sprague-Dawley rats were injected iv with recombinant murine leptin or vehicle. Plasma leptin concentrations were determined at defined time points, and the phosphorylation of signaling proteins was assessed in hypothalamic lysates. There was a marked increase in plasma leptin concentration at 2 min and a gradual decline by 45 min after leptin injection. Immunoblotting analysis of hypothalamic lysates with a phosphospecific STAT3 antibody demonstrated a time-dependent stimulation of STAT3 tyrosine phosphorylation. STAT3 phosphorylation was first evident at 5 min and was maximal at 30 min after leptin injection. By contrast, leptin did not increase the phosphorylation of Janus kinase proteins, mitogen-activated protein kinase, or STAT1 and -5 despite abundant expression of these signaling molecules in the hypothalamus. These results differ from findings in cultured cells and in vitro systems. It remains unclear how signaling is propagated downstream from the leptin receptor to STAT3, but this may involve novel signaling intermediates.
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PMID:Leptin signaling in the hypothalamus of normal rats in vivo. 979 50

Leptin is the adipocyte-specific product of the ob gene. Expression of leptin in fully fed animals reflects adipocyte size and body-fat mass. Leptin signals the status of body energy stores to the brain, where signals emanate to regulate food intake and whole-body energy expenditure. The leptin gene was identified in the leptin-deficient, obese ob/ob mouse by positional cloning techniques. Recently, leptin has been cloned in domestic species including pigs, cattle, and chickens. The leptin receptor has at least five splice variants; the long form of the receptor is primarily expressed in the hypothalamus and is thought to be the predominant signaling isoform. Leptin receptors are members of the cytokine family of receptors and signal via janus-activated kinases (JAK)/signal transducers and activators of transcription (STAT) and mitogen-activated protein kinase (MAPK) pathways. Mutations in the leptin or leptin receptor genes results in morbid obesity, infertility, and insulin resistance in rodents and humans. Leptin regulates food intake and energy expenditure via central and peripheral mechanisms. Leptin receptors are expressed in most tissues, and in vitro evidence suggests that leptin may have direct effects on some tissues such as adipose tissue, the adrenal cortex, and the pancreatic beta-cell. Leptin is thought to influence whole-body glucose homeostasis and insulin action. Studies are underway to determine the role that leptin plays in the biology of domestic animals.
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PMID:Leptin and its receptors: regulators of whole-body energy homeostasis. 986 38

Leptin is a 16-kDa hormone secreted by adipocytes and plays an important role in control of feeding behavior and energy expenditure. In obesity, circulating levels of leptin and insulin are high because of the presence of increased body fat mass and insulin resistance. Recent reports have suggested that leptin can act through some of the components of the insulin signaling cascade, such as insulin receptor substrates (IRS-1 and IRS-2), phosphatidylinositol 3-kinase (PI 3-kinase), and mitogen-activated protein kinase, and can modify insulin-induced changes in gene expression in vitro and in vivo. Well differentiated hepatoma cells (Fao) possess both the long and short forms of the leptin receptor and respond to leptin with a stimulation of c-fos gene expression. In Fao cells, leptin alone had no effects on the insulin signaling pathway, but leptin pretreatment transiently enhanced insulin-induced tyrosine phosphorylation and PI 3-kinase binding to IRS-1, while producing an inhibition of tyrosine phosphorylation and PI 3-kinase binding to IRS-2. Leptin alone also induced serine phosphorylation of Akt and glycogen synthase kinase 3 but to a lesser extent than insulin, and the combination of these hormones was not additive. These results suggest complex interactions between the leptin and insulin signaling pathways that can potentially lead to differential modification of the metabolic and mitotic effects of insulin exerted through IRS-1 and IRS-2 and the downstream kinases that they activate.
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PMID:Selective interaction between leptin and insulin signaling pathways in a hepatic cell line. 1068 12

To determine whether leptin signal transduction is exerted directly upon insulin-sensitive tissues in vivo, we examined the ability of iv leptin to acutely stimulate phosphorylation of STAT3, STAT1, and MAPK, and activities of PI 3-kinase and Akt, in insulin-sensitive tissues of normal rats. Both leptin (1 mg/kg iv x 3 min) and insulin (10 U/kg iv x 3 min) stimulated tyrosine phosphorylation of STAT3 5.6- to 6.0-fold and of STAT1 4.0-fold in adipose tissue. Leptin tended to increase STAT3 phosphorylation in liver and muscle. Both hormones also increased MAPK phosphorylation: leptin increased it 3.2- to 3.8-fold in adipose tissue and liver, whereas insulin stimulated MAPK phosphorylation 5.0-fold in adipose tissue, 6.8-fold in liver, and 2.5-fold in muscle. Leptin was much less effective than insulin at stimulating IRS pathways. Leptin increased IRS-1-associated PI 3-kinase activity in adipose tissue only 2.0-fold (P < 0.01) compared with the 10-fold effect of insulin. IRS-2-associated PI 3-kinase activity was increased 1.7-fold (P < 0.01) by leptin in liver and 6-fold by insulin. Akt phosphorylation and activity were not changed by leptin but increased with insulin. Lower concentrations of leptin (10 and 50 microg/kg) also stimulated STAT3 phosphorylation in fat. These effects appear to be direct because 3 min after leptin intracerebroventricular injection, phosphorylation of STAT3, STAT1, and MAPK were not stimulated in hypothalamus or adipose tissue. Furthermore, leptin activated STAT3 and MAPK in adipose tissue explants ex vivo and in 3T3-L1 adipocytes. Leptin did not activate STAT3 or MAPK in adipose tissue of db/db mice. Thus, leptin rapidly activates signaling pathways directly at the level of insulin sensitive tissues through the long-form leptin receptor, and these pathways overlap with, but are distinct from, those engaged by insulin.
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PMID:In vivo administration of leptin activates signal transduction directly in insulin-sensitive tissues: overlapping but distinct pathways from insulin. 1087 32

Leptin acts as a satiety factor, but there is also evidence that it affects energy expenditure. Leptin's effects are mediated by its receptors, which function as activators of a Janus family of tyrosine kinases-signal transducer and activator of transcription (JAK-STAT) pathway. We have previously shown that murine recombinant leptin markedly induces both the release of catecholamine and tyrosine hydroxylase (TH) (rate-limiting enzyme in the biosynthesis of catecholamine)-messenger RNA (mRNA) levels, probably through Ob-Rb expressed in cultured porcine chromaffin cells. In the present study, we examined the effect of leptin on Ca(2+) mobilization, TH enzyme activity, and signaling. Ca(2+) channel blockers, nicardipine and omega-Conotoxin GVIA, each at 1 microM, were effective in inhibiting leptin-induced catecholamine secretion. When intracellular Ca(2+) ([Ca(2+)](i)) was measured in fura 2-loaded chromaffin cells, leptin was found to cause a sustained increase of Ca(2+) by mobilizing Ca(2+) from both extra- and intracellular pools. Additionally, leptin significantly stimulated inositol 1.4.5-triphosphate IP(3) production in a dose-dependent manner. TH-activity is regulated by both TH enzyme activity and increased TH-mRNA levels accompanied by increased TH protein synthesis. Leptin (>/=1 nM) significantly stimulated TH enzyme activity and increased the TH protein level, indicating that it stimulates catecholamine biosynthesis. In addition, removal of external Ca(2+) completely inhibited leptin (100 nM)-induced TH enzyme activity. Leptin (>/=1 nM) caused an increase in the activity of mitogen-activated protein kinases (MAPKs) that was accompanied by increased phosphorylation of STAT-3 and -5, but not STAT-1. Moreover, MAPK activity evoked by leptin(100 nM) and TH-mRNA caused by leptin (10 nM) were inhibited by 50 and 30 microM of PD-98059 (the MAP kinase kinase-1 inhibitor), respectively. These findings indicate that leptin activates voltage-dependent Ca(2+) channels (VDCC), presumably L-type and N-type Ca(2+) channels, as well as phospholipase C, and suggest that leptin-induced catecholamine secretion is mainly mediated by activation of VDCC. In addition, leptin stimulates the JAK-STAT pathway as well as increasing the levels of TH-mRNA levels through the MAPK pathway in porcine chromaffin cells.
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PMID:Ca(2+) mobilization, tyrosine hydroxylase activity, and signaling mechanisms in cultured porcine adrenal medullary chromaffin cells: effects of leptin. 1114 92

Recently, we characterized leptin receptors in bovine adrenal medullary cells (Yanagihara et al. 2000). Here we report the stimulatory effect of leptin on catecholamine synthesis in the cells. Incubating cells with leptin (10 nM) for 20 min increased the synthesis of 14C-catecholamines from [14C]tyrosine, but not from L-3,4-dihydroxyphenyl [3-14C]alanine. The stimulation of catecholamine synthesis in the cells by leptin was associated with the phosphorylation and activation of tyrosine hydroxylase, the rate-limiting enzyme of catecholamine biosynthesis. The incubation of cells with leptin resulted in a rapid activation of the mitogen-activated protein kinases (MAPKs). An inhibitor of MAPK kinase, U0126, nullified the stimulatory effect of leptin on the synthesis of 14C-catecholamines. Leptin potentiated the stimulatory effect of acetylcholine on 14C-catecholamine synthesis, whereas leptin failed to enhance the phosphorylation and activation of tyrosine hydroxylase induced by acetylcholine. These findings suggest that leptin stimulates catecholamine synthesis via the activation of tyrosine hydroxylase by two different mechanisms, i.e., one is dependent on tyrosine hydroxylase phosphorylation mediated through the MAPK pathway and the second is independent of enzyme phosphorylation.
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PMID:Stimulation of catecholamine synthesis in cultured bovine adrenal medullary cells by leptin. 1115 65

Leptin, the ob gene product, is produced by adipose tissue and is submitted to a complex hormonal and metabolic regulation. Leptin plays a critical role in the balance of body weight. Here we report on secretion and hormonal regulation of leptin by brown adipocytes. Using the recently established T37i cell line, we show that leptin expression and secretion occurred as a function of cell differentiation. In differentiated T37i cells, insulin induced leptin release ( approximately 0.25 ng/10(6) cells/h) in a concentration-dependent manner (EC50=0.1 nM), and this was totally suppressed by beta3-adrenergic ligand, thiazolidinedione, cycloheximide, or actinomycin D. Insulin induced a strong, rapid (within 2 h) but transient fivefold increase in leptin mRNA levels. This transcriptional control of ob gene expression by insulin involved both phosphatidylinositol 3-kinase- and MAP kinase-dependent pathways. Glucocorticoids inhibited both insulin-stimulated leptin secretion and ob gene expression without affecting leptin mRNA stability (t(1/2)=3h05). Altogether, our results demonstrate that brown adipocytes express and secrete leptin, whose hormonal regulation clearly differs from that described in white adipose tissue. These findings point to tissue-specific molecular mechanisms and suggest that leptin might exert direct effects on energy homeostasis through an autocrine mechanism.
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PMID:Insulin and glucocorticoids differentially regulate leptin transcription and secretion in brown adipocytes. 1138 33


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