Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leukemia inhibitory factor (LIF) is a pleiotropic neuroimmune cytokine that promotes corticotroph cell differentiation and induces proopiomelanocortin (POMC) mRNA expression and adrenocorticotropin hormone (ACTH) secretion. However, molecular mechanisms for this induction remain elusive. We therefore developed ACTH-secreting AtT20 transformants for wild-type or mutated STAT3, a cytokine signaling molecule, to address whether STAT3 is a determinant of LIF-mediated ACTH regulation. We show that these mutants act in a dominant negative manner by blocking endogenous STAT3 tyrosine phosphorylation or STAT3 DNA binding. Attenuation of STAT3 activity in the dominant negative AtT20 clones prevented LIF from promoting transcriptional activation of the POMC promoter (2.1-fold), whereas this LIF action was enhanced (7.7-fold; p < 0.05) in wild-type STAT3-overexpressing clones in comparison to mock-transfected cells (4.5-fold). However, wild-type or dominant negative STAT3-overexpressing clones showed comparable (4-fold) POMC induction after treatment with cyclic adenosine monophosphate (cAMP), an alternate inducer of POMC transcription, indicating the STAT3 specificity for LIF signaling. Moreover, dominant negative inactivation of STAT3 activity resulted in abrogation of LIF-induced POMC mRNA levels and ACTH secretion, confirming the in vivo role of STAT3 in LIF-mediated corticotroph action. Chemical or molecular blockade of the mitogen-activated protein kinase pathway did not affect LIF-mediated corticotroph function. These results indicate that STAT3 is a critical intrapituitary component of the LIF-mediated neuroimmunoendocrine interface in corticotroph cells.
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PMID:Critical role for STAT3 in murine pituitary adrenocorticotropin hormone leukemia inhibitory factor signaling. 1019 43

The role of leptin and its receptor on the regulation of appetite and body fat was summarized. Leptin directly exerts its anorexigenic effects on arcuate nucleus via proopiomelanocortin and neuropeptide Y neurons. The anorexia and sympathetic nerve activation result in the reduction of body fat. But physiological concentrations of leptin could not reduce body fat in obese people, while genetic loss of central leptin effects induces obesity in children. Melanin concentrating hormone, orexin, and corticotropin-releasing hormone may be directly regulated by leptin. Serotonergic neurons may be separate from leptin effects. Phosphorylation of 985- and 1138-tyrosine of long-form leptin receptor activates SHP-2 and STAT3, respectively. Soluble leptin receptor concentrations in serum are negatively correlated with BMI. Clinical usefulness of leptin is now in progress.
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PMID:[Role of leptin and its receptor in the regulation of appetite and body fat]. 1126 87

Leptin, the long-sought satiety factor of adipocytes origin, has emerged as one of the major signals that relay the status of fat stores to the hypothalamus and plays a significant role in energy homeostasis. Understanding the mechanisms of leptin signaling in the hypothalamus during normal and pathological conditions, such as obesity, has been the subject of intensive research during the last decade. It is now established that leptin action in the hypothalamus in regulation of food intake and body weight is mediated by a neural circuitry comprising of orexigenic and anorectic signals, including NPY, MCH, galanin, orexin, GALP, alpha-MSH, NT, and CRH. In addition to the conventional JAK2-STAT3 pathway, it has become evident that PI3K-PDE3B-cAMP pathway plays a critical role in leptin signaling in the hypothalamus. It is now established that central leptin resistance contributes to the development of diet-induced obesity and ageing associated obesity. Central leptin resistance also occurs due to hyperleptinimia produced by exogenous leptin infusion. A defective nutritional regulation of leptin receptor gene expression and reduced STAT3 signaling may be involved in the development of leptin resistance in DIO. However, leptin resistance in the hypothalamic neurons may occur despite an intact JAK2-STAT3 pathway of leptin signaling. Thus, in addition to defective JAK2-STAT3 pathway, defects in other leptin signaling pathways may be involved in leptin resistance. We hypothesize that defective regulation of PI3K-PDE3B-cAMP pathway may be one of the mechanisms behind the development of central leptin resistance seen in obesity.
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PMID:Leptin signaling in the hypothalamus: emphasis on energy homeostasis and leptin resistance. 1472 56

Ciliary neurotrophic factor (CNTF) exerts anorectic effects by overcoming leptin resistance via activation of hypothalamic neurons. However, the exact site of CNTF action in the hypothalamus has not yet been identified. Using Cre-loxP-mediated recombination in vivo, we have selectively ablated the common cytokine signaling chain gp130, which is required for functional CNTF signaling, in proopiomelanocortin (POMC)-expressing neurons. POMC-specific gp130 knockout mice exhibit unaltered numbers of POMC cells and normal energy homeostasis under standard and high fat diet. Endotoxin (LPS) and stress-induced anorexia and adrenocorticotropin regulation were unaffected in these animals. Strikingly, the anorectic effect of centrally administered CNTF was abolished in POMC-specific gp130 knockout mice. Correspondingly, in these animals, CNTF failed to activate STAT3 phosphorylation in POMC neurons and to induce c-Fos expression in the paraventricular nucleus. These data reveal POMC neurons as a critical site of CNTF action in mediating its anorectic effect.
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PMID:gp130 signaling in proopiomelanocortin neurons mediates the acute anorectic response to centrally applied ciliary neurotrophic factor. 1681 88

Leptin, the product of the obese (ob) gene, is mainly known for its regulatory role of energy balance by direct activation of hypothalamic receptors. Recently, its function in the acute control of food intake was additionally attributed to activation of the vagus nerve to regulate meal termination. Whether vagal afferent neurones are involved in longer term effects of leptin on food intake, however, remains undetermined. Using vagotomised (VGX) rats, we sought to clarify the contributions of vagal afferents in mediating the long-lasting effect of leptin on appetite suppression. Intraperitoneal (i.p.) injection of leptin (3.5 mg/kg) attenuated food intake at 4, 6, 8 and 24 h and body weight at 24 h postinjection in SHAM-operated rats; however, this response was not abrogated by vagotomy. In a separate study using immunohistochemistry, we observed leptin-induced Fos expression in the nucleus tractus solitarii, a brain structure where vagal afferent fibres terminate. This signal was not attenuated in VGX animals compared to the SHAM group. Moreover, leptin treatment led to a similar level of nuclear STAT3 translocation, a marker of leptin signalling, in the hypothalami of SHAM and VGX animals. In addition to the effects of leptin, vagotomy surgery itself resulted in a decrease of 24 h food intake. Analyses of brains from saline-treated VGX animals revealed a significant induction of Fos in the nucleus tractus solitarii and changes in agouti-related peptide and pro-opiomelanocortin mRNA expression in the hypothalamus compared to their SHAM counterparts, indicating that the vagotomy surgery itself induced a modification of brain activity in areas involved in regulating appetite. Collectively, our data suggest that vagal afferents do not constitute a major route of mediating the regulatory effect of leptin on food intake over a period of several hours.
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PMID:The role of the vagus nerve in mediating the long-term anorectic effects of leptin. 1735 16

Multiple regulatory pathways exist to control the expression levels of neuropeptides in response to body weight and energy availability changes. Since many neuropeptides are first synthesized in a pro-neuropeptide form, the availability of processing enzymes in a neuron can control the amount of active mature neuropeptide produced at any given time. In this review, we will focus on the regulation of prohormone convertase 1 (PC1) and prohormone convertase 2 (PC2), as well as downstream neuropeptide genes. Evidence from our laboratory suggests that Nescient helix-loop-helix 2 (Nhlh2) regulates the transcription of PC1 and PC2, possibly in conjunction with the leptin-stimulated transcription factor, STAT3. Furthermore, Nhlh2 itself is a target of leptin and other energy availability signals, with high levels of expression during energy surplus, and low levels of expression in conditions of reduced energy availability such as food deprivation or cold exposure. Overall, coordinate regulation of Nhlh2, PC1, PC2 and downstream hypothalamic neuropeptides such as thyrotropin releasing hormone (TRH) and pro-opiomelanocortin (POMC) does lead to energy balance modulation and ensuing long-term changes in body weight.
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PMID:Energy balance pathways converging on the Nhlh2 transcription factor. 1748 52

Leptin controls food intake and energy expenditure by regulating hypothalamic neuron activities. Leptin exerts its actions through complex signaling pathways including STAT3 phosphorylation, nuclear translocation, and binding to target gene promoter/cofactor complexes. Deficient or defective leptin signaling leads to obesity, which may be caused by insufficient leptin levels and/or resistance to leptin signaling. To understand the molecular mechanisms of leptin resistance, we studied the regulation of pro-opiomelanocortin (POMC) gene expression by leptin. We show that phospho-STAT3 activates POMC promoter in response to leptin signaling through a mechanism that requires an SP1-binding site in the POMC promoter. Furthermore, FoxO1 binds to STAT3 and prevents STAT3 from interacting with the SP1.POMC promoter complex, and consequently, inhibits STAT3-mediated leptin action. Our study suggests that leptin action could be inhibited at a step downstream of STAT3 phosphorylation and nuclear translocation, and provides a potential mechanism of leptin resistance in which an increased FoxO1 antagonizes STAT3-mediated leptin signaling.
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PMID:FoxO1 inhibits leptin regulation of pro-opiomelanocortin promoter activity by blocking STAT3 interaction with specificity protein 1. 1904 75

Individuals who live in industrialized countries often eat a calorie-rich diet and perform little physical activity. These habits are thought to be critical contributors to the rapidly rising incidence of obesity, a condition that affects hundreds of millions of people worldwide. High-calorie intake alters metabolic-sensing pathways in central nervous system neurons, and these changes have pathogenic roles in the development of obesity. This review aims to summarize our current knowledge about the neuronal populations (the central melanocortin system in particular) and transcriptional regulators, including STAT3 and FOXO1, that are involved in the maintenance of normal body weight. We describe the interactions between these transcriptional factors and their target genes, which encode the main appetite-regulating neuropeptides (agouti-related peptide and alpha-melanocyte-stimulating hormone). We discuss the transcriptional co-activator PGC-1-alpha and the supposed metabolic-sensor protein SIRT1, and their potential roles as targets for novel antiobesity medications.
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PMID:The role of transcriptional regulators in central control of appetite and body weight. 1922 36

Leptin acts via neuronal leptin receptors to control energy balance. Hypothalamic pro-opiomelanocortin (POMC) and agouti-related peptide (AgRP)/Neuropeptide Y (NPY)/GABA neurons produce anorexigenic and orexigenic neuropeptides and neurotransmitters, and express the long signaling form of the leptin receptor (LepRb). Despite progress in the understanding of LepRb signaling and function, the sub-cellular localization of LepRb in target neurons has not been determined, primarily due to lack of sensitive anti-LepRb antibodies. Here we applied light microscopy (LM), confocal-laser scanning microscopy (CLSM), and electron microscopy (EM) to investigate LepRb localization and signaling in mice expressing a HA-tagged LepRb selectively in POMC or AgRP/NPY/GABA neurons. We report that LepRb receptors exhibit a somato-dendritic expression pattern. We further show that LepRb activates STAT3 phosphorylation in neuronal fibers within several hypothalamic and hindbrain nuclei of wild-type mice and rats, and specifically in dendrites of arcuate POMC and AgRP/NPY/GABA neurons of Leprb (+/+) mice and in Leprb (db/db) mice expressing HA-LepRb in a neuron specific manner. We did not find evidence of LepRb localization or STAT3-signaling in axon-fibers or nerve-terminals of POMC and AgRP/NPY/GABA neurons. Three-dimensional serial EM-reconstruction of dendritic segments from POMC and AgRP/NPY/GABA neurons indicates a high density of shaft synapses. In addition, we found that the leptin activates STAT3 signaling in proximity to synapses on POMC and AgRP/NPY/GABA dendritic shafts. Taken together, these data suggest that the signaling-form of the leptin receptor exhibits a somato-dendritic expression pattern in POMC and AgRP/NPY/GABA neurons. Dendritic LepRb signaling may therefore play an important role in leptin's central effects on energy balance, possibly through modulation of synaptic activity via post-synaptic mechanisms.
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PMID:Somato-dendritic localization and signaling by leptin receptors in hypothalamic POMC and AgRP neurons. 2420 98

FoxO1, which is up-regulated during early stages of diet-induced leptin resistance, directly interacts with STAT3 and prevents STAT3 from binding to specificity protein 1 (SP1)-pro-opiomelanocortin (POMC) promoter complex, and thereby inhibits STAT3-mediated regulation of POMC transcription. FoxO1 also binds directly to the POMC promoter and negatively regulates its transcription. The present study aims to understand the relative contribution of the two interactions in regulating POMC expression. We studied the structural requirement of FoxO1 for its interaction with STAT3 and POMC promoter, and tested the inhibitory action of FoxO1 mutants by using biochemical assays, molecular biology and computer modelling. FoxO1 mutant with deletion of residues Ala137-Leu160 failed to bind to STAT3 or inhibit STAT3-mediated POMC activation, although its binding to the POMC promoter was unaffected. Further analysis mapped Gly140-Leu160 to be critical for STAT3 binding. The identified region Gly140-Leu160 was conserved among mammalian FoxO1 proteins, and showed a high degree of sequence identity with FoxO3, but not FoxO4. Consistently, FoxO3 could interact with STAT3 and inhibit POMC promoter activity, whereas FoxO4 could not bind to STAT3 or affect POMC promoter activity. We further identified that five residues (Gln145, Arg147, Lys148, Arg153 and Arg154) in FoxO1 were necessary in FoxO1-STAT3 interaction, and mutation of these residues abolished its interaction with STAT3 and inhibition of POMC promoter activity. Finally, a FoxO1-STAT3 interaction interface model generated by computational docking simulations confirmed that the identified residues of FoxO1 were in close proximity to STAT3. These results show that FoxO1 inhibits STAT3-mediated leptin signalling through direct interaction with STAT3.
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PMID:FoxO1 negatively regulates leptin-induced POMC transcription through its direct interaction with STAT3. 2551 May 53


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