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

The anorexia of infection is part of the host's acute phase response (APR). Despite being beneficial in the beginning, long lasting anorexia delays recovery and is ultimately deleterious. Microbial products such as bacterial cell wall compounds (e.g., lipopolysaccharides and peptidoglycans), microbial nucleic acids (e. g., bacterial DNA and viral double-stranded RNA), and viral glycoproteins trigger the APR and presumably also the anorexia during infections. Microbial products stimulate the production of proinflammatory cytokines (e.g., interleukins [ILs], tumor necrosis factor-alpha, interferons), which serve as endogenous mediators. Several microbial products and cytokines reduce food intake after parenteral administration, suggesting a role of these substances in the anorexia during infection. Microbial products are mainly released and cytokines are produced in the periphery during most infections; they might inhibit feeding through neural and humoral pathways activated by their peripheral actions. Activation of peripheral afferents by locally produced cytokines is involved in several cytokine effects, but is not crucial for the anorectic effect of microbial products and IL-1beta. Cytokines increase leptin expression in the adipose tissue, and leptin may contribute to, but is also not essential for, the anorectic effects of microbial products and cytokines. In addition, a direct action of cytokines and microbial products on the central nervous system (CNS) is presumably involved in the anorexia during infection. Cytokines can reach CNS receptors through circumventricular organs and through active or passive transport mechanisms or they can act through receptors on endothelial cells of the brain vasculature and stimulate the release of subsequent mediators such as eicosanoids. De novo CNS cytokine synthesis occurs in response to peripheral infections, but its role in the accompanying anorexia is still open to discussion. Central mediators of the anorexia during infection appear to be neurochemicals involved in the normal control of feeding, such as serotonin, dopamine, histamine, corticotropin releasing factor, neuropeptide Y, and alpha-melanocyte-stimulating hormone. Reciprocal, synergistic, and antagonistic interactions between various pleiotropic cytokines, and between cytokines and neurochemicals, form a complex network that mediates the anorexia during infection. Current knowledge on the mechanisms involved suggests some therapeutic options for treatment. Substances that block common key steps in cytokine synthesis or cytokine action, or inhibitors of eicosanoid synthesis, may hold more promise than attempts to antagonize specific cytokines. To target the neurochemical mediation of the anorexia during infection may be even more efficient. Future research should address these neurochemical mechanisms and the cytokine actions at the blood-brain barrier. Further unanswered questions concern the modulation of the anorexia during infection by gender and nutritional state.
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PMID:Anorexia of infection: current prospects. 1105 6

Obesity in normal animals has been demonstrated to be associated with a decrease in sensitivity to leptin especially as it relates to leptin's capacity to increase sympathetic nerve activity and enhance cardiovascular dynamics. In normal animals leptin has been demonstrated to exert significant regulatory responses by its capacity to increase proopiomelanocortin (POMC) expression and especially the increase in alpha melanocyte stimulating hormone (alphaMSH). These responses to leptin are blocked by a melanocortin-4 (MC-4) receptor antagonist. In this study we investigated the responsiveness of the sympathetic nervous system and cardiovascular system of high fat fed obese animals to the intracerebroventricular (ICV) administration of the POMC products alphaMSH and beta-endorphin (beta-END). We further investigated these responses in obese animals following leptin administration in the presence of MC-4 receptor and opioid receptor blockade. The ICV administration of leptin resulted in an increase in lumbar sympathetic nerve activity (LSNA) and mean arterial pressure (MAP) in normals but decreased it in the obese. The ICV administration of alphaMSH increased the LSNA and MAP in normal animals but to a lesser degree in obese animals. On the other hand beta-endorphin decreased the LSNA and MAP in normal animals but increased it in obese animals. Additionally ICV leptin administration in obese animals in the presence of MC-4 or opioid receptor blockade resulted in an increase in sympathetic activity and a pressor response. From these studies we conclude that obesity in high fat fed animals is characterized by a decreased sensitivity to alphaMSH and a paradoxical response to beta-endorphin and this altered responsiveness may be a factor in the altered leptin resistance characteristic of obese animals.
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PMID:Leptin resistance in obesity is characterized by decreased sensitivity to proopiomelanocortin products. 1106 94

During lactation, hypothalamic levels of neuropeptide Y (NPY) and agouti related protein (AGRP) mRNA are increased, while pro-opiomelanocortin (POMC) mRNA is decreased. Serum leptin levels are also decreased during lactation. These changes may underlie the large increases of both food and water intake that occur in concert with milk production. However, additional hypothalamic substances, such as the novel peptide, orexin, may be involved. In addition, in the presence of chronically suppressed levels of serum leptin, there may be a change in leptin receptor expression in the hypothalamus. The objectives of the present study were to determine if orexin and leptin receptor mRNA levels were changed during lactation. Rats were studied on dioestrus of the oestrous cycle or on day 10 postpartum (the lactating animals were suckling eight pups). Orexin mRNA levels in the lateral hypothalamus did not differ between dioestrus and lactation. There was a significant increase in leptin receptor mRNA levels in the supraoptic nucleus during lactation compared to dioestrus. Furthermore, leptin receptor protein, as determined by immunocytochemistry, was colocalized in virtually all vasopressin and oxytocin cells in the supraoptic nucleus. Lactating animals exhibited a decrease in leptin receptor mRNA in the ventromedial hypothalamic nucleus whereas no change was apparent in other hypothalamic areas compared to the dioestrus animals. These results demonstrate that changes in orexin do not appear to contribute to the increase in food intake during lactation. It is likely that the increases in NPY and ARGP, coupled with the decrease in POMC, are primarily responsible for sustaining the chronic hyperphagia of lactation. The changes observed in leptin receptor expression in the hypothalamus, along with the suppression of serum leptin levels, also suggest that the leptin signalling system may play a significant role in the regulation of food and water intake during lactation.
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PMID:Differential regulation of leptin receptor but not orexin in the hypothalamus of the lactating rat. 1106 23

Leptin mediates neuroendocrine responses to fasting and restores the starvation-induced changes of several hypothalamic neuropeptides. Ciliary neurotrophic factor (CNTF), a cytokine closely related to leptin, reduces food intake and reverses obesity, but its role in restoring the starvation-induced changes of hormones or hypothalamic neuropeptides remains largely unknown. To comparatively assess the roles of CNTF and leptin in reversing the starvation-induced changes of hypothalamic neuropeptides and endocrine function and in inducing expression of hypothalamic inhibitors of leptin and CNTF signaling (suppressor of cytokine signaling 3 [SOCS-3]) and mediators of energy expenditure (cyclo-oxygenase 2 [COX-2]), we studied the effect of CNTF and leptin administered by intraperitoneal injections (1 microg/g twice daily) in C57Bl/6J mice fasted for 48 h. Serum corticosterone levels increased with fasting, and leptin administration partially normalized them, whereas CNTF administration had no effect. Hypothalamic neuropeptide Y (NPY) and agouti-related protein (AgRP) mRNA expression increased and pro-opiomelanocortin (POMC) decreased in response to fasting. Leptin administration decreased NPY and AgRP and increased POMC mRNA levels toward baseline, but CNTF administration in fasted mice had no effect of comparable significance. Both leptin and CNTF administration in fasted mice resulted in an induction of SOCS-3 mRNA expression. CNTF also induced hypothalamic SOCS-2 mRNA expression. Finally, neither leptin nor CNTF administration in mice fasted for 48 h alters hypothalamic COX-2 expression. Our data suggest that only falling leptin levels mediate the starvation-induced alterations in corticosterone levels and expression of hypothalamic neuropeptides, but inhibitors of leptin signaling are induced by both leptin and CNTF. This may be of clinical importance because both agents are now being evaluated for the treatment of obesity in humans.
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PMID:Unlike leptin, ciliary neurotrophic factor does not reverse the starvation-induced changes of serum corticosterone and hypothalamic neuropeptide levels but induces expression of hypothalamic inhibitors of leptin signaling. 1107 56

Agouti-related protein (AgRP), expressed in both the periphery and the brain, can result in obesity. Its active C-terminal fragment, AgRP(83-132), was recently reported to increase feeding and antagonize alpha-melanocyte-stimulating hormone (alpha-MSH) and leptin. We used multiple-time regression analysis to show that the rate at which AgRP(83-132) crossed the blood-brain barrier (BBB) from the blood to the brain was very slow (Ki = 0.6 x 10(-4) mL/g x min). Entry was not self-inhibited by excess AgRP(83-132) after either intravenous (i.v.) injection or perfusion in blood-free medium, indicating the absence of a saturable transport system, and was not cross-inhibited by alpha-MSH or leptin. Not only did AgRP(83-132) cross much slower than the saturably entering leptin, but the entry was slower than almost all other non-saturably entering endogenous peptides or neurotrophins. Nevertheless, high-performance liquid chromatography (HPLC) showed that the small amount of AgRP(83-132) crossing the BBB did so in intact form, and capillary depletion showed that it entered the brain parenchyma rather than binding to capillary endothelial cells or adhering to vascular components. There was no rapid efflux system out of the brain that might have misleadingly appeared as slow entry for AgRP(83-132). Poor lipophilicity was shown by a low octanol/buffer partition coefficient. By size-exclusion chromatography, AgRP(83-132) appeared as a 17-kd substance in both blood and buffer. Since protein was absent from the buffer, the 17-kd peak probably represented a trimer of the 5.7-kd AgRP(83-132). Capillary electrophoresis confirmed that most of the AgRP(83-132) existed as a trimer, with much smaller amounts as a dimer and monomer. Thus, although intact AgRP(83-132) can cross the BBB from the blood to the brain, its nonsaturable rate of entry is very slow, probably influenced by aggregation.
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PMID:Agouti-related protein(83-132) aggregates and crosses the blood-brain barrier slowly. 1109 9

The central melanocortin (MC) system has been demonstrated to act downstream of leptin in the regulation of body weight. The system comprises alpha-MSH, which acts as agonist, and agouti-related protein (AgRP), which acts as antagonist at the MC3 and MC4 receptors (MC3R and MC4R). This property suggests that MCR activity is tightly regulated and that opposing signals are integrated at the receptor level. We here propose another level of regulation within the melanocortin system by showing that the human (h) MC4R displays constitutive activity in vitro as assayed by adenylyl cyclase (AC) activity. Furthermore, human AgRP(83-132) acts as an inverse agonist for the hMC4R since it was able to suppress constitutive activity of the hMC4R both in intact B16/G4F melanoma cells and membrane preparations. The effect of AgRP(83-132) on the hMC4R was blocked by the MC4R ligand SHU9119. Also the hMC3R and the mouse(m)MC5R were shown to be constitutively active. AgRP(83-132) acted as an inverse agonist on the hMC3R but not on the mMC5R. Thus, AgRP is able to regulate MCR activity independently of alpha-MSH. These findings form a basis to further investigate the relevance of constitutive activity of the MC4R and of inverse agonism of AgRP for the regulation of body weight.
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PMID:AgRP(83-132) acts as an inverse agonist on the human-melanocortin-4 receptor. 1114 47

Ghrelin (Ghr), a 28 amino acid gastric peptide with an n-octanoylation on Ser 3, has recently been identified as an endogenous ligand of the growth hormone secretagogue (GHS) receptor. A cDNA was also isolated from a mouse stomach library encoding a protein named prepromotilin-related peptide (ppMTLRP) which shares sequence similarities with prepromotilin. Mouse and rat ppMTLRP sequences (rGhr) are identical and show 89% identity with human ghrelin (hGhr). By analogy with promotilin, cleavage of proMTLRP into an 18 amino acid endogenous processed peptide can be assumed on the basis of a conserved dibasic motif in position 9-10 of its sequence. In the present work, we compared the GH-releasing activity of rGhr28/MTLRP and of hGhr28/MTRLP with that of a shorter form of the peptide, hGhr18. A short peptide devoid of Ser-3 n-octanoylation hGhr18[-] was also tested. Addition of rGhr28, hGhr28 and hGhr18 stimulated GH release to the same extent from superfused pituitaries. The effect was dose dependent in a 10(-8) to 10(-6) M concentration range. In contrast, hGhr 18[-] was inactive. In freely moving animals, both rGhr28 and hGhr28 (10 microg, i.v.) stimulated GH release, whereas the same dose of hGhr18 or of hGhr18[-] was ineffective. After rGhr28, GH plasma levels increased as early as 5 min after injection and returned to basal values within 40-60 min. Expressed as percent stimulation, administration of rGhr28 was equally effective when injected during troughs or peaks of GH. Plasma concentrations of prolactin, adrenocorticotropin and leptin were not modified. Spontaneous GH secretory episodes were no longer observed within 3 h of rGhr28 treatment, but repeated administration of the secretagogue at 3- to 4-hour intervals resulted in a similar GH response. Activation of somatostatin (SRIH) release by ether stress did not blunt the GH response to rGhr28. This suggests that the secretagogue acts in part by inhibiting endogenous SRIH, as further substantiated by the ability of rGhr28 (10(-6) M), to decrease the amplitude of 25 mM K+-induced SRIH release from perifused hypothalami. In conclusion, (1) n-octanoylation of Ghrs and the shorter form hGhr18 is essential for the direct pituitary GH-releasing effect of this new family of endogenous GHSs; (2) only the longer forms are active in vivo and (3) inhibition of SRIH release appears involved in the mechanism of Ghr action.
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PMID:In vivo and in vitro effects of ghrelin/motilin-related peptide on growth hormone secretion in the rat. 1117 17

Galanin-like peptide (GALP) is a novel galanin-like peptide isolated from the porcine hypothalamus. To determine the distribution of GALP in the rat brain, we performed immunohistochemical studies using a monoclonal antibody toward the N-terminal sequence of GALP. GALP-immunoreactive neuronal cell bodies were observed only in the arcuate nucleus (Arc), which was further confirmed by in situ hybridization studies using digoxigenin-labeled antisense GALP riboprobe. Additional immunostained cells were found in the median eminence and infundibular stalk. The GALP neurons found in the Arc were further characterized by double label immunohistochemistry. More than 85% of the GALP neurons were immunostained with leptin receptor antibody. However, the GALP neurons and fibers found in the Arc were not labeled with alpha-MSH, somatostatin, neuropeptide Y, agouti-related protein, or galanin antibodies, indicating that GALP is found in neurons other than these known Arc neurons. Dense staining of GALP-containing fibers was found in the anterior parvicellular part of the paraventricular hypothalamic nucleus, in the ventral part of the lateral septal nucleus, and in the bed nucleus of the stria terminalis. Relatively dense staining was noted in the medial preoptic area (MPA), and weak staining was noted in the periventricular hypothalamic nucleus. Detailed double labeling studies in the paraventricular hypothalamic nucleus demonstrated that GALP-containing fibers converged in a more rostral direction than did agouti-related protein-containing fibers. Furthermore, GALP-immunoreactive fibers were in close apposition with GnRH-immunoreactive fibers in the MPA and bed nucleus of the stria terminalis, and about 6% of GnRH-positive neurons in the MPA showed close contact with the GALP-immunoreactive fibers. Our findings indicate that GALP neurons, as leptin-responsive neurons, may participate in the regulation of feeding behavior and/or reproductive functions.
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PMID:Distribution of galanin-like peptide in the rat brain. 1125 Sep 44

During infection, bacterial and viral products, such as bacterial lipopolysaccharide (LPS), cause the release of cytokines from immune cells. These cytokines can reach the brain by several routes. Furthermore, cytokines, such as interleukin-1 (IL-1), are induced in neurons within the brain by systemic injection of LPS. These cytokines determine the pattern of hypothalamic-pituitary secretion that characterizes infection. IL-2, by stimulation of cholinergic neurons, activates neural nitric oxide synthase (nNOS). The nitric oxide (NO) released diffuses into corticotropin-releasing hormone (CRH)-secreting neurons and releases CRH. IL-2 also acts in the pituitary to stimulate adrenocorticotropic hormone (ACTH) secretion. On the other hand, IL-1 alpha blocks the NO-induced release of luteinizing hormone-releasing hormone (LHRH) from LHRH neurons, thereby blocking pulsatile LH but not follicle-stimulating hormone (FSH) release and also inhibiting sex behavior that is induced by LHRH. IL-1 alpha and granulocyte macrophage colony-stimulating factor (GMCSF) block the response of the LHRH terminals to NO. The mechanism of action of GMCSF to inhibit LHRH release is as follows. It acts on its receptors on gamma-aminobutyric acid (GABA)ergic neurons to stimulate GABA release. GABA acts on GABAa receptors on the LHRH neuronal terminal to block NOergic stimulation of LHRH release. IL-1 alpha inhibits growth hormone (GH) release by inhibiting GH-releasing hormone (GHRH) release, which is mediated by NO, and stimulating somatostatin release, also mediated by NO. IL-1 alpha-induced stimulation of PRL release is also mediated by intrahypothlamic action of NO, which inhibits release of the PRL-inhibiting hormone dopamine. The actions of NO are brought about by its combined activation of guanylate cyclase-liberating cyclic guanosine monophosphate (cGMP) and activation of cyclooxygenase (COX) and lipoxygenase (LOX) with liberation of prostaglandin E2 and leukotrienes, respectively. Thus, NO plays a key role in inducing the changes in release of hypothalamic peptides induced in infection by cytokines. Cytokines, such as IL-1 beta, also act in the anterior pituitary gland, at least in part via induction of inducible NOS. The NO produced inhibits release of ACTH. The adipocyte hormone leptin, a member of the cytokine family, has largely opposite actions to those of the proinflammatory cytokines, stimulating the release of FSHRF and LHRH from the hypothalamus and FSH and LH from the pituitary directly by NO.
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PMID:The mechanism of action of cytokines to control the release of hypothalamic and pituitary hormones in infection. 1126 67

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


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