Impaired processing of brain proneurotensin and promelanin-concentrating hormone in obese fat/fat mice.
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Mice homozygous for the fat mutation exhibit marked hyperpro-insulinemia and develop late onset obesity. The fat mutation was recently mapped to the gene encoding carboxypeptidase E (CpE), a processing enzyme involved in trimming C-terminal paired basic residues from prohormone-derived peptides. The mutation resulted in a loss of CpE activity that correlated with aberrant proinsulin processing. Neurotensin (NT) and melanin-concentrating hormone (MCH) are two neuropeptides that, among other central effects, inhibit food intake. Here, using RIA techniques coupled to reverse phase HPLC, we analyzed the processing products derived from the NT and MCH precursors in the brain of +/fat and fat/fat mice. Compared to control hypothalamic and brain extracts, fat/fat extracts had markedly reduced levels (>80%) of NT and neuromedin N (NN), another active pro-NT-derived peptide. In contrast, they exhibited high concentrations of biologically inactive NT-KR and NN-KR (NT and NN with a C-terminal Lys-Arg extension), two peptides that were undetectable in control extracts. MCH, which is located at the C-terminus of its precursor, was present in 2- to 3-fold higher amounts in fat/fat than in +/fat hypothalamus. Neuropeptide-Glu-Ile, another pro-MCH-derived neuropeptide separated from MCH by an Arg-Arg sequence, was present in amounts similar to those of MCH in control extracts. In contrast, neuropeptide-Glu-Ile was more than 10 times less abundant than MCH in extracts from obese mice. Our data are consistent with a deficit in CpE activity affecting the maturation of both pro-NT and pro-MCH. This suggests that abnormal neuropeptide and hormone precursor processing is a general phenomenon in fat/fat mice and supports the idea that defects in the production of neuropeptide involved in the control of feeding might lead to the development of obesity in these animals.Keywords:
Melanin-concentrating hormone
A spontaneous point mutation in the coding region of the carboxypeptidase E (CPE) gene results in a loss of CPE activity that correlates with the development of late onset obesity (Nagert, J. K., Fricker, L. D., Varlamov, O., Nishina, P. M., Rouille, Y., Steiner, D. F., Carroll, R. J., Paigen, B. J., and Leiter, E. H. (1995) Nat. Genet. 10, 135–142). Examination of the level of neuropeptides in these mice showed a decrease in mature bioactive peptides as a result of a decrease in both carboxypeptidase and prohormone convertase activities. A defect in CPE is not expected to affect endoproteolytic processing. In this report we have addressed the mechanism of this unexpected finding by directly examining the expression of the major precursor processing endoproteases, prohormone convertases PC1 and PC2 in Cpe fat mice. We found that the levels of PC1 and PC2 are differentially altered in a number of brain regions and in the pituitary. Since these enzymes have been implicated in the generation of neuroendocrine peptides (dynorphin A-17, β-endorphin, and α- melanocyte-stimulating hormone) involved in the control of feeding behavior and body weight, we compared the levels of these peptides in Cpe fat and wild type animals. We found a marked increase in the level of dynorphin A-17, a decrease in the level of α-melanocyte-stimulating hormone, and an alteration in the level of C-terminally processed β-endorphin. These results suggest that the impairment in the level of these and other peptides involved in body weight regulation is mainly due to an alteration in carboxypeptidase and prohormone convertase activities and that this may lead to the development of obesity in these animals.
Prohormone convertase
Proprotein Convertases
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Secretogranin III (SgIII) and carboxypeptidase E (CPE) bind specifically to cholesterol-rich secretory granule (SG) membranes. We previously showed that SgIII binds chromogranin A (CgA) and targets CgA to the SGs in endocrine cells. We investigated the binding of SgIII and CPE because they frequently localize close to the periphery of SGs, and they bind each other in mouse corticotrope-derived AtT-20 cells. In Cpe fat mouse corticotropes, which have defective CPE, proopiomelanocortin (POMC)-derived adrenocorticotrophin hormone (ACTH)-containing peptides were distributed over the entire surface of the SGs, and displayed a regulated secretion by secretagogues. The Cpe fat pituitary exhibited elevated levels of SgIII and CgA, which suggests that they compensate for a sorting function of CPE for POMC and its intermediates to ACTH. Indeed, both SgIII and CgA were able to bind POMC-derived intermediates. In a competitive pull-down assay, excessive SgIII led to a decrease in CPE-bound POMC-derived intermediate molecules, and SgIII pulled-down by anti-ACTH antibody increased proportionately. We suggest that SgIII and CPE form the separate functional sorting complex by anchoring to cholesterol-rich SG membranes, and POMC-derived peptides are transferred from CPE to SgIII, and subsequently to CgA.
Proopiomelanocortin
Chromogranin A
Prohormone convertase
Corticotropic cell
Secretory Vesicle
Granule (geology)
Enteroendocrine cell
Secretory protein
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To study clinical significance of changes and ratio imbalance in neuropeptide Y(NPY) and neurotensin(NT) in patients with essential hypertension(EH),plasma concentration of NPY and NT in 298 patients with EH was measured by RIA.The results showed that NPY in patients with EH was markedly higher than that in the normal control group,especially in EH cases with stage Ⅲ. The NT values were significantly lower in EH cases as compared with those of the control group.The values of NT in EH patients with stage Ⅲ were lower than those in EH patients stage Ⅰ and/or Ⅱ.The increase of NPY and decrease of NT may be important factors in patients with EH.
Essential hypertension
Clinical Significance
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Abstract Peptides derived from proopiomelanocortin (POMC) are well-established neuropeptides and peptide hormones that perform multiple functions, including regulation of body weight. In humans and some animals, these peptides include α– and β–melanocyte-stimulating hormone (MSH). In certain rodent species, no β-MSH is produced from POMC because of a change in the cleavage site. Enzymes that convert POMC into MSH include prohormone convertases (PCs), carboxypeptidases (CPs), and peptidyl-α-amidating monooxygenase (PAM). Humans and mice with inactivating mutations in either PC1/3 or carboxypeptidase E (CPE) are obese, which was assumed to result from defective processing of POMC into MSH. However, recent studies have shown that selective loss of either PC1/3 or CPE in POMC-expressing cells does not cause obesity. These findings suggest that defects in POMC processing cannot alone account for the obesity observed in global PC1/3 or CPE mutants. We propose that obesity in animals lacking PC1/3 or CPE activity depends, at least in part, on deficient processing of peptides in non–POMC-expressing cells either in the brain and/or the periphery. Genetic background may also contribute to the manifestation of obesity.
Proopiomelanocortin
Proprotein Convertases
Prohormone convertase
Melanocyte-stimulating hormone
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Objective:To study significance of plasma nurotensin(NT) and neuropeptide(NPY) levels in essential hypertension(EH).Methods:By means of radioimmunoassay studied the changes of plasma neurotensin and neuropeptide Y in 60 cases.Results:Plasma NT and NPY of EHⅢ(135 8±17 4,170 2±27 4 all in pg/ml) were significantly higher than that control.Conclusion:Measured content of NT and NPY in essential hypertension may be helpful to diagnose hypertension and evaluate prognosis. Author′s address Sanming First Hospital,Sanming,Fujian province,365000
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Essential hypertension
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Melanin-concentrating hormone
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Abstract Recent evidence suggests that leptin reduces food intake (FI) by acting at the hypothalamic level. Leptin decreases hypothalamic neuropeptide Y (NPY), melanin-concentrating hormone (MCH) and galanin (GAL) gene expression in rats. The purpose of the present study was to test the hypothesis that leptin decreases FI by additionally modulating the action of NPY, MCH or GAL in the hypothalamus. Intracerebroventricular (icv) administration of NPY, MCH or GAL induced FI in satiated rats. A prior icv injection of leptin (4 μg) completely prevented the increase of FI either by MCH, GAL or NPY. These results suggest that modulation of post-synaptic actions of MCH, GAL and NPY is one of the mechanisms of leptin signaling in the hypothalamus.
Melanin-concentrating hormone
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Objective To study the effects of changes of neuropeptide Y(NPY) and neurotensin(NT) concentrations in plasma and their ratio imbalance on the incidence of essential hypertension (EH). Methods NPY and NT in plasma in 176 patients with EH were measured with radioimmunoassay(RIA). Results NPY in the EH patients was higher than that in the normal subjects (P0.01), and went up with the aggravation of the patients′ condition( P0.01).NT in the EH patients was lower compared with the normal subjects (P0.01), and went down with the aggravation of the patients′ condition ( P0.01). NPY/NT in the EH patients was higher than that in the normal subjects (P0.01), and was accordant with patients′ condition. Conclusion NPY and NT are involved in the incidence of EH.The ratio imbalance of NPY/NT may be one of the factors causing EH.
Essential hypertension
Clinical Significance
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Proinsulin
Furin
Cleavage (geology)
Proglucagon
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Neuropeptide Y (NPY) is a containing 36 amino acid residues peptides, extremely rich in human and other mammalian circulatory system. Neurotensin (NT) is a purification of bioactive peptide, widely distributed in the human heart and vascular. Recent numerous studies showed that NPY and NT took part in the regulation of cardiovascular function and the pathophysiology of cardiovascular disease by a variety of mechanisms, and closely related to with the development of hypertension. This article reviews the advancement in relationship between NPY, NT and Hypertension.
Pathophysiology
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