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PubMed1992

N-acetylation is required for the lactotrope recruitment activity of alpha-melanocyte-stimulating hormone and beta-endorphin.

Pituitary neurointermediate lobe (NIL) cells obtained from ovariectomized rats and exposed to 17 beta-estradiol in vitro have been shown to release an activity that induces acute recruitment of additional PRL-secreting cells. We have recently reported that alpha MSH, a major secretory product of the NIL, can substitute for this lactotrope-recruiting factor released by NIL cells in response to 17 beta-estradiol. beta-Endorphin (beta END) was not effective in this regard. Inasmuch as the degree of acetylation is critical to the activities of both of these molecules in other systems, we decided to assess its importance to lactotrope-recruiting activity in the present study. Anterior pituitary cells from ovariectomized rats were cultured overnight, exposed to various treatments for 3 h, and then subjected to a reverse hemolytic plaque assay for PRL. Exposure to mono- and diacetylated alpha MSH (N-ac-alpha MSH and di-ac-alpha MSH, respectively) or N-acetylated beta END (N-ac-beta END) caused a significant increase in the fraction of anterior pituitary cells that released PRL. In contrast, the Des-acetylated variants of both molecules had no lactotrope-recruiting activity. In a dose-response study, maximally effective doses of di-ac-alpha MSH and N-ac-beta END were equally effective with respect to their function as lactotrope-recruiting factors. Furthermore, the two peptides acted cooperatively when simultaneously applied in submaximal concentrations. Taken together, these results demonstrate that 1) N-acetylation is an essential requirement for the lactotrope-recruiting activity of alpha MSH and beta END in vitro; and 2) di-ac-alpha MSH and N-ac-beta END can act in a cooperative fashion to recruit additional cells into the PRL-secreting population.

Acetylation↗
PubMed1992

Neurointermediate lobe peptides recruit prolactin-secreting cells exclusively within the central region of the adenohypophysis.

There is strong evidence that the hypophyseal neurointermediate lobe (NIL) mediates 17 beta-estradiol (E2)-induced PRL secretion in rats. Our laboratory has previously demonstrated that E2 stimulates NIL cells to release an activity that acutely increases the relative abundance of PRL-releasing cells in anterior pituitary (AP) cell cultures. We later found that secretory products of the NIL melanotropes, specifically the acetylated forms of alpha MSH and beta-endorphin (beta END), can account for this activity. Given that blood from the NIL initially perfuses the region of the AP proximal to the NIL, we tested the hypothesis that this specific area was preferentially responsive to the lactotrope recruitment activities. AP glands from ovariectomized rats were dissected into an inner zone, proximal to the NIL, and the remaining outer zone of the gland, then dispersed with trypsin. The resulting cells were cultured for 16 h, either alone or in coculture with NIL cells, and subsequently treated with medium alone (control) or with alpha MSH, beta END, or E2 (all at 1 x 10(-7) M) for 3 h and then subjected to reverse hemolytic plaque assays for PRL release. Under control conditions, the proportion of PRL-secreting cells was significantly greater in cultures from the outer zone of the AP than in those from the corresponding inner zone of the gland. Treatment of AP cells from the inner zone with alpha MSH, beta END, or the E2-induced NIL activity significantly increased the percentage of PRL secretors by about 8% of all AP cells. In contrast, the fraction of PRL-secreting cells in cultures from the outer zone was not affected by these treatments. We conclude that the recruitment of PRL-secreting cells in response to products of the NIL occurs only in that region of the AP proximal to the NIL.

Animals↗
PubMed2026

Quantification of appetite-regulating hormones in children with hypothalamic and common obesity.

CONTEXT: The pathophysiology of hypothalamic obesity (HyOb) remains incompletely understood with no effective treatments. OBJECTIVE: We examined differences in appetite-regulating hormone concentrations between patients with HyOb, common obesity, and lean controls. DESIGN: Multiway cross-sectional case-control study of patients aged 2 through 19 years. SETTING: Two tertiary pediatric endocrinology centers. PATIENTS: Cases were obese (body mass index [BMI] > +2 SD score [SDS], "HyOb") and lean ("HyLean") patients with congenital (septo-optic dysplasia) or acquired (suprasellar brain tumor) hypothalamic disorders. Controls had common obesity ("Ob") or nonhypothalamic disorders and normal BMI ("Lean"). MAIN OUTCOME MEASURES: Relationships between the Dykens' Hyperphagia Questionnaire Score (DHQS), plasma or serum concentrations of leptin, insulin, α-melanocyte stimulating hormone (αMSH), brain-derived neurotrophic factor, oxytocin, acylated ghrelin, agouti-related peptide and copeptin, and BMI SDS. RESULTS: Dykens' Hyperphagia Questionnaire Score did not differ between HyOb and Ob patients (24 [17-34] vs 24 [18-31]) but correlated with BMI SDS in patients with hypothalamic disorders (P = 0.02). HyOb and Ob patients exhibited similarly increased anorexigens (insulin, leptin) and decreased orexigens (ghrelin, agouti-related peptide) compared to HyLean and Lean patients. The rate of BMI increase was independently associated with lower αMSH (β = -0.23 [-0.36 to -0.11], P = .0007) and ghrelin (β=-0.004 [-0.01 to 0.00], P = .001) concentrations, suggesting that αMSH replacement may be a therapeutic target for HyOb. HyLean patients demonstrated intermediate insulin responses to glucose compared to other subcohorts. CONCLUSION: In our cohort, patients with HyOb appeared indistinguishable from Ob in terms of their appetite and appetite-regulating neuroendocrine circuitry. Higher αMSH concentrations are associated with reduced weight gain and may be a target for therapeutic intervention.

alpha-MSH↗
PubMed1989

The immature type of pro-opiomelanocortin cell of the rat anterior pituitary as observed by immunogold electron microscopy.

The perinatal development of glandular cells in the rat anterior pituitary producing pro-opiomelanocortin (POMC), the precursor protein of peptide hormones including adrenocorticotropin (ACTH), melanocyte-stimulating hormones (MSH) and endorphins was studied by an immunoelectron microscopic technique using the colloidal gold-antibody method. The POMC cells are classified into the following three types: 1) an immature type, 2) an intermediate type, and 3) a mature type, which correspond to Types III, I and II of the ACTH cells, respectively. The average size of the secretory granules in POMC cells varies widely, measuring 98.6 +/- 8.5 nm in the immature type, 111.4 +/- 6.7 nm in the intermediate type, and 139.3 +/- 23.1 nm in the mature type. The immature type comprises more than 90% of the POMC cells in the late fetal stage, but decreases in number after birth. The intermediate type reaches a peak at 8 days (female) or 33 days (male), while the mature type is that most frequently observed at 45 days, i.e., more than 50-60% of the total POMC cells, when the immature type decreases to about 15%.

Adrenocorticotropic Hormone↗
PubMed1992

Erythropoietin treatment and plasma levels of corticotropin-releasing hormone, delta sleep-inducing peptide and opioid peptides in hemodialysis patients.

An improvement of quality of life and objective brain function has been reported in patients receiving regular hemodialysis treatment (RDT) during treatment with recombinant human erythropoietin (r-huEPO). The mechanisms explaining this improvement are unknown. In this study the plasma levels of peptides known to be involved in CNS functions, namely corticotropin-releasing hormone, delta sleep-inducing peptide, beta-endorphin, methionine-enkephalin, beta-lipotropin and alpha-melanocyte-stimulating hormone, were measured by radioimmunoassay in seven stable RDT patients before the start of r-huEPO therapy and during 28 weeks' treatment. All patients responded with significantly increased hemoglobin concentrations. An improvement of well-being, state of mood and physical fitness was reported by the patients. There were no significant changes during the study in the plasma concentrations of any of the peptides measured. However, as the plasma levels of neuropeptides will not necessarily reflect the local concentrations in the vicinity of the nerve terminals, changes in the intracerebral concentrations of these peptides might occur in response to r-huEPO.

Adult↗
PubMed1991

Quantification of MSH receptors on mouse melanoma tissue by receptor autoradiography.

MSH receptors on mouse melanoma tissue sections were quantified by receptor autoradiography, yielding results which were very similar to those obtained by a conventional receptor binding assay with isolated cells. In order to minimize non-specific binding, it proved to be crucial to use a radioactive monoiodinated MSH radioligand retaining full biological activity and to apply the binding conditions developed for isolated cells to the incubation of whole tissue sections. The displacement curves obtained after quantitative analysis of autoradiograms from tissue sections yielded a KD-value of the same order of magnitude (0.58 nM; average of n = 7 experiments) as those obtained in the normal binding assay with isolated cells (1.2 nM; average of n = 10 experiments). Similarly, receptor numbers per cell on tissue sections (14,700; n = 7) did not differ markedly from those determined with isolated cells (10,500; n = 10). These results demonstrate that receptor autoradiography can be applied to the quantification of peptide hormone receptors on peripheral tissues.

Animals↗
PubMed1992

Demonstration of coexisting catecholamine (dopamine), amino acid (GABA), and peptide (NPY) involved in inhibition of melanotrope cell activity in Xenopus laevis: a quantitative ultrastructural, freeze-substitution immunocytochemical study.

This quantitative ultrastructural immunocytochemical study demonstrates the coexistence of a catecholamine [dopamine (DA)], an amino acid (GABA), and a neuropeptide [neuropeptide Y (NPY)] in axon varicosities innervating the pars intermedia of Xenopus laevis. The varicosities are assumed to control the pars intermedia melanotrope cells, which regulate skin color during the physiological process of background adaptation. Varicosity profiles appear to abut melanotrope cells and folliculostellate cells, star-shaped cells that intimately contact the melanotropes. All varicosity profiles contain two morphological types of vesicle. Monolabeling studies on routinely fixed and freeze-substituted tissues showed that the small, electron-lucent vesicles store GABA, whereas DA and NPY occur in larger, electron-dense ones. Double and triple labeling experiments, in which the degree of immunoreactivity was quantified per varicosity profile and per vesicle, led to the conclusion that (1) DA, GABA, and NPY coexist within almost all varicosity profiles and (2) DA and NPY are costored within electron-dense vesicles. Varicosity profiles that about melanotrope cells show a much higher ratio between the numbers of electron-lucent and electron-dense vesicles than varicosities contacting folliculostellate cells (15.8 and 3.3, respectively). This differential distribution is in line with the previous demonstration that, in contrast to GABA, NPY does not act directly on the melanotrope cells but indirectly, by controlling the activity of the folliculostellate cells.

Animals↗
PubMed1992

Processing of adrenocorticotropin by two proteases in bovine intermediate lobe secretory vesicle membranes. A distinct acidic, tetrabasic residue-specific calcium-activated serine protease and a PC2-like enzyme.

Adrenocorticotropin (ACTH) is cleaved at the tetrabasic residue site, in pituitary intermediate lobe secretory vesicles, to yield ACTH1-17 and corticotropin-like intermediate lobe peptide (CLIP). ACTH1-17 is then converted to alpha-melanocyte-stimulating hormone (N-AcACTH1-13NH2) by first removing the Lys15-Lys16-Arg17 residues, followed by amidation of the COOH terminus and acetylation of the NH2 terminus. Bovine intermediate lobe secretory vesicle membranes were screened for proteolytic enzyme activity that will cleave the tetrabasic residues of ACTH. Two activities with pH optima of 5.0-6.0 and 7.5-8.0 were detected. The acidic, ACTH-converting enzyme cleaved ACTH1-39 at the tetrabasic residues between the Arg17-Arg18 bond to yield ACTH1-17 and CLIP, but did not cleave paired basic residues of pro-opiomelanocortin. This enzyme activity was characterized as a Ca(2+)-activated serine protease with unique specificity for the tetrabasic residues of ACTH1-39. The neutral activity preferentially generated ACTH1-17 and to a small extent ACTH1-16 from ACTH1-39 and ACTH1-24. This enzyme activity was Ca(2+)-dependent but was not inhibited by serine or aspartic protease inhibitors. The neutral activity was significantly immunodepleted by antiserum raised against bovine PC2/PC3, and together with specificity studies, suggests that the enzyme is a PC2-like serine protease. The pH optimum, distinct specificity for tetrabasic residues, and subcellular localization of the acidic ACTH-converting enzyme indicate a function of this enzyme in the in vivo conversion of ACTH1-39 to alpha-melanocyte-stimulating hormone in intermediate lobe secretory vesicles which have an acidic internal pH.

Adrenocorticotropic Hormone↗
PubMed1992

Effects of synthetic ovine corticotropin-releasing hormone on plasma concentrations of immunoreactive adrenocorticotropin, alpha-melanocyte-stimulating hormone, and cortisol in dogs with naturally acquired adrenocortical insufficiency.

We evaluated the effect of ovine corticotropin-releasing hormone (CRH) on plasma immunoreactive (IR) concentrations of ACTH, alpha-melanocyte-stimulating hormone, and cortisol in 8 dogs with naturally acquired adrenocortical insufficiency. Of the 7 dogs with primary adrenal insufficiency, 6 had markedly high basal plasma IR-ACTH concentrations and exaggerated ACTH responses to CRH administration, whereas 1 dog that was receiving replacement doses of prednisone at the time of testing had normal basal IR-ACTH concentrations and a nearly normal response to CRH. In contrast, the 1 dog with secondary adrenocortical insufficiency had undetectable basal plasma IR-ACTH concentrations, which failed to increase after administration of CRH. Basal plasma alpha-melanocyte-stimulating hormone concentrations in the dogs with adrenal insufficiency were within normal range and were unaffected by CRH administration. In all 8 dogs with adrenal insufficiency, plasma cortisol concentrations were low and did not increase after administration of CRH. Therefore, stimulation with CRH produced 2 patterns of plasma IR-ACTH response when administered to dogs with naturally acquired adrenal insufficiency. Dogs with primary adrenal insufficiency had high basal plasma IR-ACTH concentrations and exaggerated responses to CRH, whereas the dog with secondary adrenal insufficiency had undetectable basal plasma concentrations of IR-ACTH that did not increase after stimulation with CRH.

Adrenal Cortex Hormones↗
PubMed1992

Effects of temperature and neuroactive substances on hypothalamic neurones in vitro: possible implications for the induction of fever.

This paper reviews some of our findings which have shown the usefulness of in vitro methods in the study of hypothalamic neurones. (1) Membrane current analyses of dispersed neurones of the rat preoptic and anterior hypothalamus (POA) during thermal stimulation have revealed that warm-sensitive neurones are endowed with a non-inactivating Na+ channel having a high Q10 in the hyperthermic range (35-41 degrees C). (2) A brain slice study has shown that neurones in the organum vasculosum lamina terminalis (OVLT) region have much higher sensitivity to PGE2 than POA neurones. This provides further evidence of a critical role of the OVLT in translation of blood-borne cytokine signals into brain signals for fever induction. (3) Local application of IL-1 beta and IFN alpha altered the activity of thermosensitive (TS) neurones and glucose responsive (GR) neurones in vitro in an appropriate way to produce fever and anorexia. While the responses to IL-1 beta required the local release of prostaglandins, the responses to IFN alpha were found to be mediated by opioid receptor mechanisms. (4) The responses of POA TS neurones and VMH GR neurones to IL-1 beta but not those to IFN alpha, were reversibly blocked by alpha MSH, an endogenous antipyretic peptide. Thus, immune cytokines and their related neuroactive substances may affect hypothalamic TS and GR neurones thereby producing elaborately regulated changes in homeostatic functions such as thermoregulation (fever) and feeding (anorexia), which are considered as host defence responses.

Animals↗
PubMed1991

Phencyclidine increased release of beta-endorphin from anterior lobe of the pituitary.

Phencyclidine (PCP) has been found to affect neuroendocrine function by altering the release of the anterior pituitary hormones, adrenocorticotrophin, luteinizing hormone and prolactin. The purpose of this study was to examine the effect of PCP on release of the two pituitary hormones also derived from the adrenocorticotropin precursor, namely, alpha-melanocyte-stimulating hormone and beta-endorphin (beta-E), synthesized in the neurointermediate and anterior lobes of the pituitary. At behaviorally active doses, PCP administered i.c.v. increased plasma levels of immunoreactive beta-E (i beta-E) without affecting the concentration of immunoreactive alpha-melanocyte-stimulating hormone, suggesting that PCP increased the release of beta-E from only the anterior lobe of the pituitary. Dexamethasone pretreatment blocked the PCP-induced increase in i beta-E which indicated further the anterior lobe effects of PCP. MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine maleate), a selective PCP ligand, at behaviorally active doses also increased the plasma concentration of i beta-E. The dose-response curves for induction of behavior was very different from that for increasing the concentration of i beta-E in plasma. The increase in release of i beta-E was stereoselective as (+)-(1-(1-phenylcyclohexyl)-3 methylpiperidine but not (-)-(1-(1-phenylcyclohexyl)-3 methylpiperidine increased release of i beta-E. The increase in plasma levels of beta-E was not due to an interaction with opioid receptors because naloxone did not block PCP-induced release of beta-E. In vitro, PCP also significantly increased release of i beta-E from anterior lobe of the pituitary.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Induction of skin tanning by subcutaneous administration of a potent synthetic melanotropin.

UNLABELLED: OBJECTIVE--To determine the efficacy of short-term administration of a synthetic analogue of alpha-melanotropin, [Nle4D-Phe7] (NDP)-alpha-melanocyte-stimulating hormone (MSH), in darkening (tanning) human skin. DESIGN--Randomized, placebo-controlled, double-blind clinical trial. SETTING--Clinical research unit of a university medical center. SUBJECTS--Twenty-eight healthy white men with a history of either poor tanning (skin type I or II) or good tanning (skin type III or IV) recruited from advertisements and paid to participate in the study. METHODS--Each subject received 10 subcutaneous injections of either a purified NDP preparation or saline over 12 days. They were followed up for 7 weeks after therapy was completed. All subjects used a high-potency sunscreen during the trial. MAIN OUTCOME MEASURE--Skin darkening was quantified by serial chromaticity measurements prior to, during, and after therapy. RESULTS: -A significant parabolic curve of skin darkening activity was noted in subjects with skin type I or II (P less than .001) and with skin type III or IV (P much less than .001) who were given NDP. No darkening occurred in the subjects who were given a placebo. Peak changes were seen 1 to 3 weeks after therapy was completed. CONCLUSION--Human skin darkens as a response to a synthetic melanotropin given by subcutaneous injection. Skin tanning appears possible without potentially harmful exposure to ultraviolet radiation.

Adult↗
PubMedDate not supplied

Acute and chronic effects of diethylstilbestrol on serum levels of alpha melanocyte stimulating hormone and prolactin in the hamster.

Continuous exposure to diethylstilbestrol (DES) induces renal tumors in male hamsters. The tumor formation is preceded by an increase in pituitary weight and elevation of the pituitary hormones-alpha melanocyte stimulating hormone (aMSH) and prolactin (Pr1). A decline in Pr1 (to normal levels) but not aMSH then accompanies the development of tumors and the enlargement of the intermediate lobe of the pituitary. Hypophysectomy, castration and thymectomy reduced serum levels of aMSH. DES administered for one week increased the serum levels of both hormones in normal and castrated animals, but not in hypophysectomized hamsters.

Adenocarcinoma↗
PubMed1989

Modulation of IL-1, tumor necrosis factor, and C5a-mediated murine neutrophil migration by alpha-melanocyte-stimulating hormone.

This study was designed to examine the effects of i.p.-injected alpha-melanocyte stimulating hormone (MSH) on murine neutrophil migration into subcutaneously implanted sponges in response to IL-1-alpha, TNF-alpha, and C5a. The results show that as little as 0.1 ml of 5 x 10(-7) M MSH injected i.p. significantly blocked the accumulation of neutrophils in sponges in response to IL-1. This action of MSH was dose dependent, reversible, and was maximally effective if MSH was given at the same time as the injection of IL-1. This effect of MSH was not restricted to IL-1-induced neutrophil emigration, because MSH also antagonized the accumulation of neutrophils in response to both TNF and C5a. The proopiomelanocortin-derived peptide ACTH which contains the MSH sequence also significantly reduced neutrophil accumulation in response to IL-1, although less effectively than MSH. Similar studies with beta-endorphin showed that it had no effect on neutrophil accumulation in this system. The direct injection of MSH, beta-endorphin and ACTH into sponges or i.p. did not stimulate a neutrophil emigration and eliminated the possibility that MSH or ACTH suppressed the neutrophil influx in response to IL-1, TNF, or C5a by competing for circulating neutrophils. The action of MSH on IL-1, TNF, and C5a-induced neutrophil emigration suggests that this peptide may be an important regulator of the inflammatory response.

Adrenocorticotropic Hormone↗
PubMedDate not supplied

Pro-opiomelanocortin-derived peptides in transected and contralateral motor nerves of the rat.

An immunocytochemical method was used to reveal beta-endorphin and alpha-melanotropin peptides in nerve profiles at the neuromuscular junctions in the soleus and extensor digitorum longus muscles of the adult rat. After unilateral section of the sciatic nerve, the proportion of endplates with immunoreactive nerve profiles increased in the denervated muscles even after the axonal material in the distal nerve segments had degenerated. When the nerve was sectioned in the mid-thigh region the proportion of immunoreactive endplates increased with time up to 24-36 h after the nerve section and then eventually declined. The incidence of immunoreactive nerve profiles also increased in the proximal stump. After unilateral sciatic nerve section there was also an increase in the incidence of immunoreactive endplates in the contralateral muscles. The increases in the contralateral muscles could be detected at an earlier time if the nerve was sectioned closer to the spinal cord. The possibility is discussed that the expression of pro-opiomelanocortin peptides in the motor nerves is tonically suppressed in the normal adult but the inhibition is released after section of the nerve. The findings indicate that a signal is transferred from the site of injury in the transected nerves to the motor nerves of the contralateral limb via a transneuronal mechanism through the spinal cord.

Adrenocorticotropic Hormone↗
PubMed1989

[Cloning and sequence analysis of cDNA of common precursors of three hypothalamic neuropeptides immunologically related to human somatocrinin 1-37, alpha melanotropin and salmon melanin-concentrating hormone].

We have cloned and sequenced DNAs complementary to the mRNA encoding the precursor of the rat melanin-concentrating hormone. This allowed us to elucidate the primary structure of the 96 C-terminal residues of this precursor. It contains three possible sites for enzymatic cleavage enabling the generation of MCH and of two additional neuropeptides. These three peptides can bind one of our antisera raised against human somatocrinin 1-37, alpha-melanotropin and salmon melanin-concentrating hormone, which immunocytochemically stain the same neuron population in the hypothalamus.

Amino Acid Sequence↗