Localization of α-Melanocyte-Stimulating Hormone in Rat Brain and Pituitary

Dubé, Donald; Lissitzky, Jean‐Claude; Leclerc, Rachel; Pelletier, Georges

doi:10.1210/endo-102-4-1283

Cited by 161 publications

(34 citation statements)

References 14 publications

(14 reference statements)

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“…These data are consistent with previous light microscopic findings that ACTH, also a post-translational cleavage product of POMC, is contained in axons adjacent to TRH neurons in the PVN (Liao et al, 1991). Although ␣-MSH is synthesized in two regions within the brain, the arcuate nucleus and the nucleus tractus solitarius (Dube et al, 1978;Joseph et al, 1983), the arcuate nucleus is probably the only source of ␣-MSHcontaining fibers in the PVN. Deafferentation of the mediobasal hypothalamus that separates the arcuate nucleus from the rest of the brain results in marked depletion of ␣-MSH in the dorsal hypothalamus (Eskay et al, 1979), whereas nearly half of the POMC-synthesizing neurons in the arcuate nucleus are labeled by the retrograde transport of marker substances injected into the PVN (Sawchenko et al, 1982).…”

Section: Discussionsupporting

confidence: 92%

α-Melanocyte-Stimulating Hormone Is Contained in Nerve Terminals Innervating Thyrotropin-Releasing Hormone-Synthesizing Neurons in the Hypothalamic Paraventricular Nucleus and Prevents Fasting-Induced Suppression of Prothyrotropin-Releasing Hormone Gene Expression

et al. 2000

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The hypothalamic arcuate nucleus has an essential role in mediating the homeostatic responses of the thyroid axis to fasting by altering the sensitivity of prothyrotropin-releasing hormone (pro-TRH) gene expression in the paraventricular nucleus (PVN) to feedback regulation by thyroid hormone. Because agouti-related protein (AGRP), a leptin-regulated, arcuate nucleus-derived peptide with ␣-MSH antagonist activity, is contained in axon terminals that terminate on TRH neurons in the PVN, we raised the possibility that ␣-MSH may also participate in the mechanism by which leptin influences pro-TRH gene expression. By double-labeling immunocytochemistry, ␣-MSH-IR axon varicosities were juxtaposed to ϳ70% of pro-TRH neurons in the anterior and periventricular parvocellular subdivisions of the PVN and to 34% of pro-TRH neurons in the medial parvocellular subdivision, establishing synaptic contacts both on the cell soma and dendrites. All pro-TRH neurons receiving contacts by ␣-MSH-containing fibers also were innervated by axons containing AGRP. The intracerebroventricular infusion of 300 ng of ␣-MSH every 6 hr for 3 d prevented fasting-induced suppression of pro-TRH in the PVN but had no effect on AGRP mRNA in the arcuate nucleus. ␣-MSH also increased circulating levels of free thyroxine (T4) 2.5-fold over the levels in fasted controls, but free T4 did not reach the levels in fed controls. These data suggest that ␣-MSH has an important role in the activation of pro-TRH gene expression in hypophysiotropic neurons via either a mono-and/or multisynaptic pathway to the PVN, but factors in addition to ␣-MSH also contribute to the mechanism by which leptin administration restores thyroid hormone levels to normal in fasted animals.

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Section: Discussionsupporting

confidence: 92%

α-Melanocyte-Stimulating Hormone Is Contained in Nerve Terminals Innervating Thyrotropin-Releasing Hormone-Synthesizing Neurons in the Hypothalamic Paraventricular Nucleus and Prevents Fasting-Induced Suppression of Prothyrotropin-Releasing Hormone Gene Expression

et al. 2000

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“…7), both of which are known to represent the most abundant POMC-derived peptides in the AP. Even though some VEnd was detected in the AP, it is interesting that no significant production of aMSH was found (22). Therefore, it is possible that in the AP, PC1 is the convertase responsible for the minor /3End production.…”

Section: Discussionmentioning

confidence: 96%

PC1 and PC2 are proprotein convertases capable of cleaving proopiomelanocortin at distinct pairs of basic residues.

Benjannet

Rondeau

Day

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

568

371

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A recombinant vaccinia virus vector was used to coexpress the two candidate mouse prohormone convertases, PC1 and PC2, together with mouse proopiomelanocortin (POMC) in the constitutively secreting cell line BSC-40 and in the endocrine tissue-derived cell lines PC12 and AtT-20, which exhibit regulated secretion. Monitoring of POMC processing demonstrated the distinct cleavage specificities of PCi and PC2, since in the cell lines analyzed (i) PCi cleaves POMC into corticotropin and fB-lipotropin, (ii) PC2 cleaves POMC into (3-endorphin, an N-terminally extended corticotropin containing the joining peptide, and either aMSH or desacetyl-aMSH, and (iii) PC2 cleaves POMC at the five pairs of basic residues analyzed, whereas PC1 cleaves two of them preferentially, suggesting that PC2 has a broader spectrum of activity than PC1. These data are consistent with our hypothesis on the physiological role of PCi and PC2 as distinct proprotein convertases acting alone or together to produce a set of tissuespecific maturation products in the brain and in peripheral tissues.Limited proteolysis of inactive precursors at pairs of basic residues or, less frequently, at single basic amino acids (1, 2) is a general mechanism by which the cell produces a variety of active proteins and peptides. Until recently, the molecular nature of the processing enzyme(s) was not identified except for the yeast pro-a mating factor precursor, where a subtilisin-like serine proteinase called KEX2 was proven to be the physiological convertase (3). In the last year, different groups obtained the complete cDNA structures of three distinct candidate mammalian convertases, furin (4), PC1 (5, 6), and PC2 (5, 7). The putative convertase function of these proteins was largely based on sequence homology with KEX2 (8, 9) and on their tissue and cellular distribution, especially for PC1 and PC2 (5, 6). Here we show that the expression of PC1 or PC2 by vaccinia virus (VV) recombinants results in the production of distinct proteolytic enzymes in three cell lines: the mouse pituitary corticotroph line AtT-20 and two that do not express these enzymes endogenously, the African green monkey kidney epithelial cell line BSC-40 and the rat pheochromocytoma cell line PC12. These proteinases cleave proopiomelanocortin (POMC) into the same set of distinct peptides known to be produced in vivo in the hypothalamus, adenohypophysis (AP), and pars intermedia of the pituitary, including adrenocorticotropin (ACTH), p-lipotropin (,8LPH), ,f-endorphin (f3End), and a-melanotropin (aMSH) or desacetyl-aMSH.MATERIALS AND METHODS Ws. Purified recombinant VVs using the full-length mouse (i) PC1 and mPC2 cDNA inserts (5, 6) (VV:mPC1 and VV:mPC2) were prepared as described (10). VV:POMC (mouse) was a gift of G. Thomas (Vollum Institute, Portland, OR).Northern Blot Analysis. Total RNA was prepared as described (11). The [a-32P]UTP-labeled cRNA probes were generated from cDNA sequences of mPC1 (6) and mPC2 (5) inserted in plasmid Rc/CMV vector (Invitrogen, San Diego) and linearized...

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“…POMC neurons in the ARC are known to be primary recipients of circulating nutritional information, and their output to the PVN via the MC4-R can strongly inhibit food intake (53). These neurons project to feeding-related areas of the CNS, including the PVN (11). Although melanocortin receptors are expressed in a number of distinct regions in the CNS that could mediate the effects of ␣-MSH on energy balance, there is substantial evidence to implicate the hypothalamic PVN as a major center for the action of the MC signaling system on the regulation of appetite and satiety.…”

Section: Discussionmentioning

confidence: 99%

Aminoprocalcitonin-mediated suppression of feeding involves the hypothalamic melanocortin system

Tavares

Maldonado

Miñano

2013

American Journal of Physiology-Endocrinology and Metabolism

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Tavares E, Maldonado R, Miñano FJ. Aminoprocalcitonin-mediated suppression of feeding involves the hypothalamic melanocortin system. Am J Physiol Endocrinol Metab 304: E1251-E1262, 2013. First published April 9, 2013; doi:10.1152/ajpendo.00590.2012, a neuroendocrine peptide encoded by the calcitonin-I (CALC-I) gene, suppresses food intake when administered centrally in rats. However, the neural pathways underlying this effect remain unclear. N-PCT and calcitonin receptors (CT-R) have been identified in hypothalamic regions involved in energy homeostasis, including the arcuate nucleus (ARC). Here, we hypothesized an involvement of the hypothalamic ARC in mediating the anorexic effects of central N-PCT based on its content of peptidergic neurons involved in feeding and its expression of N-PCT and CT-R. Fasting strongly reduced expression of the N-PCT precursor gene CALC-I in the ARC, and central immunoneutralization of endogenous N-PCT increased food intake. Intracerebroventricular administration of N-PCT reduced food intake in fed and fasted rats, and its effect was attenuated by a neutralizing anti-N-PCT antibody. Immunohistochemistry for N-PCT showed that it is expressed in astrocytes and neurons in the ARC and is colocalized with anorexigenic proopiomelanocortin (POMC) neurons. Fasting reduced coexpression of N-PCT and POMC, and N-PCT administration activated hypothalamic neurons, including rostral POMC neurons. We also found that N-PCT stimulates POMC mRNA expression in fed and fasted rats, whereas it reduced the expression of orexigenic peptides neuropeptide Y (NPY) and agouti-related peptide (AgRP) only in fasted rats in which those mRNAs are normally elevated. Finally, we showed that the melanocortin-3/4 receptor antagonist SHU 9119 attenuates the intake-suppressive effect of N-PCT. These data demonstrate that hypothalamic N-PCT is involved in control of energy balance and that its anorexigenic effects are mediated through the melanocortin system. food intake; aminoprocalcitonin; arcuate nucleus; melanocortin system; proopiomelanocortin; neuropeptide Y AMINOPROCALCITONIN (N-PCT) was originally described as a 57-amino acid neuroendocrine peptide derived from the aminoterminal half of rat prohormone procalcitonin with bone cell mitogenic properties (6, 7). N-PCT derives from the calcitonin-I gene (CALC-I), which is localized in chromosome 11 (21, 50), a chromosome associated with body metabolism and obesity in humans (8). N-PCT, a highly conserved amino acid peptide with Ͼ85% amino acid identity in human and rodents (41), belongs to the calcitonin (CT) peptide family, which is made up by CT, CT gene-related peptide (CGRP), amylin, adrenomedullin, intermedin, and CT receptor-stimulating protein (3). These peptides function as ligands for a complex family of G protein-coupled receptors consisting of the CT receptor (CT-R), CT receptor-like receptor, and three receptorassociated modified proteins (40). CALC-I gene products and their receptors are widely distributed in the central nervous system (CNS), and sever...

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Localization of α-Melanocyte-Stimulating Hormone in Rat Brain and Pituitary

Cited by 161 publications

References 14 publications

α-Melanocyte-Stimulating Hormone Is Contained in Nerve Terminals Innervating Thyrotropin-Releasing Hormone-Synthesizing Neurons in the Hypothalamic Paraventricular Nucleus and Prevents Fasting-Induced Suppression of Prothyrotropin-Releasing Hormone Gene Expression

α-Melanocyte-Stimulating Hormone Is Contained in Nerve Terminals Innervating Thyrotropin-Releasing Hormone-Synthesizing Neurons in the Hypothalamic Paraventricular Nucleus and Prevents Fasting-Induced Suppression of Prothyrotropin-Releasing Hormone Gene Expression

PC1 and PC2 are proprotein convertases capable of cleaving proopiomelanocortin at distinct pairs of basic residues.

Aminoprocalcitonin-mediated suppression of feeding involves the hypothalamic melanocortin system

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