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PubMed2002

Ups and downs for neuropeptides in body weight homeostasis: pharmacological potential of cocaine amphetamine regulated transcript and pre-proglucagon-derived peptides.

Although most humans experience an underlying upwards drift of the body-weight set-point, body weight appears tightly regulated throughout life. The present review describes the structural basis of the adipostat and hypothesise, which components may constitute available targets for pharmacotherapy of excess body weight. Hypothalamic neurones constitute the major components of the body weight homeostasis maintaining device. Together with neurones of the nucleus of the solitary tract, neurones of the hypothalamic arcuate nucleus constitute the sensory components of the adipostat. The arcuate nucleus neurones respond to circulating levels of leptin and insulin, both of which reflect the levels of energy stored as triacylglycerol in adipocytes. The arcuate nucleus projects heavily to the hypothalamic paraventricular nucleus. Neurones of the hypothalamic paraventricular nucleus are hypothesised to constitute, at least partly, the adipostat motor pattern generator, which upon stimulation activates either net anabolic or catabolic physiological responses. The overall sensitivity of the adipostat is influenced by gain setting neurones hypothesised to be located in the dorsomedial hypothalamic nucleus and lateral hypothalamic area. Cocaine amphetamine regulated transcript (CART) peptides and pre-proglucagon derived peptides, glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are catabolic neurotransmitters synthesised in neurones of the arcuate nucleus and the nucleus of the solitary tract, respectively. The present review summarises the available evidence that both families of peptides constitute endogenous transmitters mediating satiety and touch upon potential pharmacological exploitation of this knowledge.

Adipose Tissue↗
PubMed1979

Identification and processing of proglucagon in pancreatic islets.

Immunoprecipitation and tryptic peptide analysis of newly synthesized proteins from rat islets have identified an 18,000 molecular weight (MW) protein as proglucagon. Conversion of this precursor was kinetically similar to the conversion of proinsulin and resulted in the formation of both pancreatic glucagon and a 10,000-MW protein lacking this hormonal sequence.

Animals↗
PubMed1973

Isolation of a glucagon-containing peptide: primary structure of a possible fragment of proglucagon.

The heterogeneity of crystalline bovine (ox)/porcine glucagon has been examined by gel filtration and ion-exchange chromatography. A strongly basic peptide that reacted well with antibodies to bovine/porcine glucagon was isolated and its primary structure was determined. The amino-acid sequence of the NH(2)-terminal 29 residues of the 4500-dalton peptide is identical with that of intact bovine or porcine glucagon. The remaining eight residues at its COOH-terminus are Lys-Arg-Asn-Asn-Lys-Asn-Ile-Ala. Small amounts of other glucagon-immunoreactive peptides having molecular weights ranging from 3700 to 9000 were also detected in crystals of bovine/porcine glucagon. We propose that the 37-residue peptide is a fragment of bovine or porcine proglucagon.

Amino Acid Sequence↗
PubMed1977

Studies on proinsulin and proglucagon biosynthesis and conversion at the subcellular level. I. Fractionation procedure and characterization of the subcellular fractions.

Anglerfish islets were homogenized in 0.25 M sucrose and separated into seven separate subcellular fractions by differential and discontinuous density gradient centrifugation. The objective was to isolate microsomes and secretory granules in a highly purified state. The fractions were characterized by electron microscopy and chemical analyses. Each fraction was assayed for its content of protein, RNA, DNA, immunoreactive insulin (IRI), and immunoreactive glucagon (IRG). Ultrastructural examination showed that two of the seven subcellular fractions contain primarily mitochondria, and that two others consist almost exclusively of secretory granules. A fifth fraction contains rough and smooth microsomal vesicles. The remaining two fractions are the cell supernate and the nuclei and cell debris. The content of DNA and RNA in all fractions is consistent with the observed ultrastructure. More than 82 percent of the total cellular IRI and 89(percent) of the total cellular IRG are found in the fractions of secretory granules. The combined fractions of secretory granules and microsomes consistently yield >93 percent of the total IRG. These results indicate that the fractionation procedure employed yields fractions of microsomes and secretory granules that contain nearly all the immunoassayable insulin and glucagons found in whole islet tissue. These fractions are thus considered suitable for study of proinsulin and proglucagon biosynthesis and their metabolic conversion at the subcellular level.

Animals↗
PubMed1975

Evidence of sequential metabolic cleavage of proglucagon to glucagon in glucagon biosynthesis.

Following a 30 min preincubation in medium containing no isotopes, anglerfish islet tissue was incubated in the presence of [3H]tryptophan and [14C]isoleucine for 20 min. A portion of the tissue was removed for immediate extraction. The remainder was washed thoroughly with unlabeled medium and post-incubated in medium containing an excess of unlabeled tryptophan and isoleucine for varying periods of time. The distribution of radioactive proteins in alcoholic tissue extracts was analyzed by gel filtration and polyacrylamide gel electrophoresis. The distribution of immunoreactive glucagon was determined by radioimmunoassay. Following the 20 min pulse incubation, only proinsulin was labeled with [14C]isoleucine. Two glucagon immunoreactive molecules, one larger than proinsulin (mol wt near 11,400) and the other slightly smaller than proinsulin (mol wt near 9,000), were the primary proteins labeled with [3H]tryptophan following the 20 min. pulse. During chase incubations of increasing duration, 3H-radioactivity appeared in a glucagon immunoreactive molecule with the approximate molecular size of glucagon and increased with chase time while radioactivity in the 11,400 mol wt tryptophan-labeled molecule decreased. With increasing chase time, the 3H-radioactivity attributable to the 9,000 mol wt tryptophan-labeled molecule initially increased and subsequently decreased which is consistent with the pattern that would be expected for a conversion intermediate. The presence of glucagon immunoreactivity in [3H]tryptophan-labeled molecules having molecular weights near that of proinsulin was established by radioimmunoassay of alternate gel slices following electrophoresis of labeled proteins recovered from the proinsulin containing portions of gel filtration eluates. That [14C]isoleucine became incorporated into insulin and [3H]tryptophan became incorporated into glucagon was established by determination of the distribution of radioactivity in polyacrylamide gels following electrophoresis of labeled proteins recovered from the insulin and glucagon containing portions of gel filtration eluates. These results provide preliminary evidence for sequential metabolic cleavage of proglucagon in glucagon biosynthesis.

Animals↗
PubMed1993

Regulation of intestinal proglucagon-derived peptide secretion by glucose-dependent insulinotropic peptide in a novel enteroendocrine loop.

Incretins are intestinal factors that stimulate postprandial insulin secretion in preparation for subsequent rises in plasma levels of ingested nutrients. Glucose-dependent insulinotropic peptide (GIP), a duodenal endocrine peptide, is ideally located for such a function. In contrast, the intestinal proglucagon-derived peptide (PGDP), truncated GLP-1 [GLP-1(7-37) or tGLP-1] is equipotent to GIP in insulinotropic activity, but due to its localization in the distal ileum, appears to be poorly situated to fulfill an incretin role in response to direct nutrient stimulation. Despite its distribution, rapid increments in plasma levels of tGLP-1 have been noted in response to nutrient ingestion. We have recently reported that GIP (but not other nutrient-stimulated duodenal endocrine peptides) can stimulate intestinal PGDP secretion in vitro, and therefore hypothesized that GIP might regulate secretion of the intestinal PGDPs, including tGLP-1, in response to nutrient ingestion in vivo in the rat. Placement of either fat or glucose directly into the ileal lumen was demonstrated to significantly stimulate secretion of the intestinal PGDPs (P < 0.05), whereas fat or glucose in the duodenal lumen significantly increased plasma levels of GIP (P < 0.05). In addition, however, duodenal fat treatment also increased the secretion of intestinal PGDPs into the circulation (P < 0.05), with levels rising to same extent as observed after direct administration of fat into the ileum. The rise in plasma GIP levels in response to duodenal fat treatment occurred slightly before the increments in intestinal PGDP levels, suggesting a relationship between the two peptides. Intravenous infusion of GIP to give concentrations similar to those observed after duodenal fat administration induced a 2-fold increase in plasma levels of intestinal PGDPs that was independent of glycemic levels (P < 0.05). No increment in intestinal PGDPs was found in response to infusion of another duodenal endocrine peptide, cholecystokinin. Thus, these data demonstrate a specific effect of GIP to stimulate secretion of the intestinal PGDPs in vivo in the rat. This enteroendocrine loop between the duodenal peptide GIP and the ileal PGDPs may account for some of the early rises in secretion of tGLP-1 observed in response to nutrient ingestion.

Animals↗
PubMed1996

Isolation and structural characterization of proglucagon-derived peptides, pancreatic polypeptide, and somatostatin from the urodele Amphiuma tridactylum.

The expression of the preproglucagon gene in vertebrates is markedly species- and tissue-dependent. Three peptides derived from the posttranslational processing of preproglucagon were isolated from an extract of the pancreas of the urodele Amphiuma tridactylum (threetoed amphiuma). The primary structures of the peptides indicated identity with glucagon (HSQGTFTSDY10 SKYLDNRRAQ20 DFIQWLMST), glucagon-like peptide-1 (GLP-1) (HADGTLTSDI10 SSFLEKQATK20 EFIAWLVSGR30 GRRQ), and glucagon-like peptide-2 (GLP-2) (HADGSFTSDI10 NKVLDTIAAK20 EFLNWLISTK30 VTE). Thus, in a urodele, as in the bullfrog but in contrast to the chicken and all nontetrapod species yet studied, pancreatic preproglucagon mRNA encodes a GLP-2 sequence. The amino acid sequence of glucagon has been better conserved during evolution of tetrapods (3 substitutions between amphiuma and human) than the sequences of either GLP-1 (7 substitutions) or GLP-2 (15 substitutions). Pancreatic polypeptide was also isolated from the extract and its primary structure (APKEPEHPGD10 DASPEQLEKY20 YQDLFQYIIF30 ITRPRY.NH2) indicates that the amino acid sequence of this peptide has been very poorly conserved, even among the amphibia. Amphiuma pancreatic somatostatin is identical to mammalian somatostatin-14.

Amino Acid Sequence↗
PubMed1987

Pancreatic and intestinal processing of proglucagon in man.

We developed antisera and radioimmunoassays against synthetic replicas of glucagon-like peptide-1 (1-36) and -2, predicted products of the glucagon precursor, and against glucagon-like peptide-1 (7-36) identical to the sequence of glucagon-like peptide-1, but lacking its first six N-terminal amino acids. With these tools, we studied the localisation and molecular nature of glucagon-like immunoreactivity in human pancreas, small intestine and plasma. By immunohistochemistry glucagon-like peptide-1, and glucagon-like peptide-2 immunoreactivity coexisted with glucagon in pancreatic islet cells and with enteroglucagon in small intestinal enteroglucagon-producing cells. By chromatography of tissue extracts we found that glucagon-like peptide-1 and glucagon-like peptide-2-immunoreactivities in the human pancreas (307 +/- 51 and 107 +/- 37 pmol/g tissue) were mainly contained in a large peptide, whereas in the small intestine glucagon-like peptide-1 and glucagon-like peptide-2 immunoreactivities were found in separate smaller molecules (49 +/- 21 and 77 +/- 28/g tissue). By isocratic high pressure liquid chromatography of the large pancreatic glucagon-like peptide we found that this peptide is heterogeneous. By chromatographic analysis glucagon-like peptide-1 immunoreactivity in fasting plasma was mainly found in a large peptide corresponding to the pancreatic form, while after a meal a smaller molecular form coeluting by gel filtration with glucagon-like peptide-1 predominated.

Adult↗
PubMedDate not supplied

Specific glucagon-related peptides isolated from anglerfish islets are metabolic cleavage products of (pre)proglucagon-II.

Sequence analyses of cDNAs prepared from anglerfish islet mRNA have demonstrated the presence of mRNAs coding for two different preproglucagons, aPPG-I and aPPG-II. Each of these precursors was predicted to contain 29 residue and 34 residue glucagon-related peptides as potential cleavage products. Recently, several glucagon-related peptides found in extracts of anglerfish islets have been isolated and characterized. In order to determine whether any of these peptides could be identified as metabolic cleavage products in anglerfish islets, differentially radiolabeled Mr 2,500-8,000 peptides from islet extracts were subjected to reverse phase HPLC under varying conditions. The potential cleavage products aPPG-II[52-80] and aPPG-II[89-122] could be readily identified among the extract peptides. Both peptides became labeled appropriately (as predicted from their sequences) with 13 different amino acids and demonstrated glucagon-like immunoreactivity in a radioimmunoassay. Conversely, a third peptide (aPPG-II[89-119]) could be found among the labeled products in small amounts only. These results demonstrate that glucagon-II[52-80] and aGLP-II[89-112] are primary cleavage products of aPPG-II and suggest that aGLP-IIc[89-119] may be a peptide generated more slowly by post-translational modification of aGLP-II.

Amino Acids↗
PubMed2000

Characterization of insulin and atypically processed proglucagon-derived peptides from the surinam toad Pipa pipa (Anura:Pipidae).

Electrospray mass spectrometry was used to identify insulin, glucagon and two peptides related to glucagon-like peptide-1 (GLP-1) in an extract of the pancreas of the Surinam toad, Pipa pipa, a species belonging to the same family as the African clawed frog, Xenopus laevis. Purification and characterization of the peptides established the primary structure of Pipa insulin as A-chain: GIVEQCCHSS(10)CTLLQLETYC(20) N and B-Chain: FSNQR LCGSH(10) LVEALHLVCG(20) DRGFFYYPKA(30). This amino acid sequence contains several substitutions (B5 His --> Arg, B16 Tyr --> His, A12 Ser --> Thr, A14 Tyr--> Leu, A18Asn --> Thr) of residues that have otherwise been quite strongly conserved during vertebrate evolution. Pipa glucagon comprises 37 amino acid residues (HSQGTFTSDY(10) SKYLDSRRAQ(20) DFVQWLMNTK(30)QSGGLSS) and the 29 amino-acid-residue peptide was not identified in the extract. In Xenopus and mammalian preproglucagons, the glucagon-29 sequence is followed by Lys-Arg which functions as a recognition site for a prohormone convertase. We propose that a point mutation in the gene encoding Pipa preproglucagon has transformed the Lys(30)-Arg(31) processing site into Lys-Gln with the result that the site in no longer recognized by the processing enzyme. In contrast, Pipa GLP-32 and GLP-37 are of the same molecular size as the corresponding peptides from Xenopus.

Amino Acid Sequence↗
PubMed1999

Purification and characterization of insulin and peptides derived from proglucagon and prosomatostatin from the fruit-eating fish, the pacu Piaractus mesopotamicus.

The fruit-eating teleost fish, the pacu Piaractus mesopotamicus (Characiformes, Characidae) is classified along with the carp and the catfish in the superorder Ostariophysi. The pacu is able to survive and grow in captive conditions feeding exclusively on carbohydrates. Hormonal polypeptides in an extract of pacu Brockmann bodies were purified to homogeneity by reversed phase HPLC and their primary structures determined by automated Edman degradation. Pacu insulin contains only two substitutions, Glu-->Asp at A15 and Thr-->Ser at B24 (corresponding to B22 in mammalian insulins) compared with carp insulin. The B-chains of both insulins contain a dipeptide extension to the N-terminus and a deletion of the C-terminal residue compared with human insulin. Pacu glucagon differs from catfish glucagon by a single substitution at position 17 (Arg-->Gln. The primary structure of the 34 amino acid residue glucagon-like peptide (GLP) differs from catfish GLP only at positions 12 (Ser-->Ala) and 33 (Pro-->Gln). In common with other teleost species, the pacu expresses two somatostatin genes. Somatostatin-14, derived from preprosomatostatin-I (PSS-I), is identical to mammalian/catfish somatostatin-14. Although pacu somatostatin-II was not identified in this study, a peptide was purified that shows 67% sequence identity with residues (1-58) of catfish preprosomatostatin-II (PSS-II). This relatively high degree of sequence similarity contrasts with the fact that catfish PSS-II shows virtually no sequence identity with the corresponding PSS-II from anglerfish (Acanthopterygii) and trout (Protoacanthopterygii). A comparison of the primary structures of the islet hormones suggest that amino acid sequences may have been better conserved within the Ostariophysi than in other groups of the taxon Euteleostei that have been studied.

Amino Acid Sequence↗
PubMed2000

The proglucagon-derived peptide, glucagon-like peptide-2, is a neurotransmitter involved in the regulation of food intake.

The dorsomedial hypothalamic nucleus harbors leptin sensitive neurons and is intrinsically connected to hypothalamic nuclei involved in feeding behavior. However, it also receives ascending input from the visceroceptive neurons of the brainstem. We have identified a unique glucagon-like-peptide-2 containing neuronal pathway connecting the nucleus of the solitary tract with the dorsomedial hypothalamic nucleus. A glucagon-like-peptide-2 fiber plexus targets neurons expressing its receptor within the dorsomedial hypothalamic nucleus. Pharmacological and behavioral studies confirmed that glucagon-like-peptide-2 signaling is a specific transmitter inhibiting rodent feeding behavior and with potential long-term effects on body weight homeostasis. The glucagon-like-peptide-1 receptor antagonist, Exendin (9-39) is also a functional antagonist of centrally applied glucagon-like-peptide-2.

Animals↗