Endocrine Peptide - an overview | ScienceDirect Topics

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Physiological Effects

Gut peptides can be separated into three functional categories: endocrine, paracrine, and neurocrine, reflecting their cellular location and mode of delivery to target cells (Table 2). Endocrine peptides reach their targets via the general circulation, paracrine by diffusion or via the local circulation, and neural peptides by synaptic transmission.

Table 2. Functional categories of gut hormones

Hormone	Endocrine	Paracrine	Neurocrine
Secretin	+
Gastric-inhibitory peptide	+
Glucagon-like peptides	+
Vascular-inhibitory peptide			+
Gastrin	+
Cholecystokinin	+		+
Pancreatic polypeptide family	+		+
Tachykinin family			+
Bombesin-like peptides			+
Somatostatin	+	+	+
Neurotensin	+
Motilin	+	+
Galanin			+

Essential first steps in identifying the physiological function of a gut peptide are to determine its cellular location, pharmacological properties, and the regulation of its secretion. This is hindered by two features of the neurendocrine system of the gut. The first is the wide dispersion and comingling of peptide-containing cells which make it difficult to excise one endocrine or neural system without interfering with another. The second feature, characteristic of neurons, is the existence of different peptides within the cell along with nonpeptide neurotransmitters, leading to the possibilities of very complex interactions. Nevertheless, the physiological roles of gut hormones in several major functions of the GI tract and the interaction between endocrine and nervous systems have been elucidated and are described below.

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Endothelin

Another endocrine peptide that has been implicated in the development of hypertension is ET-1. ET-1 is a 21–amino acid peptide generated from cleavage of the precursor pre-proendoethlin and is widely recognized as the most potent vasoconstrictor. Like Ang II, it has vascular, renal, and central effects (Reviewed in Miyauchi and Masaki50, and Simonson51) to mediate blood pressure. Although it has not been extensively examined in humans, presently available data suggest a relationship among ET-1, inflammation, and hypertension.9,28

Several studies using animal models of hypertension have examined this relationship. For example, stroke-prone SHR rats fed a high-salt diet have increased renal expression of pre-proendothelin and TGF-β, the latter of which is attenuated by pharmacologic blockade of the ETa receptor.52 Evidence also indicates that inflammatory cytokines promote the generation and release of ET-1, suggesting a feed-forward mechanism to promote inflammation. For example, incubation of vascular smooth muscle cells (VSMC) with TNF-α causes NFκB and STAT1 translocation to the nucleus and increased expression of ET-1.53 Inhibitors of NFκB and STAT1 abrogated the ET-1–stimulating actions of TNF-α.

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There is a growing body of evidence indicating that endocrine peptides, such as AST, AKH, CCAP and FLRFamides, and biogenic amines are part of complex regulatory loops involved in coordinating key aspects in insect digestive processes, including enzyme secretion, muscle contraction, ion transport and foraging behavior [39,42,46,62,65,97]. However, we still need a better understanding of the processes involved. An outline of potential interactions that merit clarification, based on information in this review, is presented in Fig. 2. The same neuropeptide may play very different roles in different species, so we realize that the proposed interactions drawn from an interspecific database may not all hold true for caterpillars. However, we believe that this model provides a good point of departure when designing experiments to study the roles of neuropeptides, for ultimately they will increase our basic understanding of caterpillar nutrition. These data also have relevance from a broader ecological perspective, as well as in pest management.

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In mammals, most neuronal and endocrine peptides are interacting with G protein-coupled receptors (GPCRs), seven-transmembrane-domain proteins that activate heterotrimeric G proteins. Many other peptides, such as growth and differentiation factors, are usually eliciting their responses through binding with single-transmembrane-domain receptors, which can trigger intrinsic or associated enzymatic (usually protein kinase) activities.

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2 Classification and identification of peptide

Peptides are specific protein fragments with supposedly improved activity and physiological functions. Peptides are of many types with dipeptides being the shortest of them all because they consist of just two amino acids linked by a peptide bond. Conversely, polypeptides usually contain >50 amino acids. These basic descriptions conveniently allow peptides to be called biological polymers.

Details on the identification of peptides are discussed in the next section. For their classification, they are based on numerous factors. For instance, if they are to be classified based on production, there are the peptones, produced from the breakdown of animal milk/meat, or built up from metals, fats, vitamins, and certain salts (Payne, 1976). In cultures and microbiology experiments, the peptones are used in preparing nutrient media, particularly for bacterial and fungal growth. Another class in this category is the milk peptides. They are formed from casein during milk protein digestion in the gastrointestinal tract or lactic acid bacterial fermentation of milk. Ribosomal peptides are produced by cellular ribosomes in a translation process of ribonucleic acid (RNA) into messenger RNA (mRNA), which is an AA sequence. The residues are linked together to form more matured peptides. Some bacteria produce microcins or bacteriocins, which are peptides, as their substances of defense mechanism, but these peptides undergo post-translational modifications such as hydroxylation, phosphorylation, sulfonation, and glycosylation (Duquesne, 2007). Another class of peptides based on source include the non-ribosomal peptides, which are formed by enzymes that are not ribosomes, such as glutathione (Anderson & Meister, 1996, pp. 213–226). They also undergo the same post-translational modifications as ribosomal peptides after the amino acid sequences are connected. Several peptides are linear, but some are cyclic, forming rings and/or are lariat in structure (Pons et al., 1991). Non-ribosomal peptides often are cyclic, and therefore, have highly complex structures, but less often, D-amino acids are produced from the racemization of L-amino acids occurring within peptides (Torres et al., 2002). Lastly, under this category, there are peptide fragments, which are protein fragments used to identify protein sources (Hummel et al., 2007). Other than being controlled in the laboratory, the natural degradation of paleontological or forensic samples can also form peptide fragments (Webster & Oxley, 2005).

Based on function, there are neuropeptides, which are associated with neural tissues. Lipopeptides have lipid connections, and some of them have interactions with G-protein coupled receptors (GPCRs); they are called pepducins. Hormonal peptides act as hormones, while proteoses are unpurified peptides after protein hydrolyzation. Then, based on family, there are antimicrobial peptides (e.g. magainin, cecropin, cathelicidin, and defensin); tachykinin peptides (e.g. kassinin, neurokinin, and eledoisin); vasoactive intestinal peptides (e.g. secretin and glucagon); pancreatic polypeptide-related peptides (e.g. neuropeptide Y, peptide YY, and pancreatic polypeptide); opioid peptides (e.g. proopiomelanocortin, enkephalin pentapeptides, and prodynorphin); calcitonin peptides (e.g. calcitonin and amylin); and self-assembling peptides (e.g. aromatic short peptides, biomimetic, peptide amphiphiles and, peptide dendrimers) (Hamley, 2011; Zhu et al., 2018; Kastin & 2nded., 2013). Whether based on function, source or family classes, other peptides include antimicrobial, anticancer, cardiovascular, endocrine, fungal, gastrointestinal, invertebrate, opiate, plant, renal, respiratory, and venom peptides (Khalifa et al., 2019).

Structurally, linear peptides have free NH2 and COOH at both respective ends while branched peptides have many amino acids branching out on a linear peptide chain via either the ω-carboxylic group of dicarboxylic amino acid, or the ε-amino group of lysine. Cyclic peptides do not have N-terminal or C-terminal end. Semi-cyclic peptides have just one end, in which if it is an N-terminal, the α-COOH of the last amino acid will be linked to the ε-NH2 of an endopeptide lysine. If it is a C-terminal, the α-NH2 of the first amino acid will be linked to the ω-COOH of an endopeptide dicarboxylic amino acid (Du & Shen, 2001; Torres et al., 2002).

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Miscellaneous Gut Endocrine Peptides

In addition to the peptide hormones outlined previously and summarized in Table 38-4, several other gut endocrine peptides exist. Chromogranins and secretogranins are a family of secretory proteins that are found in secretory vesicles of endocrine cells and neurons. Chromogranin A (CgA), a protein belonging to this family of peptides, induces the formation of mobile secretory granules and is secreted into the circulation by several neuroendocrine tumors, especially small gastrinomas and pheochromocytomas. Circulating levels of CgA directly correlate with tumor burden, making this a well-suited marker for assessing treatment response. CgA likely helps to regulate blood pressure, because elimination of CgA expression in a knockout mouse led to decreased size and number of chromaffin granules and hypertension, whereas transgenic expression of human CgA or exogenous injection of human catestatin, a CgA-derived cholinergic antagonist, restored normal blood pressure in CgA knockout mice.136

Opioid peptides regulate intestinal motility and inhibit gastric acid secretion. Neuromedin B and its receptor are expressed in the gut, where they activate pathways coupled to epithelial mitogenesis. Neuromedin U is a neurotransmitter that is expressed in the enteric nervous system, where it regulates intestinal motility and ion secretion. Several hormones are secreted by the gastrointestinal tract directly into the lumen, where they modulate the secretion and release of other hormones. Guanylin and uroguanylin stimulate water, bicarbonate, and chloride secretion by the intestine and kidney while inhibiting sodium reabsorption.137 Guanylin may also regulate cell proliferation in the colon; guanylin−/− mice have increased epithelial cell migration and colonocyte proliferation. A missense mutation in the coding region of the GUCY2C guanylate cyclase C gene, resulting in enhanced receptor signaling, increased cyclic guanosine monophosphate, and excessive chloride and water secretion from enterocytes, has been described in a large family with autosomal dominant familial diarrhea.138 Other luminally secreted peptides include sorbin, a 153–amino acid peptide involved with monitoring fluid and sodium fluxes in the duodenum, and monitor peptide, which is a 61–amino acid peptide that stimulates CCK release. Xenin-25 is a 25–amino acid neurotensin-related peptide produced by a subset of K cells in the intestine. Its functions are uncertain, although in animals it decreases food ingestion and alters gastrointestinal motility. In humans, it appears to act as a weak insulin secretagogue and delays gastric emptying.139

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VI.A Proteolytic Cleavage

Neural and endocrine peptide pro-hormones are cleaved by endoproteolytic enzymes that recognize definable cis amino acid motifs. In mammals, the best studied are the pro-hormone convertases (PCs), which are members of the subtilisin-like, serine endopeptidase family of enzymes. Their substrates include polypeptide hormone precursors, growth factors, and viral envelope glycoproteins. For example, the PC1/3 and PC2 endopeptidases have well-defined roles in processing numerous neuropeptide pro-hormones in both neural and endocrine tissues, and both enzymes are packaged within secretory granules.

Sequence information supports the hypothesis that insect neuropeptide pro-hormones are also often cleaved at dibasic and monobasic residues. In Drosophila, there are three genes that are highly related to PCs, and at least some of these appear to be involved in neuropeptide biosynthesis. The dfurin 1 (CG10772 at 96D1) and dfurin 2 (CG18734 at 14C1) genes were identified by sequence homology to mammalian furin. When tested with specific substrates in vitro, both have enzymatic activities similar to that of mammalian furin and different from that of mammalian PC2. dfurin1 is expressed in a small number of identified peptidergic neurons. No phenotypic analysis has been reported for either dfurin gene. The third Drosophila PC-like gene, called amontillado (amon, CG6438 at 97C3), is highly related to mammalian PC2. Reported alleles of amon include one with a deficiency in its genomic region and another that may also have a P-element in close proximity. Deletion analysis indicated that animals homozygous for amon deficiencies are morphologically normal but die trying to hatch from the egg. It is presumed that amon is required for the production of one or more secretory peptides needed to display the normal hatching behavior. AMON enzymatic activity has not been examined nor have its effects on neuropeptide biosynthesis been reported. However, the recombinant protein does display predicted interactions with both Drosophila and mammalian 7B2′, the protein normally associated with its maturation in mammals.

Angiotensin-converting enzyme (ACE) is a Zn2+ peptidyl-dipeptidase that plays an important role in blood pressure homeostasis in mammals. There are six ACE-related gene sequences in the Drosophila genome, of which only two, ACER (CG10593 at 29D1) and ANCE (CG10593 at 34D7), are predicted to be active enzymes. The active sites of ANCE and ACER have structural features that are (respectively) highly similar to those of the two adjacent, active domains of mammalian somatic ACE. In other insects, ACE protein distribution is consistent with a role in neuropeptide processing; it is especially enriched in neurons producing peptides of the FXPRLamide family. Insect ACE can process neuropeptide pro-hormone intermediates to remove C-terminal dibasic residues. In Drosophila, ACER is represented by a single recessive lethal and ANCE is represented by two recessive lethals. The possible consequences of these mutations on neuropeptide biosynthesis have not yet been evaluated.

After pro-hormone cleavage by the pro-protein convertases, C-terminal basic residues are removed by a separate carboxypeptidase (CP) activity. Of the >15 characterized mammalian metallocarboxypeptidase enzymes, only CPE/H and CPD are thought to participate in neuropeptide biosynthesis. In Drosophila, silver (CG4122 at 1B3) and a second gene (CG4678 at 15A2) are the two closest orthologues to the mammalian CP genes associated with neural and endocrine peptide biosynthesis. silver (svr) is a complex locus encoding large proteins that contain as many as four predicted enzymatic domains. It is represented by 40 null and hypomorphic alleles; some hypomorphic alleles display alterations in wing development and in melanization and sclerotization of the cuticle (the latter phenotypes generate the gene name). The degree to which neuropeptide biosynthesis is altered in svr mutant animals has not been determined. No alleles of CG4678 have yet been recorded.

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Introduction

The pituitary, the thyroid, and the adrenal glands are endocrine organs with the sole known function of synthesizing and secreting hormones that act on distant tissues and organs. Other organs have emerged as endocrine peptide secretors that regulate energy homeostasis through secretion of the adipose-derived satiety hormone leptin [1], the incretin glucagon like peptide-1 (GLP-1) produced by intestinal L cells [2], and the bone-derived regulator of energy homeostasis osteocalcin [3]. The liver can also be considered an endocrine organ that stimulates energy metabolism via production of the fasting hormone fibroblast growth factor 21 and influences pancreatic β cell function and proliferation by producing kisspeptin [4] and serpin B1 [5]. The list can be extended to include the hunger hormone ghrelin produced by the stomach and the controversial myokine irisin produced by skeletal muscle during exercise [6]. Historically, the gonads have been viewed as endocrine organs secreting steroids for the sole purpose of sexual differentiation, puberty, and reproduction. However, because energy stores need to reach a minimum threshold to allow reproduction to occur, reproduction is tightly linked to energy metabolism. Thus, under physiological conditions gonadal hormones play an important role in sex-specific aspects of energy metabolism [7,8]. For example, secretion of insulin, an anabolic hormone produced by the β cells of the pancreatic islets of Langerhans that promotes energy storage, is influenced by gonadal steroids in a sex-specific manner. This review discusses the physiological roles of the ovarian– and testicular–islet axes in the biology of insulin-producing β cells in females and males. I discuss the roles of estrogens, androgens, and progestogens via their receptors (ER, AR, and PR, respectively) in the gender-specific tuning of insulin secretion and outline potential gender-specific therapeutic avenues that these signaling pathways open.

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VII.B Vasoactive Intestinal Peptide (VIP)

VIP was originally isolated from the porcine small intestine in the early 1970s by Dr. Said in the laboratory of Professor Mutt. The peptide has been shown to consist of a 28-amino acid residue with a C-terminal α-amidation. It shows structural similarities to the so-called glucagon family of peptides, i.e., glucagon, gastric inhibitory peptide (GIP), glucagon-like peptide-1 (GLP-1), and secretin. There is a high degree of identity in the VIP sequence between different species. For example, human, porcine, and rat VIPs are identical, differing from guinea pig VIP in only two amino acids. The human gene coding for VIP is located on chromosome 6q24 and contains seven exons. It encodes, besides for VIP, for peptide histidine methionine (PHM). This is a 27-residue peptide showing a high degree of homology to VIP because 15 of the amino acids are identical. VIP is encoded in exon 5, whereas PHM is encoded in exon 4 of the gene. Exon 2 encodes the signal peptide, which contains 21 residues, and proVIP is encoded in exons 3–6, which contains 149 residues, of which PHM is equivalent to proVIP60–86 and VIP is equivalent to proVIP104–131 (Fig. 3).

Figure 3. Schematic representation of the VIP gene and proVIP. The first exon is non-encoding, exon 2 encodes the signal peptide, exons 3–6 encode the proVIP sequence, and exon 7 is non-encoding. At the bottom of the figure are the amino acid sequences of VIP, glucagon, human PHM, secretin, and human GIP. * indicates a C-terminal NH2 group.

VIP is a neuropeptide exhibiting widespread distribution in the body. Thus, VIP nerves are localized to both the central nervous system and the respiratory, gastrointestinal, and genitourinary systems. In these systems, a variety of actions of VIP have been reported, such as relaxation of smooth muscle cells and stimulation of exocrine and endocrine secretions. A notably powerful action of VIP is its relaxation of smooth muscles in vessels, leading to vasodilatation. In the 1970s, it was also demonstrated that VIP occurs in the pancreas. Initially, the peptide was assumed to be an endocrine peptide in the islets, but it is now established that VIP is exclusively a neuropeptide localized to nerve terminals in the islets, ganglia, and exocrine pancreatic tissue. A neural VIP network surrounding the islets has also been demonstrated in both humans and experimental animals, suggesting important contributions of VIP to islet function. VIP may be involved in the local regulation of islet blood flow, because the peptide is a powerful vasodilatory agent and also has been demonstrated to increase islet blood flow upon exogenous administration. VIP may also be involved in the local regulation of islet hormone secretion. Thus, VIP is released from the pancreas when the vagal nerves are activated, and, furthermore, VIP is a powerful stimulator of both insulin and glucagon secretion under a number of conditions.

Two different VIP binding receptors have been cloned. They both show affinity for PACAP and are called the VPAC1 and VPAC2 receptors, respectively. They are both of the seven transmembranous domain type and they are G-protein-coupled. The VPAC1 receptor consists of 460 residues and the VPAC2 receptor consists of 438 residues. VPAC1 is encoded by chromosome 3p22, whereas VPAC2 is encoded by chromosome 7q36.3. Both of these genes consist of 13 exons. Activation of the VIP receptors is followed by activation of adenylate cyclase with the formation of cAMP, as has been demonstrated in islet cells. Cyclic AMP in turn activates PKA, which enhances exocytosis. Hence, the stimulation of insulin and glucagon secretion by VIP seems to be a classical cAMP–PKA-mediated process.

The relative contribution of VIP to islet function has not been established. Changing the VIP structure by substituting methionine in position 17 for leucine and inserting a 4-chloro substitution on phenylalanine in position 6 results in a VIP antagonist, [4-Cl-d-Phe6, Leu17]VIP, which inhibits islet hormone secretion after exogenous administration of VIP. However, this antagonist was without effect on the insulin or glucagon response to autonomic nerve activation in an in vivo study of the mouse. Therefore, further studies are required to examine the role of VIP in the regulation of islet function.

The VIP gene product, PHM, may also be of potential importance in the regulation of islet function, because this peptide, like VIP, stimulates insulin and glucagon secretion. However, much less is known about this peptide. For example, the receptors mediating its actions and its signaling pathways have not been established.

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The direct and indirect effects of other endocrine peptide effectors not discussed here will have to be integrated into the overall scheme presented in Fig. 2. Furthermore, the importance of the pathways may vary with other physiological and ecological parameters. For example, the activity of endocrine peptides is dose-dependent although at high concentrations, the effect may be abolished or truncated [22]. Such effects may be stage-specific, and the outcome of a feeding bout could differ markedly depending on abiotic conditions such as temperature [146]. In addition, several different neuropeptide families may induce the same response in vitro and, thus, one challenge will be to clarify how the “chemical language” (sensu [125]) actually functions in vivo [126].

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