© 2000 by The Society for Integrative and Comparative Biology
Glucagon-like Peptide-1 in Fishes: The Liver and Beyond1
1 Department of Biochemistry and Microbiology, University of Victoria, Victoria, Canada
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The incretin hormone glucagon-like peptide-1 (GLP-1), coencoded and expressed in the proglucagon gene in intestine and endocrine pancreas of all vertebrates, is an important regulator of insulin secretion in the postprandial state of mammals. Additionally, the hormone acts in concert with insulin to remove glucose from the plasma. In mammalian B cells, lung, intestine and brain, GLP-1 receptors activate the adenylyl cyclase/cAMP system of message transduction, with ancillary involvement of calcium and inositoltrisphosphate. While the peptide is fairly conserved in vertebrates, the fishes show dramatic biochemical and physiological differences to the situation in mammals and an incretin function in fishes is questionable. Fish GLP-1 acts preferentially on the liver, and recently enterocytes and brain membranes have been shown to be potential targets. GLP-1 actions generally oppose those of insulin and supplant or supplement those of glucagon by activating glycogenolysis, gluconeogenesis and lipolysis in liver and by accelerating glucose transport and curtailing glucose oxidation in enterocytes. In brain and enterocytes, GLP-1 targets adenylyl cyclase, while in the liver adenylyl cyclase and cAMP play subordinate roles only. Although phospholipase C had been implicated in GLP-1 action, the prevalent route of message transduction in fish liver needs to be elucidated. The unique functional switch of GLP-1 from a hyperglycemic hormone in fish to a glucostatic incretin in mammals remains a matter of conjecture.
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GLUCAGON-LIKE PEPTIDES IN VERTEBRATES |
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The proglucagon genes of all vertebrates encode at least two glucagon-like peptides (GLPs), namely GLP-1 and GLP-2, arranged in series. Both the endocrine pancreas and the intestine are known to actively process the proglucagon gene, and release a mixture of bioactive peptides, including GLPs with distinct physiological functions. The following is largely concerned with glucagon-like peptide-1, a 31-residue peptide that shows about 50% amino acid sequence homology to glucagon and is characterized by an N-terminal histidine. The peptides themselves are fairly conserved throughout vertebrate phylogeny (see below) and they are interchangeable in their specific functions, yet fundamental differences exist between fishes and mammals in the biological activities of glucagon-like peptide-1. Differences are apparent in the sites of expression, sites of processing and production, and finally targets, intracellular message transduction and, most importantly, function. While biological functions for GLP-2 in the fishes are as yet unclear, the functions of GLP-1 have been elucidated in some detail, but their evolutionary implications are not entirely apparent.
Mammals
In mammals, GLP-1(7–37) or GLP-1(7–36amide), is produced by key regions of the intestine from GLP-1(1–37), a largely inactive N-terminally extended precursor. The peptide is a powerful incretin, secreted from the intestine after a glucose-containing meal, and targets islet B cells to release insulin (Mojsov et al., 1987
, 2000), while also curtailing the release of glucagon from A cells. The hormone acts on pancreatic and gastric D cells to activate the release of somatostatin (Beales and Calam, 1996; Brubaker et al., 1997), on lung (Benito et al., 1998), on fundic cells to control gastric acid secretion, and on intestine to decrease motility (Giralt and Vergara, 1998). The latter function supports the incretin role by indirectly reducing the chance of plasma swamping with glucose following a meal. Infused into the mammalian brain, GLP-1 also decreases appetite (Donahey et al., 1998). While still actively disputed, direct metabolic actions for GLP-1 have been described for mammalian liver (activation of glycogen synthase a), adipocytes (Egan et al., 1994), and muscle (Alcántara et al., 1997; Yang et al., 1998). Apart from those in the brain, all functions are insulinomimetic in nature; recently, some evidence has been provided that of the multifacetted actions of GLP-1, only the incretin role on the pancreatic B cells is essential for glucose homeostasis (Scrocchi et al., 1998). Together with PACAP-38, GLP-1 also functions as a competence factor on the actions of glucose on transcriptional activation of immediate early response genes coding for a variety of transcription factors (Susini et al., 1998), but exerts no action on its own or at low glucose levels. This function assigns an important role to this incretin in the response of B cells to hyperglycemia in mammals.
In mammalian cells expressing the pancreatic type of GLP-1 receptors, GLP-1 conveys its message to the intracellular targets through cell surface receptors with seven transmembrane domains, associated with stimulatory G-proteins that activate the adenylyl cyclase/cAMP cascade. The receptor itself is subject to regulation by phosphorylation (Widmann et al., 1997). In addition, ancillary roles have been postulated in GLP-1 message transduction for intracellular calcium, phospholipase C, diacylglycerol and inositoltrisphosphate. Whether increases in intracellular calcium are voltage-sensitive (Holz et al., 1995) or involve inositoltrisphosphate (Gromada et al., 1998) is under debate. In responsive tissues lacking the pancreatic type of receptor, such as muscle, adipose and liver, both decreases in intracellular cAMP (Yang et al., 1998) and increases in inositolphosphoglycans (Márquez et al., 1998) have been postulated as intracellular mediators for GLP-1. The peptide has a half-life of only a few minutes (Deacon et al., 1996), and is removed from the circulation preferentially by the kidney.
Fishes
Starting with the site of production and gene structure, the picture emerging from more limited analysis in the fishes is diametrically opposed to mammals. Yet, it should be reiterated that the biologically active peptide is highly conserved and fish hormone will activate mammalian receptors and mammalian hormones will bind to receptors present in fish tissues (Plisetskaya and Mommsen, 1996) or to fish receptors transfected into a mammalian cell line (Y. Wei and S. Mojsov, unpublished results). Two statements must be made categorically. First, the likelihood that GLP-1 will emerge as an important incretin in fishes are very small, not least because Brockmann bodies are fairly impervious to GLP-1 even in the presence of glucose. Considering the minor importance of glucose to metabolism in fishes, their general glucose intolerance and insulin resistance (Mommsen and Plisetskaya, 1991; Wright, 2000), it is debatable whether the incretin concept based on glucose applies to this group of vertebrates. Second, just like glucagon (Moon, 1998), its molecular neighbour, the peptide seems to oppose the actions of insulin at every turn.
The proglucagon gene in fish endocrine pancreas encodes only GLP-1, but not GLP-2. The GLP-1 does not require processing from an inactive precursors and even the gene contains no indication of the presence of an N-terminal extension or additional up-stream processing sites (Plisetskaya and Mommsen, 1996). The peptide has been recovered in appreciable amounts and purified from Brockmann bodies with relative ease, leading to the characterization of GLP-1 in more than a dozen fish species. However, the exact nature of peptides released from the fish endocrine cells, i.e., GLP-1 vs. glucagon, and their secretagogues are still unknown. In some species, the peptide has been isolated from the intestine, GLP-1 immunoreactivity has been localized to the intestine (reviewed by Plisetskaya and Mommsen, 1996) and intestinal mRNA coencodes GLP-1 and GLP-2 (Irwin and Wong, 1995). Largely due to limited analysis, the list of potential targets in fishes includes just liver, intestine and brain, with physiological functions defined for liver and enterocytes only.
Functions of GLP-1 in fish liver
The piscine liver appears to be the major site of GLP-1 removal from the circulation and contains highly specific receptors for glucagon (Navarro and Moon, 1994; Yuen et al., 1996) and for GLP-1 (Y. Wei and S. Mojsov, in preparation). Both peptides act on similar if not identical targets with slightly higher potencies being noted for GLP-1 than for glucagon (Mommsen and Mojsov, 1998) (cf. Fig. 1). GLP-1 activates numerous liver functions, including glycogenolysis, gluconeogenesis and lipolysis. Since glycogen synthesis and degradation are reciprocally regulated in all vertebrates, we can also postulate that the hormone inhibits the rate of glycogen synthesis. In addition, we have shown that acetyl-coenzyme A carboxylase, the key step in fatty acid biosynthesis is inhibited in the presence of GLP-1 (T. P. Mommsen and C. Quayle, unpublished results).
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The powerful glycogenolytic response of freshly isolated rockfish (Sebastes caurinus) hepatocytes to various GLPs and glucagon is depicted in Figure 1. The figure shows that GLPs from human, Xenopus laevis and zebrafish are almost equipotent, while zebrafish glucagon, and the full length mammalian GLP-1(1–37) are less effective at increasing the rate of glycogenolysis. A similar difference in effectiveness exists between mammalian GLP-1 and bovine glucagon when tested in the rockfish hepatocyte system (data not shown). Least potent is the bowfin GLP-1 containing some uniquely GIP-like (and growth hormone releasing factor-like) characteristics, including a substitution of the N-terminal histidine with a tyrosine residue (Table 1). As shown elsewhere (Plisetskaya and Mommsen, 1996
), the sequence variability in fish GLP-1 can be used to identify residues essential for physiological action. Not surprisingly, such analyses arrive at similar conclusions as those done with directed amino acid substitutions on mammalian GLP-1 using a peptide synthesizer. The data point out the importance of the N-terminal histidine for glycogenolytic function. Further, all residues in the N-terminal half appear critical to function, while a basic residue in position 20, Phe22, Val/Ile23, Leu26, preferentially followed by Lys27, seem also indispensable. Ala2, a potential processing site for dipeptidyl peptidase IV (Deacon et al., 1998a) and probably at the root of the short half-life of the peptide in mammals, is invariant in the fishes and signifies a clear distinction from Ser2 found in all vertebrate glucagons. Interestingly, replacement of Ala2 with Ser2 increases the biological half-life of GLP-1 in a mammal (Deacon et al., 1998b).
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Recently, our understanding of GLP-1 action on fish liver glycogenolysis has been refined by an analysis of glycogen phosphorylase (GPase). Vertebrate liver GPase is subject to covalent modification through phosphorylation, usually implicating activation of cAMP-dependent protein kinase in the process. The fish liver enzyme is a highly sensitive indicator of hormonal activation (Moon et al., 1999
). Application of GLP-1 to isolated brown bullhead (Ameiurus nebulosus) hepatocytes transiently increases the activity of GPase by phosphorylating the enzyme into the active a-form (Fig. 2); increases in GPase a activity can be detected within 30 sec of hormone application and at concentrations of GLP-1 commonly found in fish plasma. It is interesting to note that exendin(9–39), a powerful antagonist of GLP-1 binding in mammalian tissues expressing the pancreatic GLP-1 receptor, does not constitute a good antagonist to the physiological role of GLP-1 in fish liver (Fig. 2). At the lower concentration of GLP-1 and in the absence of phosphodiesterase inhibitors, the effect on GPase is transient and subsides within about 40 min. Numerous intracellular factors are likely to coordinate this decrease, ranging from removal of active peptide—which can be substantial in fish liver (Plisetskaya and Sullivan, 1989)—to increased turnover of cAMP and desensitization of adenylyl cyclase and protein kinase A.
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Hepatic message transduction
With respect to message transduction, the situation in fish liver is not clear-cut, although after transfection of a recombinant zebrafish GLP-1 receptor into COS cells, cAMP appears to be the dominant route (S. Mojsov, personal communication). In contrast, only minor—if any—increases in cAMP are noted in isolated hepatocytes in vitro (Fig. 3). These alterations pale in comparison with cAMP increases measured with epinephrine under identical conditions. The same results are found for the activation of adenylyl cyclase in isolated liver membranes; yet in terms of glycogenolytic potency, the peptide and the catecholamine are not significantly different (Fig. 3). The data presented in Figure 3 confirm results gathered for other teleostean species (Mommsen and Moon, 1990
). It should also be mentioned that often increases in cellular cAMP are only noted at hormone concentrations well above those that are physiologically relevant and effective in vitro. As shown in Figure 2, liver GPase of brown bullhead catfish responds well to 1 nM GLP-1, but increases in cellular cAMP or phospholipase C (cf. Fig. 4 below) do not become significant until much higher concentrations of GLP-1 (Mommsen and Moon, 1990; Moon et al., 1997). With the importance of cAMP to GLP-1 transduction under review, other messenger systems have been implicated in GLP-1 action; yet none of these seem to play a dominant role either. Catfish and eel hepatocytes show minor transient increases in intracellular calcium with activation of glycogenolysis (Zhang et al., 1992) and significant increases in the activity of phospholipase C with GLP-1 (Fig. 4), although intracellular concentrations for inositoltrisphosphate did not seem to be affected (Moon et al., 1997). Clearly, a better analysis of the intrahepatocyte message transduction in fishes seems warranted; this may include a concerted search for suitable antagonists of GLP-1 binding in fishes. From the existing data sets, one can expect that numerous intracellular message transduction systems will interact to bring about the various physiological functions. In the context of activation of glycogenolysis and gluconeogenesis, we can expect that regulation of protein kinase A will be at the center of this regulation.
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Extra-hepatic actions—Enterocytes
The physiological role of GLP-1 in fishes is not restricted to the hepatocytes, and important actions for the peptide have recently been identified in intestine. Several lines of evidence have converged to confirm our contention that GLP-1 does not function as an incretin or a glucostat, but rather as a powerful hyperglycemic hormone. In isolated enterocytes of black bullhead catfish, for instance, GLP-1 application leads to substantial and dose-dependent increases in the capacity for glucose transport, as does exposure of the cells to glucagon (Fig. 5). At the same time, the oxidation of glucose is decreased by two-thirds, while the affinity of the oxidative route for glucose is unaffected (Table 2). The mechanisms underlying the increase in glucose flux and glucose oxidation were not analyzed, but we recently presented evidence that GLP-1 increases the rate of adenylyl cyclase in isolated enterocytes from a marine scorpaenid (Mommsen and Mojsov, 1998
). The overall activation is smaller than for prostaglandin E2 or forskolin (almost 9-fold), but at three-fold above control rate is much larger than in liver and reaches one third of the maximum obtained with forskolin (Fig. 6). The result is not quite as clear-cut for isolated enterocytes, which, although also responsive, produce a much smaller, statistically significant, increase in intracellular cAMP under the influence of GLP-1. In comparison, the increase noted for hepatocytes amounts to less than 5% of the rate reached with forskolin.
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Extra-hepatic actions—Brain membranes
A recent addition to the target tissues for GLP-1 is the fish brain, more specifically, fish brain membranes. We found that crude brain membranes of a rockfish will respond quickly and reproducibly to GLP-1 with a dose-dependent increase in adenylyl cyclase activity (Fig. 7). Just like mammalian brain, fish brain contains specific GLP-1 receptors whose expression can be followed and genes sequenced with probes based on GLP-1 receptors localized to the intestine of fishes (S. Mojsov et al., in preparation). Based on limited analysis and on the apparent similarities in receptors and message transduction (cf. Fig. 7), one can dare to predict that the situation in the brain is similar in fishes and mammals. Therefore one can expect that indirect actions mediated via neuropeptide Y or other neuropeptides will define the fascinating neural actions of GLP-1 (Thiele et al., 1997
). As a result, the brain may be the only tissue where the functions of GLP-1 have been conserved entirely in the course of vertebrate evolution. We are therefore looking forward to the first results of experiments on feeding control in piscine systems and potential interactions of GLP-1 with neuropeptide Y.
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GLP-1 is not an incretin in fishes
Fish are generally considered to be insulin resistant and glucose intolerant (reviewed by Mommsen and Plisetskaya, 1991
) and seem to lack GLUT-4, the insulin-sensitive glucose transporter that is instrumental to the hypoglycemic effects of insulin in mammals (Wright, Jr. et al., 1998). Even in omnivorous catfish that may naturally feed on glucose-rich diets, plasma glucose will not return to baseline within 10 hr after a tolerance test (Ottolenghi et al., 1995). Albeit based on a limited data set, all observations for GLP-1 argue against an incretin function based on glucose in fishes. Instead, the data support the notion of a hormonal principle opposing the actions of insulin. First, the endocrine pancreatic cells appear non-responsive to GLP-1 and GLP-1 immunoneutralization fails to alter plasma insulin concentrations (Plisetskaya et al., 1989), in spite of the surprising fact that fish Brockmann bodies are glucose responsive when transplanted into diabetic nude mice (Wright, Jr. et al., 1998). Second, actions in liver are glycogenolytic and gluconeogenic, leading to hyperglycemia. Third, intestine is likely to contribute to this hyperglycemia by GLP-1 dependent increases in glucose transport and decreased rate of endogenous glucose oxidation (Soengas and Moon, 1998). Internally, these actions are consistent in their anti-insulin actions, with activation of glycogenolysis and gluconeogenesis in the liver, lipolysis in adipose tissue and glucose transport in enterocytes. In fact, all metabolic observations run counter to what has been observed in mammals, namely that GLP-1 activates glycogen synthesis in liver, intestinal glucose transport remains unaltered (Cheeseman and Tsang, 1996), but overall glucose transport capabilities are reduced due to decreased motility. Unfortunately, the control of acid secretion and gut motility remain to be analyzed for fish systems, although some predictions can be made for gut motility. In line with the hyperglycemic role of GLP-1 either positive or no effects of GLP-1 on gut motility can be expected.
The fact that immunoneutralization of GLP-1 in coho salmon failed to affect plasma insulin levels (Plisetskaya et al., 1989), is consistent with the other, glucose mobilizing, actions of GLP-1. However, it is possible that the salmon compensated by increasing the release of GIP, another (mammalian) insulinotropin. Such a phenomenon was noted for mice with a null-mutation in the GLP-1 receptor, where increased GIP release largely counterbalanced the shortfall in GLP-1 effectiveness (Pederson et al., 1998). It would be interesting to probe the potential overlap in function, expression and receptor specificity between GIP and GLP-1 in the fishes. Unfortunately, our studies (Mommsen and Mojsov, 1998) and those by Soengas and Moon (1998) did not analyze the effects GIP in enterocytes, although we have preliminary evidence that (mammalian) GIP exerts only a very mild glycogenolytic action in rockfish hepatocytes (T. P. Mommsen and E. R. Busby, unpublished results; cf. dose-response to bowfin GLP-1 in Fig. 1). Further, in fish liver, GLP does not antagonize any of the actions of glucagon. In fact, as pointed out before (cf. Fig. 1), at least in the rockfish, GLP-1 is a super-glucagon, antagonizing insulin's actions on glucose metabolism.
Obviously, the evolutionary or metabolic driving forces behind the group-specific roles for GLP-1 and the retention of glucagon in the face of the existence of a "better glucagon" in vertebrates need to be elucidated. It seems that many approaches display our inherent mammalian bias, namely that glucose is of monumental significance. Without trying to minimize the importance of glucose to some aspects of piscine metabolism, it may be necessary to replace the underlying mammalian partiality and venture into an analysis of other pathways and probe the importance of GLP-1 to metabolic regulation. Clearly, GLP-1 receptors are abundant and the peptide appears to be powerful, but does not act through insulin as its frontispiece; it is likely that a wider analysis of GLP-1 action in fish tissues, starting with liver and intestine, will open new windows on the organization of intermediary metabolism. It is conceivable that such an analysis will provide new insights into the evolutionary driving forces which have made insulin and glucose such central tenets to mammalian metabolism, similar to what a paradigm shift away from carbohydrates might do for mammalian insulin and our understanding of diabetes (McGarry, 1992).
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ACKNOWLEDGMENTS |
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Erika Plisetskaya provided the initial gift of purified coho salmon GLP-1 that started the search for a physiological role of GLP-1 in fishes. I wish to thank Erika Plisetskaya, Svetlana Mojsov, Tom Moon and Ellen Busby for many fruitful discussions on life, the universe, and not least GLPs. The efforts by Stacia Sower and Mark Sheridan to make this symposium in Erika's honour a reality are deeply appreciated. Research in my laboratory is supported by NSERC Canada.
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FOOTNOTES |
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1 From the symposium A Tribute to Erika M. Plisetskaya: New Insights on the Function and Evolution of Gastroenteropancreatic Hormones presented at the Annual Meeting of the Society for Integrative and Comparative Biology, 6–10 January 1999, at Denver, Colorado.
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