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Peptides are sustainable alternatives to conventional therapeutics for G protein-coupled receptor (GPCR) linked disorders, promising biocompatible and tailorable next-generation therapeutics for metabolic disorders including type-2 diabetes, as agonists of the glucagon receptor (GCGR) and the glucagon-like peptide-1 receptor (GLP-1R). However, single agonist peptides activating GLP-1R to stimulate insulin secretion also suppress obesity-linked glucagon release. Hence, bioactive peptides cotargeting GCGR and GLP-1R may remediate the blood glucose and fatty acid metabolism imbalance, tackling both diabetes and obesity to supersede current monoagonist therapy. Here, we design and model optimized peptide sequences starting from peptide sequences derived from earlier phage-displayed library screening, identifying those with predicted molecular binding profiles for dual agonism of GCGR and GLP-1R. We derive design rules from extensive molecular dynamics simulations based on peptide-receptor binding. Our newly designed coagonist peptide exhibits improved predicted coupled binding affinity for GCGR and GLP-1R relative to endogenous ligands and could in the future be tested experimentally, which may provide superior glycemic and weight loss control.
The genes encoding the peptide precursors for glucagon (GCG), glucose-dependent insulinotropic peptide (GIP), and ortholog of exendin belong to the same family as shown by sequence similarity. The peptides similar to glucagon encoded by these genes signal through a closely related subfamily of G-protein coupled receptors. A total of five types of genes for receptors for these peptides have been identified, three for the products of GCG (GCGR, GLP1R, and GLP2R) and one each for the products of GIP (GIPR) and the ortholog of exendin (Grlr). Phylogenetic and genomic neighborhood analyses clearly show that these genes originated very early in vertebrate evolution and all were present in the common ancestor of tetrapods and bony fish. Despite their ancient origins, some of these genes are dispensable, with the Glp1r, Gipr, and Grlr being lost on the lineages leading to bony fish, birds, and mammals, respectively. The loss of the genes for these receptors may have been driving forces in the evolution of new functions for these peptides similar to glucagon.
Glucagon is thought to increase heart rate and contractility by stimulating glucagon receptors and increasing 3',5'-cyclic adenosine monophosphate (cAMP) production in the myocardium. This has been confirmed in animal studies but not in the human heart. The cardiostimulatory effects of glucagon have been correlated with the degree of cardiac dysfunction, as well as with the enzymatic activity of phosphodiesterase (PDE), which hydrolyses cAMP. In this study, the presence of glucagon receptors in the human heart and the inotropic and chronotropic effects of glucagon in samples of failing and nonfailing (NF) human hearts were investigated.
The gut-brain peptide glucagon-like peptide-1 (GLP-1) reduces reward from palatable food and drugs of abuse. Recent rodent studies show that activation of GLP-1 receptors (GLP-1R) within the nucleus of the solitary tract (NTS) not only suppresses the motivation and intake of palatable food, but also reduces alcohol-related behaviors. As reward induced by addictive drugs and sexual behaviors involve similar neurocircuits, we hypothesized that activation of GLP-1R suppresses sexual behavior in sexually naïve male mice. We initially identified that systemic administration of the GLP-1R agonist, exendin-4 (Ex4), decreased the frequency and duration of mounting behaviors, but did not alter the preference for females or female bedding. Thereafter infusion of Ex4 into the NTS decreased various behaviors of the sexual interaction chain, namely social, mounting and self-grooming behaviors. In male mice tested in the sexual interaction test, NTS-Ex4 increased dopamine turnover and enhanced serotonin levels in the nucleus accumbens (NAc). In addition, these mice displayed higher corticosterone, but not testosterone, levels in plasma. Finally, GLP-1R antagonist, exendin-3 (9-39) amide (Ex9), infused into the NTS differentially altered the ability of systemic-Ex4 to suppress the various behaviors of the sexual interaction chain, indicating that GLP-1R within the NTS is one of many sub-regions contributing to the GLP-1 dependent sexual behavior link. In these mice NTS-Ex9 partly blocked the systemic-Ex4 enhancement of corticosterone levels. Collectively, these data highlight that activation of GLP-1R, specifically those in the NTS, reduces sexual interaction behaviors in sexually naïve male mice and further provide a link between NTS-GLP-1R activation and reward-related behaviors.
Glucagon-like peptide-1 receptor (GLP-1R) agonists, such as exendin-4 (Ex4), liraglutide and dulaglutide, regulate glucose homeostasis and are thus used to treat diabetes type II. GLP-1 also contributes towards a variety of additional physiological functions, including suppression of reward and improvement of learning. Acute activation of GLP-1R in the nucleus accumbens (NAc) shell, an area essential for motivation, reduces the motivation to consume sucrose or alcohol when assessed in a simple motor task. However, the effects of repeated administration of the different GLP-1R agonists on behaviours in a more complex motor task are unknown. The aim was therefore to investigate the effects of repeated Ex4, liraglutide or dulaglutide on the motivation and learning of a complex motor tasks such as skilled reach foraging in the Montoya staircase test. To explore the neurophysiological correlates of the different GLP-1R agonists on motivation, ex vivo electrophysiological recordings were conducted. In rats with an acquired skilled reach performance, Ex4 or liraglutide but not dulaglutide reduced the motivation of skilled reach foraging. In trained rats, Ex4 infusion into NAc shell decreased this motivated behaviour, and both Ex4 and liraglutide supressed the evoked field potentials in NAc shell. In rats without prior Montoya experience, dulaglutide but not Ex4 or liraglutide enhanced the learning of skilled reach foraging. Taken together, these findings indicate that the tested GLP-1R agonists have different behavioural outcomes depending on the context.
Myopia is a condition in which the eye is too long for the focal length of cornea and lens. Analysis of the messengers that are released by the retina to control axial eye growth in the animal model of the chicken revealed that glucagon-immunoreactive amacrine cells are involved in the retinal image processing that controls the growth of the sclera. It was found that the amount of retinal glucagon mRNA increased during treatment with positive lenses and pharmacological studies supported the idea that glucagon may act as a stop signal for eye growth. Glucagon exerts its regulatory effects by binding to a single type of glucagon receptor. In this study, we have sequenced the chicken glucagon receptor and compared its DNA and amino acid sequence with the human and mouse homologues. After sequencing about 80% of the receptor, we found a homology between 79.4 and 75.6% on cDNA level. At the protein level, about 73% of the amino acids were identical. Moreover, the cellular localization and regulation of the glucagon receptor in the chick retina was studied. In situ hybridization studies showed that many cells in the ganglion cell layer and inner nuclear layer, and some cells in the outer nuclear layer, express the receptor mRNA. Injection of the glucagon agonist Lys17,18,Glu21-glucagon induced a down-regulation of glucagon receptor mRNA content. Since the mouse would be an attractive mammalian model to study the biochemical and genetic basis of myopia, and because recent studies have demonstrated that form deprivation myopia can be induced, the expression of preproglucagon and glucagon receptor genes were also studied in the mouse retina and were found to be expressed.
Dopamine (DA) and norepinephrine (NE) are catecholamines primarily studied in the central nervous system that also act in the pancreas as peripheral regulators of metabolism. Pancreatic catecholamine signaling has also been increasingly implicated as a mechanism responsible for the metabolic disturbances produced by antipsychotic drugs (APDs). Critically, however, the mechanisms by which catecholamines modulate pancreatic hormone release are not completely understood. We show that human and mouse pancreatic α- and β-cells express the catecholamine biosynthetic and signaling machinery, and that α-cells synthesize DA de novo. This locally-produced pancreatic DA signals via both α- and β-cell adrenergic and dopaminergic receptors with different affinities to regulate glucagon and insulin release. Significantly, we show DA functions as a biased agonist at α2A-adrenergic receptors, preferentially signaling via the canonical G protein-mediated pathway. Our findings highlight the interplay between DA and NE signaling as a novel form of regulation to modulate pancreatic hormone release. Lastly, pharmacological blockade of DA D2-like receptors in human islets with APDs significantly raises insulin and glucagon release. This offers a new mechanism where APDs act directly on islet α- and β-cell targets to produce metabolic disturbances.
Glucagon-like peptide-1 (GLP-1) promotes glucose homeostasis through regulation of islet hormone secretion, as well as hepatic and gastric function. Because GLP-1 is also synthesized in the brain, where it regulates food intake, we hypothesized that the central GLP-1 system regulates glucose tolerance as well.
Multiple G protein-coupled receptors (GPCRs) are expressed in pancreatic islet cells, but the majority have unknown functions. We observed specific GPCRs localized to primary cilia, a prominent signaling organelle, in pancreatic α and β cells. Loss of cilia disrupts β-cell endocrine function, but the molecular drivers are unknown. Using functional expression, we identified multiple GPCRs localized to cilia in mouse and human islet α and β cells, including FFAR4, PTGER4, ADRB2, KISS1R, and P2RY14. Free fatty acid receptor 4 (FFAR4) and prostaglandin E receptor 4 (PTGER4) agonists stimulate ciliary cAMP signaling and promote glucagon and insulin secretion by α- and β-cell lines and by mouse and human islets. Transport of GPCRs to primary cilia requires TULP3, whose knockdown in primary human and mouse islets relocalized ciliary FFAR4 and PTGER4 and impaired regulated glucagon or insulin secretion, without affecting ciliary structure. Our findings provide index evidence that regulated hormone secretion by islet α and β cells is controlled by ciliary GPCRs providing new targets for diabetes.
Ingested glucose is detected by specialized sensors in the enteric/hepatoportal vein, which send neural signals to the brain, which in turn regulates key peripheral tissues. Hence, impairment in the control of enteric-neural glucose sensing could contribute to disordered glucose homeostasis. The aim of this study was to determine the cells in the brain targeted by the activation of the enteric glucose-sensing system.
There has been a dramatic increase in illicit fentanyl use in the United States over the last decade. In 2018, more than 31,000 overdose deaths involved fentanyl or fentanyl analogs, highlighting an urgent need to identify effective treatments for fentanyl use disorder. An emerging literature shows that glucagon-like peptide-1 receptor (GLP-1R) agonists attenuate the reinforcing efficacy of drugs of abuse. However, the effects of GLP-1R agonists on fentanyl-mediated behaviors are unknown. The first goal of this study was to determine if the GLP-1R agonist exendin-4 reduced fentanyl self-administration and the reinstatement of fentanyl-seeking behavior, an animal model of relapse, in rats. We found that systemic exendin-4 attenuated fentanyl taking and seeking at doses that also produced malaise-like effects in rats. To overcome these adverse effects and enhance the clinical potential of GLP-1R agonists, we recently developed a novel dual agonist of GLP-1Rs and neuropeptide Y2 receptors (Y2Rs), GEP44, that does not produce nausea-like behavior in drug-naïve rats or emesis in drug-naïve shrews. The second goal of this study was to determine if GEP44 reduced fentanyl self-administration and reinstatement with fewer adverse effects compared to exendin-4 alone. In contrast to exendin-4, GEP44 attenuated opioid taking and seeking at a dose that did not suppress food intake or produce adverse malaise-like effects in fentanyl-experienced rats. Taken together, these findings indicate a novel role for GLP-1Rs and Y2Rs in fentanyl reinforcement and highlight a potential new therapeutic approach to treating opioid use disorders.
Glucagon-like peptide-1 (GLP-1) and glucagon (GCG) receptor dual agonist have promising therapeutic effects in the treatment of obesity and diabetes. Moreover, GLP-1 and cholecystokinin 2 (CCK2 ) dual agonists have been shown to restore pancreas function and improve glycaemic control in preclinical studies. We describe, for the first time, the beneficial effects of GLP-1/glucagon receptor and GLP-1/CCK2 dual agonists, which can be integrated into one peptide, resulting in significant anti-diabetes and anti-obesity effectiveness.
Receptors for the peptide hormones glucagon-like peptide-1 (GLP-1R), glucose-dependent insulinotropic polypeptide (GIPR), and glucagon (GCGR) are important regulators of insulin secretion and energy metabolism. GLP-1R agonists have been successfully deployed for the treatment of type 2 diabetes, but it has been suggested that their efficacy is limited by target receptor desensitization and downregulation due to recruitment of β-arrestins. Indeed, recently described GLP-1R agonists with reduced β-arrestin-2 recruitment have delivered promising results in preclinical and clinical studies. We therefore aimed to determine if the same phenomenon could apply to the closely related GIPR and GCGR. In HEK293 cells depleted of both β-arrestin isoforms the duration of G protein-dependent cAMP/PKA signaling was increased in response to the endogenous ligand for each receptor. Moreover, in wildtype cells, "biased" GLP-1, GCG, and GIP analogs with selective reductions in β-arrestin-2 recruitment led to reduced receptor endocytosis and increased insulin secretion over a prolonged stimulation period, although the latter effect was only seen at high agonist concentrations. Biased GCG analogs increased the duration of cAMP signaling, but this did not lead to increased glucose output from hepatocytes. Our study provides a rationale for the development of GLP-1R, GIPR, and GCGR agonists with reduced β-arrestin recruitment, but further work is needed to maximally exploit this strategy for therapeutic purposes.
Adrenaline reacts with three types of adrenergic receptors, α1, α2 and β-adrenergic receptors (ARs), inducing many physiological events including exocytosis. Although adrenaline has been shown to induce glucagon-like peptide-1 (GLP-1) secretion from intestinal L cells, the precise molecular mechanism by which adrenaline regulates GLP-1 secretion remains unknown. Here we show by live cell imaging that all types of adrenergic receptors are stimulated by adrenaline in enteroendocrine L cell line GLUTag cells and are involved in GLP-1 exocytosis. We performed RT-PCR analysis and found that α1B-, α2A-, α2B-, and β1-ARs were expressed in GLUTag cells. Application of adrenaline induced a significant increase of intracellular Ca(2+) and cAMP concentration ([Ca(2+)]i and [cAMP]i, respectively), and GLP-1 exocytosis in GLUTag cells. Blockade of α1-AR inhibited adrenaline-induced [Ca(2+)]i increase and exocytosis but not [cAMP]i increase, while blockade of β1-AR inhibited adrenaline-induced [cAMP]i increase and exocytosis but not [Ca(2+)]i increase. Furthermore, overexpression of α2A-AR suppressed the adrenaline-induced [cAMP]i increase and exocytosis. These results suggest that the fine-turning of GLP-1 secretion from enteroendocrine L cells is established by the balance between α1-, α2-, and β-ARs activation.
The exopolysaccharide preparation of Bacillus amyloliquefaciens amy-1 (EPS) regulates glycemic levels and promotes glucagon-like peptide 1 (GLP-1) secretion in vivo and in vitro. This study aimed to identify the molecular mechanism underlying EPS-induced GLP-1 secretion. HEK293T cells stably expressing human Gα-gustducin were used as a heterologous system for expressing the genes of human bitter taste receptor (T2R) 10, 14, 30, 38 (PAV), 38 (AVI), 43, and 46, which were expressed as recombinant proteins with an N-terminal tag composed of a Lucy peptide and a human somatostatin receptor subtype 3 fragment for membrane targeting and a C-terminal red fluorescent protein for expression monitoring. EPS induced a dose-dependent calcium response from the human NCI-H716 enteroendocrine cell line revealed by fluorescent calcium imaging, but inhibitors of the G protein-coupled receptor pathway suppressed the response. EPS activated heterologously expressed T2R14 and T2R38 (PAV). shRNAs of T2R14 effectively inhibited EPS-induced calcium response and GLP-1 secretion in NCI-H716 cells, suggesting the involvement of T2R14 in these effects. The involvement of T2R38 was not characterized because NCI-H716 cells express T2R38 (AVI). In conclusion, the activation of T2Rs mediates EPS-induced GLP-1 secretion from enteroendocrine cells, and T2R14 is a critical target activated by EPS in these cells.
Aggression is a complex social behavior, which is provoked in the defense of limited resources including food and mates. Recent advances show that the gut-brain hormone ghrelin modulates aggressive behaviors. As the gut-brain hormone glucagon-like peptide-1 (GLP-1) reduces food intake and sexual behaviors its potential role in aggressive behaviors is likely. Therefore, we investigated a tentative link between GLP-1 and aggressive behaviors by combining preclinical and human genetic-association studies. The influence of acute or repeated injections of a GLP-1 receptor (GLP-1R) agonist, exendin-4 (Ex4), on aggressive behaviors was assessed in male mice exposed to the resident-intruder paradigm. Besides, possible mechanisms participating in the ability of Ex4 to reduce aggressive behaviors were evaluated. Associations of polymorphisms in GLP-1R genes and overt aggression in males of the CATSS cohort were assessed. In male mice, repeated, but not acute, Ex4 treatment dose-dependently reduced aggressive behaviors. Neurochemical and western blot studies further revealed that putative serotonergic and noradrenergic signaling in nucleus accumbens, specifically the shell compartment, may participate in the interaction between Ex4 and aggression. As high-fat diet (HFD) impairs the responsiveness to GLP-1 on various behaviors the possibility that HFD blunts the ability of Ex4 to reduce aggressive behaviors was explored. Indeed, the levels of aggression was similar in vehicle and Ex4 treated mice consuming HFD. In humans, there were no associations between polymorphisms of the GLP-1R genes and overt aggression. Overall, GLP-1 signaling suppresses acquisition of aggressive behaviors via central neurotransmission and additional studies exploring this link are warranted.
The glucagon receptor (GCGR) activated by the peptide hormone glucagon is a seven-transmembrane G protein-coupled receptor (GPCR) that regulates blood glucose levels. Ubiquitination influences trafficking and signaling of many GPCRs, but its characterization for the GCGR is lacking. Using endocytic colocalization and ubiquitination assays, we have identified a correlation between the ubiquitination profile and recycling of the GCGR. Our experiments revealed that GCGRs are constitutively ubiquitinated at the cell surface. Glucagon stimulation not only promoted GCGR endocytic trafficking through Rab5a early endosomes and Rab4a recycling endosomes, but also induced rapid deubiquitination of GCGRs. Inhibiting GCGR internalization or disrupting endocytic trafficking prevented agonist-induced deubiquitination of the GCGR. Furthermore, a Rab4a dominant negative (DN) that blocks trafficking at recycling endosomes enabled GCGR deubiquitination, whereas a Rab5a DN that blocks trafficking at early endosomes eliminated agonist-induced GCGR deubiquitination. By down-regulating candidate deubiquitinases that are either linked with GPCR trafficking or localized on endosomes, we identified signal-transducing adaptor molecule-binding protein (STAMBP) and ubiquitin-specific protease 33 (USP33) as cognate deubiquitinases for the GCGR. Our data suggest that USP33 constitutively deubiquitinates the GCGR, whereas both STAMBP and USP33 deubiquitinate agonist-activated GCGRs at early endosomes. A mutant GCGR with all five intracellular lysines altered to arginines remains deubiquitinated and shows augmented trafficking to Rab4a recycling endosomes compared with the WT, thus affirming the role of deubiquitination in GCGR recycling. We conclude that the GCGRs are rapidly deubiquitinated after agonist-activation to facilitate Rab4a-dependent recycling and that USP33 and STAMBP activities are critical for the endocytic recycling of the GCGR.
The detrimental effects of high fructose consumption on metabolic health have been extensively studied. However, limited research has focused on the impact of fructose intake on neuroprotective mechanisms, specifically the expression of insulin receptor (INSR) and glucagon-like peptide-1 receptor (GLP-1R) in the hippocampus. Understanding the effects of fructose on these neuroprotective molecules can provide valuable insights into the potential role of fructose in hippocampal dysfunction. The goal of this study is to aim at the basal plasma levels of lipid profile, insulin, GLP-1, and HOMA-IR, as well as the mRNA and protein expression of neuroprotective molecules such as INSR and GLP-1R in Wistar rats fed a high fructose diet.
Family B G protein-coupled receptors (GPCRs) play vital roles in hormone-regulated homeostasis. They are drug targets for metabolic diseases, including type 2 diabetes and osteoporosis. Despite their importance, the signaling mechanisms for family B GPCRs at the molecular level remain largely unexplored due to the challenges in purification of functional receptors in sufficient amount for biophysical characterization. Here, we purified the family B GPCR human glucagon-like peptide-1 (GLP-1) receptor (GLP1R), whose agonists, e.g. exendin-4, are used for the treatment of type 2 diabetes mellitus. The receptor was expressed in HEK293S GnTl- cells using our recently developed protocol. The protocol incorporates the receptor into the native-like lipid environment of reconstituted high density lipoprotein (rHDL) particles, also known as nanodiscs, immediately after the membrane solubilization step followed by chromatographic purification, minimizing detergent contact with the target receptor to reduce denaturation and prolonging stabilization of receptor in lipid bilayers without extra steps of reconstitution. This method yielded purified GLP1R in nanodiscs that could bind to GLP-1 and exendin-4 and activate Gs protein. This nanodisc purification method can potentially be a general strategy to routinely obtain purified family B GPCRs in the 10s of microgram amounts useful for spectroscopic analysis of receptor functions and activation mechanisms.
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