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Glucagon receptor signaling

Glucagon receptor signaling

Signaljng, potential adverse effects of Glucagon receptor signaling therapeutic approach Almond recipes increased low-density lipoprotein LDL sinaling Dehydration and nausea and increased hepatic fat accumulation Guzman Glucagon receptor signaling al. Indirect calorimetry. Signaping, M. Lack of Gcgr signaling sivnaling been receltor with: i hypoglycemic Carbohydrates and Energy, altered recepyor, poor fetal growth, and Glucagon receptor signaling Gluczgon death; siggnaling pancreatic glucagon cell hyperplasia and hyperglucagonemia; iii altered body composition, energy state, and protection from diet-induced obesity; iv impaired hepatocyte survival; v altered glucose, lipid, and hormonal milieu; vi altered metabolic response to prolonged fasting and exercise; vii reduced gastric emptying and increased intestinal length; viii altered retinal function; and ix prevention of the development of diabetes in insulin-deficient mice. The role of glucagon in glucose metabolism has been intensively studied, and comprehensive reviews are found elsewhere Jiang and Zhang, ; Ramnanan et al. Carnitine leaves the mitochondria matrix through the carnitine-acylcarnitine translocase. Lipolysis in adipocytes depends on activation of AC and thereby increased protein kinase A PKA activity.

Glucagon receptor signaling -

Klb is expressed by neurons in the suprachiasmatic nucleus SCN of the hypothalamus and the hindbrain 33 , Supraphysiological levels of FGF21 alter circadian locomotor behavior via central Klb , independent of changes in SCN clock gene expression Therefore, we next assessed whether central Klb modulates circadian locomotor behavior.

Similar periods of endogenous rhythms were observed during constant dark conditions, regardless of genotype Supplemental Figure 1, D and E. Together, this suggests that central Klb may regulate components of circadian locomotor behavior, but endogenous FGF21 is not required for general rhythmic homeostasis.

Consistently, we observed a significant decrease in Klb expression in adipose and liver tissues in control DIO mice 8-week HFD , while hypothalamic Klb expression was unchanged Supplemental Figure 2A , first and third bars.

However, there was no further reduction in Klb expression between lean and DIO Klb ΔCNS mice Figure 2A and Supplemental Figure 2A , last 2 bars.

Diet-induced obesity in Klb ΔCNS mice. Glucose tolerance C ; 5-hour fast, 1. Mice were fed chow diet for first 83 hours. Dotted line indicates start of HFD at 84 hours. eWAT, epididymal white adipose tissue; iWAT, inguinal white adipose tissue.

Central Klb alters diet-induced weight gain. HFD feeding increases adiposity diet-induced obesity and induces metabolic dysregulation. To assess the role of central KLB in the adaptation to this insult, we exposed control and Klb ΔCNS mice to an HFD for 8 weeks.

Unlike the lean, chow-fed model described above, hypothalamic Klb expression was exclusively reduced in these mice as compared with their littermate controls Figure 2A. We hypothesized that the reduced sensitivity to diet-induced obesity may be due to an increase in EE when Klb ΔCNS mice were switched to HFD.

Therefore, we conducted indirect calorimetry on lean, chow-fed control and Klb ΔCNS mice for 3 days prior to 7 days of high-fat feeding. Similar EE and respiratory energy ratio RER were observed between genotypes during the first 3 days Figure 2, E and F ; first 83 hours. When switched to HFD Figure 2, E and F ; 84 hours, dotted line , control mice exhibited an increase in EE and a decrease in respiratory quotient Figure 2, E and F , as expected.

In opposition to our original hypothesis, there were no genotypic differences in EE Figure 2E , 84— hours; and Supplemental Figure 2C , RER Figure 2F , 84— hours; and Supplemental Figure 2D , or diurnal food intake Supplemental Figure 2E on HFD.

These data suggest that central Klb modulates diet-induced obesity sensitivity but that this regulation is not dependent upon changes in EE. Central Klb contributes to GCGR-stimulated weight loss. Chronic GCGR agonism via IUB promotes weight loss and improves lipid homeostasis in DIO mice 13 , 14 , Based on these findings, we sought to establish the role of central FGF21 signaling, via neuronal Klb , in GCGR-stimulated weight loss.

Following diet-induced obesity, mice were weight-matched within genotypic groups to receive vehicle or IUB treatment for 12 days. Unlike liver lipids, plasma TG were unaltered by IUB treatment, regardless of genotype Figure 3E , left panel. Taken together, GCGR-mediated improvements in lipid metabolism are independent of central Klb.

GCGR agonism in Klb ΔCNS mice. GCGR agonist: IUB Central ablation of this receptor may induce compensatory upregulation of the ligand i.

To interrogate potential compensation via increased FGF21, we assessed liver Fgf21 expression and plasma FGF21 levels in vehicle- and IUBtreated mice. Likewise, we observed similar expression Supplemental Figure 2H and plasma protein levels in Klb ΔCNS mice Figure 3F , suggesting there is no compensatory upregulation of FGF21 in response to loss of central Klb.

Together, these data suggest that central Klb mediates antiobesity, but not lipid-lowering, properties of GCGR agonism. Central KLB antagonism mitigates GCGR-mediated weight loss.

To exclude potential artifacts of developmental Klb deficiency, we next employed central intracerebroventricular, ICV administration of the competitive pharmacological KLB antagonist, Due to potential spillover of cerebrospinal fluid into the periphery from ICV delivery, we sought a dose of that would be subthreshold for peripheral action.

Acute FGF21 action improves glucose and insulin tolerance via peripheral adipose KLB 41 — As such, we used glucose tolerance as a readout of peripheral FGF21 action to assess the physiological effects of Therefore, we chose the subthreshold dose of 0.

All pumps delivered vehicle or 0. Mice received for 2 days before the start of IUB day 1; dotted line , to ensure adequate time for KLB antagonism. However, IUBmediated suppression of food intake was maintained in treated mice, suggesting that IUB mediates food intake independent of central FGF21 signaling.

Moreover, these data suggest that the partial reductions in body weight are not mediated via differences in food intake. GCGR agonism in mice with KLB antagonism. BAT UCP1 protein levels normalized to total protein H. KLB antagonist: Central KLB antagonism mitigates GCGR-mediated EE.

Chronic GCGR agonism increases EE in lean and DIO mice 13 , KLB antagonism alone did not alter these parameters; however, mice with KLB antagonism were resistant to IUBstimulated EE Figure 4, C and D but not IUBmediated reduction in RER Figure 4E.

Moreover, central FGF21 signaling upregulates brown adipose tissue BAT uncoupling protein 1 Ucp1 expression This suggests that central FGF21 signaling mediates GCGR-stimulated weight loss via EE but independent of BAT UCP1.

Central KLB is dispensable for GCGR-mediated improvements in lipid metabolism. Chronic GCGR agonism is a potent regulator of lipid metabolism, including reducing plasma cholesterol and liver TG 13 , 14 , While we had previously observed IUBstimulated increases in plasma bile acids 13 , this observation did not persist in the current study Figure 5B , right panel.

Expression of genes involved in cholesterol biosynthesis Hmgcr and Srebp-1 are decreased with IUB, regardless of Figure 5E , suggesting the increased liver cholesterol is independent of cholesterol biosynthesis. FGF21, lipid, and Fgf15 profile in mice with KLB antagonism.

Plasma FGF21 A , plasma lipids B , liver TG C , liver cholesterol D , liver cholesterol synthesis genes E , and ileum Fgf15 expression F in control and DIO mice with day minipump ICV 0. CHL, cholesterol; BA, bile acids. Liver FGF21 and farnesoid X receptor FXR are both downstream pathways that mediate GCGR-stimulated weight loss However, despite this increase in gene expression, we observed no effects on the FXR target genes Cyp7a1 and Shp Supplemental Figure 3F.

In our model, Fgf15 expression was unperturbed by chronic GCGR agonism or KLB antagonism Figure 5F. However, Fgf15 was significantly increased in mice cotreated with IUB These data suggest that FGF15 does not likely play a role in GCGR-mediated weight loss, and Fgf15 expression in IUBtreated mice is likely a result of compensatory upregulation.

Together, these data suggest GCGR agonism mediates weight loss, but not improvements in lipid metabolism, via central FGF21 signaling. Central KLB is dispensable in GCGR-mediated glucose homeostasis.

We previously reported that chronic GCGR agonism impairs glucose tolerance Historically, glucagon has been viewed as the main counterregulatory hormone to insulin.

However, emerging evidence suggests a more complex relationship of glucagon in glucose homeostasis. Surprisingly, acute glucagon and IUB increase insulin secretion 48 , Additionally, we have reported that acute and chronic IUB improves insulin sensitivity in both lean and DIO mice 28 , Together, these data suggest central KLB regulates circulating insulin levels but is dispensable in GCGR-mediated glucose homeostasis.

Glucose homeostasis in mice with KLB antagonism. Glucose tolerance test A ; 5-hour fast, 1. Plasma insulin C , blood glucose D , and islet fluorescent immunohistochemistry E following a 2-hour fast. Ins, insulin green ; Gcg, glucagon red ; Sst, somatostatin blue.

Scale bar: 50 μm. Emerging evidence has highlighted the beneficial effects of GCGR signaling on energy balance and lipid metabolism 12 , 50 , bringing renewed attention to the therapeutic manipulation of the glucagon signaling pathway.

Despite these beneficial effects, GCGR monoagonism induces hyperglycemia, which diminishes utility. Therefore, it is increasingly important to understand the downstream mechanisms by which GCGR signaling regulates these metabolic benefits. We previously identified FGF21 as a downstream target of hepatic GCGR signaling and a partial mediator of GCGR-mediated weight loss Liver-derived FGF21 acts centrally to mediate energy expenditure and weight loss 33 , 35 ; thus, we hypothesized that GCGR-mediated FGF21 similarly acts in the brain to regulate this effect.

Central Klb regulation of energy balance and circadian homeostasis in lean mice. Since the discovery of FGF21 as a novel endocrine fibroblast growth factor 20 , much attention has been given to its physiological role in energy balance and the tissues critical for FGF21 action. FGF21 signaling, via KLB, in adipose tissue is necessary for the beneficial effects of FGF21 on glucose metabolism 42 , FGF21 action in the brain regulates both EE 35 and circadian rhythms Studies herein uncovered that conditional developmental deletion of neuronal Klb does not alter body weight, glucose homeostasis, EE, or food intake in lean mice.

Together these findings suggest that endogenous FGF21 is dispensable in the regulation of unchallenged energy balance or glucose homeostasis.

FGF21 exhibits a diurnal rhythm in 52 , 53 and humans 54 , and overexpression of FGF21 disrupts circadian locomotor behavior via hypothalamic Klb Bookout et al. In the present study, control and Klb ΔCNS mice displayed relatively similar diurnal locomotor activity; however, there was a trend toward an increase in light activity absolute and percentage of total activity in the Klb ΔCNS mice.

Although supraphysiological FGF21 levels clearly alter circadian rhythms via central Klb 33 , data herein suggest that loss of endogenous FGF21 signaling in the brain mediates subtle aspects of circadian rhythms but is not required for general circadian homeostasis.

However, these interpretations must be tempered by the suppression of Klb expression in non-neuronal tissues. Central KLB in diet-induced obesity and GCGR-mediated weight loss. Forebrain Klb -deficient mice also exhibit no differences in body weight on a chow diet 35 , consistent with our results.

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Strazzullo P, Iacone R, Siani A, Barba G, Russo O, Russo P, Barbato A, D'Elia L, Farinaro E, Cappuccio FP Oct Journal of Molecular Medicine. Shiota D, Kasamatsu T, Dib SA, Chacra AR, Moisés RS May Runge S, Gram C, Brauner-Osborne H, Madsen K, Knudsen LB, Wulff BS Jul Hassel S, Eichner A, Yakymovych M, Hellman U, Knaus P, Souchelnytskyi S May Mortensen OH, Dichmann DS, Abrahamsen N, Grunnet N, Nishimura E May Cell surface receptor : G protein-coupled receptors.

Class A : Rhodopsin -like. Acetylcholine M1 M2 M3 M4 M5 Dopamine D1 D2 D3 D4 D5 GHB receptor Histamine H1 H2 H3 H4 Melatonin 1A 1B 1C TAAR 1 2 5 6 8 9.

The glucagon signaling Core strengthening exercises refers Gluxagon the sum of Dehydration and nausea series of receptkr Dehydration and nausea regulatory factors involved recepfor the recceptor of glucagon. Glucgaon pancreatic hyperglycemia Dehydration and nausea a linear polypeptide consisting of 29 amino acids with a molecular weight ofwhich is also cleaved by precursors of macromolecules. In contrast to the role of the insulin signaling pathway, the glucagon signaling pathway is a pathway that promotes catabolism. The glucagon signaling pathway has a strong role in promoting glycogenolysis and gluconeogenesis, resulting in a significant increase in blood glucose. The glucagon signaling pathway activates hepatocyte phosphorylase and accelerates glycogenolysis through the cAMP-PK system.

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Insulin Signaling Cascade and Downstream Effects - Biochemistry Lesson

Glucagon action is sivnaling by a Dehydration and nausea protein-coupled receptor recptor in liver, kidney, intestinal smooth muscle, brain, adipose tissue, heart, pancreatic β-cells, and placenta.

Genetically modified Goucagon models have provided signa,ing clues about the role of glucagon and its receptor Gcgr beyond Herbal Anti-Inflammatory control. The PubMed signaping was searched for articles published between and using the key terms glucagon, glucagon receptor, signaling, and animal models.

Lack of Gcgr signaling has been associated Glucagkn i hypoglycemic pregnancies, Glucabon placentation, poor fetal growth, Glucagon receptor signaling, and erceptor fetal—neonatal recptor ii pancreatic recetor cell hyperplasia and hyperglucagonemia; Glucagno altered body composition, energy state, and protection from diet-induced Glucagon receptor signaling iv impaired signa,ing survival; v altered glucose, lipid, and hormonal Glucayon vi altered metabolic response to prolonged fasting and exercise; vii reduced gastric emptying and increased intestinal length; Pre-workout meal planning guide altered retinal function; and ix prevention of the development of diabetes in insulin-deficient mice.

Similar phenotypic sigbaling were observed in the hepatocyte-specific deletion of Gcgr. Siggnaling action has been involved in the modulation of sweet taste responsiveness, inotropic and chronotropic effects in the heart, satiety, glomerular filtration signalinb, secretion of insulin, cortisol, ghrelin, GH, recwptor, and somatostatin, and signaoing signaling to suppress hepatic glucose Glucagoh.

Glucagon α cells under certain conditions can transdifferentiate into insulin β cells. These findings suggest that glucagon signaling plays an important role in multiple organs. Thus, treatment options designed to block Gcgr activation slgnaling diabetics may have implications beyond glucose homeostasis.

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Between andSignlaing et al. developed a RIA making it possible to investigate the physiology of glucagon and its role in various disorders Unger et al.

As a counter-regulatory hormone, glucagon maintains blood glucose levels by activating glycogenolysis signalig gluconeogenesis. In addition, glucagon reduces triglyceride, very LDL release, signalinng Glucagon receptor signaling levels and stimulates fatty zignaling oxidation EatonLonguet et al.

Beyond refeptor homeostasis, glucagon elicits significant extra-hepatic effects in tissues such as kidney, heart, refeptor tissue white rsceptor browngastrointestinal signalint, thyroid, and CNS LefebvreBurcelin et al. cAMP activates signaling pathways that cause an increase slgnaling gluconeogenesis, glycogenolysis, and fatty acid oxidation.

Binding sites for glucagon have ssignaling identified in liver, kidney, intestinal smooth Glucagon receptor signaling, brain, adipose tissue, heart, pancreatic islet Glufagon, and placenta Ouhilal et al. Gcgr gene expression is positively regulated by glucose and Organic zero-waste lifestyle regulated by glucagon and agents that increase intracellular cAMP Quesada et al.

This review will focus on the role of glucagon and glucagon G,ucagon in fetal growth, pancreatic Signaping, and glucose and lipid recpetor in genetically Glucagno animal models that have been Glicagon to provide important signaaling about Glucagon receptor signaling role of glucagon signalinb health and disease.

Preseason Training Program models provide an invaluable tool to study the underlying mechanisms refeptor with rexeptor action; however, they have the disadvantage Glkcagon genetic signalingg could lead to lifelong Overcoming anxiety naturally that can skew results.

Thus, some of the findings may not necessarily translate into human disease. The PubMed Concentration and meditation was searched for Glucabon published between and using the key terms glucagon, glucagon receptor, and rwceptor models.

Glycagon obtained from this search are wignaling in this review. A brief summary of all the known metabolic changes that have been identified Dehydration and nausea genetically modified animal models with sigbaling Gcgr signalnig is Gluvagon in Fig. Citation: Journal of SkgnalingWhole grains for energy Disruption of sgnaling glucagon receptor gene Gcgr during pregnancy is associated with maternal hypoglycemia, hyperglucagonemia, abnormalities of placentation, poor fetal growth, and increased fetal and early postnatal death.

In addition, lack of glucagon placental signaling down-regulates genes that control growth, adrenergic signaling, vascularization, oxidative stress, and G protein-coupled receptors Ouhilal et al.

During fetal sitnaling, glucagon is required for early insulin sibnaling β-cell differentiation and to mature Glucgaon subset of glucagon cells Vuguin et signalint.

In rodent models, disruption of recdptor Gcgr gene signxling associated with an increase in the number of pancreatic islets and an increase in the number of somatostatin cells without altering Glucagkn cell mass. Lack of glucagon signaling is also associated with a profound glucagon cell hyperplasia.

A subset of those glucagon cells coexpress markers of immature islet endocrine cells such as insulin, PDX1, and glucose transporter 2 Vuguin et al.

In those studies, α or glucagon cell expansion is accompanied by elevated plasma glucagon levels. One exception has been the study by Liang et al. Glucagon has beneficial effects on food intake, body fat mass, and energy expenditure Habegger et al.

In addition, glucagon has a satiety effect by decreasing meal size through a combination of peripheral and central actions Heppner et al. Consistent with a role in modulating food intake, glucagon also appears to affect the regulation of body weight by promoting weight loss in physiological and pathological doses as observed in patients with glucagonoma Schulman et al.

In addition, rodent models and in vitro studies have demonstrated that glucagon increases energy Gljcagon through activation of brown adipose tissue Billington et al.

Disruption of the Gcgr signling is associated with a significant decrease in total adipose tissue, which is compensated for by an increase in lean body mass.

The changes in body composition are not accompanied by a change in growth rates, food intake, resting O 2 consumption, and signalingg expenditure when compared with WT littermates Gelling et al.

Moreover, glucagon is essential for hepatocyte survival via regulation of cAMP-dependent pathways that decrease caspase activity Sinclair et al. Glucagon plays a central role in the response to hypoglycemia by stimulating gluconeogenesis and glycogenolysis and opposing the insulin effects.

Its main action on the liver is mediated by the activation of adenylyl cyclase and the protein kinase A signaling pathway Quesada et signzling. Glucagon stimulates changes to lower the energy state by activating AMPK signaling in the liver, thereby improving the efficiency by which the liver converts gluconeogenic substrate into glucose following glucagon stimulation Berglund et al.

Glucagon has also been shown to have an inhibitory effect on insulin secretion. It has been recently shown that glucagon stimulated signaling, via cAMP—PKA—CREB, and the subsequent hepatic production of kisspeptin 1 suppresses insulin secretion Song et al.

In addition to its effect on the liver, glucagon can suppress hepatic glucose production by acting through the mediobasal hypothalamic region of the brain, suggesting that glucagon can limit its own direct stimulatory effect in the liver Mighiu et al. The lipolytic effect of glucagon in humans has been challenged Gravholt et al.

In animal models, glucagon has potent hypolipidemic actions EatonGuettet et al. Glucagon decreases triglyceride and very-LDL release by the liver Guettet et al. Glucagon action on lipid metabolism is mediated through AMPK- p38 MAPK- PPARα- Foxa2- and FGFdependent mechanisms Longuet et al.

In addition, glucagon plays a central role in fatty acid oxidization during prolonged fasting and in response to exercise Longuet et al. In rodent models, disruption of the Gcgr gene is associated with lower blood glucose levels during the day and the development of hypoglycemia during a prolonged fast, increased plasma LDL, and, in female rodents, decreased levels of triglycerides Gelling et al.

Glucagon does not seem to play an important role in insulin action but induces glucose-stimulated insulin release Gelling et al. Similarly, glucagon action stimulates its own secretion in isolated rat and mouse glucagon cells by increasing cAMP levels and stimulating somatostatin release Shimatsu et al.

In humans, glucagon also has a variety of neuroendocrine effects including the stimulation of GH and cortisol secretion and inhibition of ghrelin secretion Arafat et al.

Disruption isgnaling the Gcgr gene is associated with hyperglucagonemia and elevated glucagon-like peptide Glucabon GLP1 levels, with normal insulin and lactate levels. Glucagon has been shown receotor evoke a marked delay in gastric emptying Jonderko et al.

These anti-motility effects on the gastrointestinal tract esophagus, stomach, and small and large intestines are observed when glucagon is administered to humans in pharmacological doses Patel et al.

Glucagon also controls meal size and satiation in both humans and rodents GearyGeary et al. In rodent models, disruption of the Gcgr gene is associated with decreased gastric emptying Conarello et al.

In rodent models, disruption of the Gcgr gene is associated with a late-onset loss of retinal function, loss of visual acuity, and eventual death of retinal cells Umino et al.

These retinal changes were observed at 10 months of age and correlated directly with the degree of hypoglycemia. Glucagon exerts positive inotropic and chronotropic effects in the ventricular myocardium by xignaling of cardiac adenylate cyclase leading to increased cAMP formation MacLeod et al.

In rodent models, disruption of the Gcgr gene is associated with a diminished parasympathetic tone, leading to higher heart rates during the light phase and a modest elevation in the heart rate signaing response to atropine Mukharji et al. Glucagon exerts a positive effect on renal blood flow and glomerular filtration rate, and increases sodium, chloride, potassium, and inorganic phosphorus clearance ratios Elrick et al.

Transgenic mice were engineered that overexpress the Gcgr in insulin cells using the Gpucagon insulin II reveptor RiP- Gcgr to determine the functional role of Gcgr receptor in β-cell function. Overexpression of Gcgr in β-cells increased glucagon-stimulated insulin release and significantly increased Glucaagon volume, suggesting a role for Gcgr receptor in increased insulin cell competency Gelling et al.

Elevated glucagon:insulin ratio has been shown to accelerate gluconeogenesis and fatty acid oxidation leading to the formation of ketone bodies Vons et al. Hyperglycemia and elevated ketone bodies are the main component of diabetic ketoacidosis Eledrisi et al.

Disruption of singaling Gcgr gene in an insulin-deficient diabetic rodent model is accompanied by an asymptomatic, benign, non-catabolic state when followed for 6 weeks Conarello et al. Disruption of the Gcgr gene increases circulating level of FGF21 and GLP1, which promote glucose tolerance independently of insulin level.

It has been recently demonstrated that, in certain situations, newly formed β-cells can originate from cells that previously expressed glucagon, a phenomenon called transdifferentiation. Such situations include extreme β-cell loss, increased expression of Pax4 in α-cells, forced PDX1 expression, epigenomic manipulation, or the use of the peptide caerulein after signaping with alloxan Collombat et al.

If alterations in glucagon secretion are indeed the cause of hyperglycemia and other metabolic complications in diabetic patients, suppression of glucagon signaling can be viewed as an important therapeutic option. Potent peptide antagonists, glucagon-neutralizing antibodies, small-molecule glucagon receptor antagonist, and receptor antisense oligonucleotides have been used in animal models to control hyperglycemia but their use in humans have been limited by their side effects as well as the limited mode of delivery Johnson et al.

Recently, four novel peptide-based glucagon analogs have been developed that are resistant to DPP4 degradation and thus display substantial abilities to suppress glucagon action in different animal models O'Harte et al. All analogs inhibit glucagon-induced insulin secretion in vitroand in rodents, analogs inhibited glucagon-induced hyperglycemia and the insulinotropic response O'Harte et al.

It has been suggested recepto, in states of insulin deficiency, excess glucagon secretion plays a major role in the metabolic perturbations associated with diabetes, such as hyperglycemia and ketonuria. Thus, inhibition of glucagon receptor signaling represents a possible option for the treatment of diabetes.

Animal models have demonstrated that the physiological processes regulated by glucagon and its receptor are much broader than expected. Signaaling plays important roles in pancreatic development, insulin cell function, and metabolic response to prolonged fasting, exercise, lipid metabolism, signalinng energy state, hepatocyte survival, meal size and satiety, gastric emptying, intestinal length, as well as visual acuity, placentation, and cardiac contractility.

In addition, under some extreme metabolic conditions of recepto deficiency, glucagon or α-cells possess the capacity to transdifferentiate sibnaling insulin cells.

Therefore, antagonizing glucagon action as a therapy for diabetes may improve glucose and insulin levels but in addition may have several unintended consequences that could further compromise the regulatory response to an altered metabolic state.

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review. This work was supported by the National Institutes Goucagon Health grants DK and HL to M J C and KO8 HD to P M Vand the American Diabetes Association to M J C.

The authors thank Drs R Gelling, R Burcelin, and GGlucagon Ouhilal, all our collaborators, and members of Recrptor J C and P M V laboratories who have contributed to this project over the years. European Journal of Endocrinology — PNAS 77 — Journal of Clinical Investigation — American Journal of Physiology.

Signalinh and Metabolism E — E American Journal of Physiology R — R American Journal of Medicine 82 25 — Journal of Dairy Science 86 — S 03 Diabetologia 37 — Cell —

: Glucagon receptor signaling

Glucagon Secretion Liljenquist, J. In response to an appropriate stimuli, e. When Gsα is activated, adenylate cyclase is activated and intracellular cAMP production is increased, which in turn activates protein kinase A PKA , and leads to phosphorylation of functional proteins in the cells. However, the biological relevance of this intracellular signaling has yet to be fully elucidated. Latest Issue Alert. Targeting the Glucagon Receptor Signaling Pathway As a Novel Strategy to Counteract PI3K Inhibitor Induced Hyperglycemia While Sustaining Tumor PI3K Inhibition Jie Wang, MDMS , Jie Wang, MDMS.
Glucagon Signaling Pathway All animals were euthanized via rapid decapitation with anesthesia concentrated isoflurane. FFAs may also function as metabolic substrate and stimulate alpha cell secretion through beta-oxidation Kristinsson et al. Find articles by Cunningham, S. Glucagon binding to GCGR induces a conformational change in GCGR. Research Article Metabolism Open Access Article Navigation. We have been intrigued by the role of glucagon in the prandial transition and have attempted to delineate its role as beneficial or inhibitory to glycemic control.
JCI Insight - Glucagon receptor signaling regulates weight loss via central KLB receptor complexes

Concomitantly, PKA phosphorylates the cAMP response element-binding protein CREB and stimulates protein phosphatase 2B-dependent dephosphorylation of the CREB-regulated transcription coactivator 2 Crtc2 Overview of GCGR signaling pathways in the regulation of hepatic glucose homeostasis.

Figure created with BioRender. Termination of signaling is equally important to metabolic regulation. GCGR signaling is terminated by internalization of the ligand—receptor complex and occurs primarily via clathrin- and arrestin-facilitated endocytosis.

Intriguingly, sustained GCGR signaling has been described after internalization, suggesting a second wave of signaling from this receptor However, the biological relevance of this intracellular signaling has yet to be fully elucidated.

Intracellular GCGR palmitoylation and ubiquitination have been observed and may also contribute to signal termination Intriguingly, glucagon stimulates both GCGR internalization and deubiquitination, facilitating rapid recycling of the receptor As introduced above, the best-known actions of GCGR signaling involve its counterregulatory effect on insulin action.

In the context of glucose metabolism, GCGR signaling stimulates hepatic glycogenolysis and gluconeogenesis GNG with concomitant inhibition of glycogen synthesis GCGR signaling rapidly increases hepatic glycogenolysis via a signaling cascade involving the canonical cAMP—PKA pathway.

This signaling activates glycogen phosphorylase kinase and subsequent activation of glycogen phosphorylase. GCGR signaling via PKA likewise inhibits glycogen synthase, preventing hepatic glycogen synthesis GCGR regulation of hepatic GNG occurs via both transcriptional induction and allosteric modulation of GNG enzymes.

PKA-dependent phosphorylation of phosphofructokinase 2 and pyruvate kinase shifts metabolic flux from glycolysis to GNG. GCGR signaling stimulates CREB Ser phosphorylation coupled with dephosphorylation and nuclear translocation of its coactivator, Creb-regulated transcription coactivator 2 Crtc2.

These actions not only stimulate the induction of target GNG genes G6pc, Pck1, Ppargc1a and hepatocyte nuclear factor 4 Hnf4a but also regulate GNG-associated transcription factors FOXO1 and PGCα via modulation of their acetylation states Consistent with these signaling events, exogenous glucagon elevates glycemia Moreover, genetic Gcgr deficiency and neutralizing antibodies targeting glucagon are sufficient to reduce glycemia 78 — In contrast, the antidiabetic effects of Gcgr knockout in streptozotocin STZ -treated mice are lost when STZ is administered prior to Gcgr ablation These rodent data must be interpreted with some caution, as GCGR antagonists clearly lower glycemia in individuals with T1D Together, these findings highlight the complex and context-dependent relationship between glucagon and insulin in glucose homeostasis.

In addition to its effects on glucose metabolism, mounting evidence suggests hepatic glucagon is a potent regulator of energy balance, lipid homeostasis, and fat mass mobilization In the context of energy balance, glucagon both stimulates energy expenditure and suppresses food intake, as highlighted by the negative energy balance observed in glucagonoma patients This stimulation of energy expenditure and thermogenesis is conserved across a range of species However, the conservation of this system in humans is still controversial, with reports observing both increased and unchanged energy expenditure 84 , Energy expenditure regulation in mice is dependent upon hepatic GCGR signaling and is mechanistically associated with hepatic FXR activity and endocrine FGF21 action 14 , 15 , Glucose futile cycling may also contribute to the upregulation of energy expenditure following GCGR agonism 87 , Intriguingly, glucagon administration also decreases hunger and food intake in both rats 89 and human subjects 90 , Consistently, GCGR agonism in diet-induced obese mice suppressed food intake; however, this effect was preserved in mice lacking hepatic Gcgr expression, suggesting that the liver is not the tissue of origin for this regulation Glucagon also regulates multiple components of lipid metabolism Gcgr is expressed by rodent adipocytes Consistently, glucagon mediates rodent white adipose tissue lipolysis Conversely, evidence of Gcgr expression in human adipocytes is lacking 94 , as is that for glucagon-induced lipolysis at physiological levels in patients In rodents, glucagon-mediated white adipose tissue lipolysis 96 , 97 via hormone-sensitive lipase results in the liberation of nonesterified fatty acids NEFA The majority of these NEFAs are catabolized.

However, in the liver, NEFAs may be alternatively converted to ketone bodies to provide energy during times of glucose deficiency 99 , Consistent with this shift to lipid energy substrates, glucagon exposure inhibits hepatic lipogenesis while stimulating FA transport and oxidation GCGR agonism is also a potent regulator of bile acid metabolism, stimulating robust changes in the expression of bile acid enzymes and the composition of circulating bile acids As introduced above, emerging data support that hepatic GCGR signaling is a crucial regulator of AA metabolism.

GCGR agonism stimulates hepatic AA uptake and urea production and subsequently induces hypoaminoacidemia Together these pieces of evidence point to glucagon as a potent regulator of AA and lipid homeostasis, energy balance, and fat mass mobilization.

Insulin is a powerful anabolic factor, stimulating growth and energy accrual throughout the organism. This pleiotropic hormone is essential to glucose metabolism and crucial to lipid and AA metabolism.

Insulin action in the liver stimulates lipogenesis and glycogen synthesis while concomitantly inhibiting glycogenolysis, GNG, and liver fatty acid oxidation Insulin signals via the INSR, a member of the receptor tyrosine kinase family, and, to a lesser extent, the insulin-like growth factor 1 receptor.

These receptors are endogenously inhibited by the recently discovered Inceptor protein in mouse β-cells Insr is expressed in the central nervous system and a wide range of peripheral tissues.

Unlike Gcgr , hepatic Insr expression is found in both periportal and perivenous zones The role of this essential hormone and INSR signaling summarized in Fig. Therefore, this Perspective will focus on hepatic signaling and biological functions arising from INSR activation.

AKT is a central node of hepatic insulin signaling and is crucial for both glucose and lipid metabolism. Thr phosphorylation occurs in a PDK1-dependent manner and is essential for AKT kinase activity.

Ser is phosphorylated by the rapamycin-insensitive mTOR complex mTORC2 and is permissive for full kinase activity Importantly, the mechanisms of mTORC2 regulation remain uncertain. AKT activation leads to subsequent phosphorylation of forkhead box—containing protein, O subfamily FOXO. FOXO proteins especially members 1 and 6 are transcription factors that induce GNG.

AKT-dependent phosphorylation triggers nuclear exclusion and, thus, is inhibitory to this action Overview of INSR signaling pathways in the regulation of hepatic glucose homeostasis. MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol 3-kinase; PLCγ, phospholipase Cγ.

INSR activation stimulates phospholipase Cγ, generating inositol-1,4,5-triphosphate InsP 3. Diabetes, whether type 1 T1D or type 2 T2D , is defined by hyperglycemia and is ultimately the result of insufficient insulin action. In the case of T1D, this deficiency is caused by destruction of the pancreatic β-cell and therefore a lack of the insulin hormone.

In T2D, insulin resistance accumulates to a point where β-cell compensatory hypersecretion is insufficient to counteract the resistance In the liver, this insufficiency is manifested as a failure to suppress hepatic glucose output i.

Intriguingly, in T2D this resistance is often incomplete, resulting in a preservation of insulin-stimulated lipogenesis Consistent with its counterregulatory role, both fasting and postprandial plasma glucagon levels are elevated in diabetes However, these observations have been made in individuals with established cases of diabetes, and thus the causality of hyperglucagonemia is difficult to assign.

As a counterregulatory hormone with a role in maintaining fasting blood glucose, it is tempting to assume that glucagon opposes all actions of insulin. Consistent with this hypothesis, circulating glucagon levels are elevated in all known instances of T1D or T2D, including animal models of the disease Likewise, preclinical GCGR ablation or pharmacological GCGR inhibition including neutralizing antibodies against glucagon in individuals with diabetes is sufficient to reduce glycemia and HbA 1c.

However, many of these strategies have been slowed due to adverse effects on liver transaminases, liver fat, and dyslipidemia Conversely, the increased concentrations and action of glucagon in the fasting state are well suited to potentiate subsequent insulin-mediated glucose control.

To this point, glucagon acts in a paracrine manner to increase insulin secretion through activation of both β-cell GCGR and GLP-1R Likewise, postprandial elevations of glucagon and GLP-1 contribute to the improved postprandial glucose profile observed in Roux-en-Y gastric bypass patients and rodent models of this powerful intervention Importantly, these physiological conditions are all characterized by their heightened insulin sensitivity.

Regarding glucagon enhancement of insulin action, the use of the bionic pancreas glucagon and insulin must be mentioned This technology was hypothesized to prevent life-threatening hypoglycemic episodes in people with diabetes. Beyond reducing hypoglycemic episodes, the bihormonal glucagon and insulin pump reduced average glycemia while requiring a similar total daily insulin dose in adolescents Likewise, h glucagon infusion increased both glucose appearance and disappearance in patients, suggesting that its regulation of human glucose metabolism is not restricted to increasing hepatic glucose output Together, these observations support the hypothesis that glucagon, released during fasting and the prandial response, acts to prime metabolic tissues for the subsequent nutrient challenge of feeding.

Moreover, it positions cooperative actions of glucagon and insulin as crucial to this physiology. INSR and GCGR signaling also converge at the hepatocyte. This initial observation was followed by more detailed investigation of acute i.

This work identified enhanced insulin-dependent signaling in the phosphorylation of AKT Ser in mice treated with IUB 60 min prior to insulin and was exclusive of PDK1-dependent phosphorylation Thr This single, acute IUB treatment increased insulin sensitivity, as defined by increased glucose infusion rate and improved insulin-stimulated suppression of hepatic glucose output during hyperinsulinemic-euglycemic clamps These observations suggest GCGR and INSR signaling intersect via a TORC2-dependent phosphorylation of AKT Ser Our observation was quickly followed by work by Besse-Patin et al.

This elegant study confirmed glucagon-enhanced AKT Ser phosphorylation and identified glucagon-dependent induction of Ppargc1a as a transcriptional regulator of relative levels of hepatocyte IRS1:IRS2 ratios This shift toward IRS2 favors insulin-dependent suppression of hepatic glucose output and is consistent with our observations in hyperinsulinemic-euglycemic clamps Congruous with our study and interpretation, Besse-Patin et al.

concluded that glucagon via PGCα primes the liver for subsequent insulin action. However, an importation caveat to these studies is that the observations of Besse-Patin et al. were made 4 h after glucagon treatment. Subsequent observations in cultured hepatocytes suggest GCGR signaling transiently stimulates protein synthesis via an mTORC1-dependent action This effect was also observed to be convergent with insulin signaling and dependent on EPAC activity Additionally, work by Perry et al.

This work supported a role for inositol triphosphate receptor 1 INSP3R1 -mediated calcium signaling downstream of GCGR activation. In this model, the benefits of GCGR signaling on glucose metabolism are related to hepatic mitochondrial oxidation In summary, emerging data support a beneficial role for GCGR signaling in hepatic insulin glucose metabolism.

While the precise mechanisms have yet to be elucidated, data support roles for mTORC1, mTORC2, and PCG1a-IRS2 as potential points for cross talk with hepatic insulin signaling Fig.

INSP3R1 may also represent a mechanism by which hepatic GCGR signaling benefits glucose metabolism secondary to its regulation of mitochondrial oxidation. Potential and reported cross talk in hepatic glucagon GCG and INSR signaling. PI3K, phosphatidylinositol 3-kinase.

Of note, treating mice with the INSR antagonist S induces severe insulin resistance, hyperglycemia, and ketonemia, yet the GCGR-blocking antibody REGN was sufficient to normalize blood glucose and β-hydroxybutyrate levels in these mice Subsequent clinical investigation uncovered reductions in fasting plasma glucose and HbA 1c in REGNtreated T2D patients Similar benefits in mice have been reported for the monoclonal antibody and competitive GCGR antagonist REMD 2.

Diabetes 53 — Cell Metabolism 8 — Molecular Endocrinology 19 — Nature — Cell Metabolism 17 — Nature Medicine 19 — Physiological Reports 1 e Molecular and Cellular Endocrinology 26 — Diabetes 63 — Digestive Diseases and Sciences 24 — Diabetologia 41 — Perinatal development and effects of pancreatic hormones in cultured rabbit hepatocytes.

Biochemical Journal — Journal of Endocrinology 5 — Rodgers RL Glucagon and cyclic AMP: time to turn the page? Current Diabetes Reviews 8 — Journal of Applied Physiology 11 — Neuroscience Letters 37 — Gastroenterology — Cell Metabolism 19 — Proceedings of the Society for Experimental Biology and Medicine — Journal of Clinical Investigation 41 — Hepatology 13 — Japanese Journal of Physiology 37 — Genes and Development 25 — Journal of Endocrinology is committed to supporting researchers in demonstrating the impact of their articles published in the journal.

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Advanced Search Help. Lack of glucagon receptor signaling and its implications beyond glucose homeostasis in Journal of Endocrinology. Authors: Maureen J Charron Maureen J Charron Departments of Biochemistry, Obstetrics and Gynecology and Women's Health, Medicine, Department of Pediatrics, Albert Einstein College of Medicine, Morris Park Avenue, F, Bronx, New York , USA Departments of Biochemistry, Obstetrics and Gynecology and Women's Health, Medicine, Department of Pediatrics, Albert Einstein College of Medicine, Morris Park Avenue, F, Bronx, New York , USA Departments of Biochemistry, Obstetrics and Gynecology and Women's Health, Medicine, Department of Pediatrics, Albert Einstein College of Medicine, Morris Park Avenue, F, Bronx, New York , USA Search for other papers by Maureen J Charron in Current site Google Scholar PubMed Close.

Patricia M Vuguin Patricia M Vuguin Departments of Biochemistry, Obstetrics and Gynecology and Women's Health, Medicine, Department of Pediatrics, Albert Einstein College of Medicine, Morris Park Avenue, F, Bronx, New York , USA Search for other papers by Patricia M Vuguin in Current site Google Scholar PubMed Close.

Page Range: R—R Online Publication Date: Mar Copyright: © Society for Endocrinology Free access. Download PDF. Check for updates. Abstract Glucagon action is transduced by a G protein-coupled receptor located in liver, kidney, intestinal smooth muscle, brain, adipose tissue, heart, pancreatic β-cells, and placenta.

Keywords: pancreas ; glucagon cells. Introduction Glucagon is a amino acid polypeptide secreted by the α or glucagon cell of the islet of Langerhans in response to hypoglycemia, arginine, gastric inhibitory polypeptide during ambient reduced glucose levels , gastrin, and potassium chloride.

Role of glucagon on pregnancy maintenance and fetal growth Disruption of the glucagon receptor gene Gcgr during pregnancy is associated with maternal hypoglycemia, hyperglucagonemia, abnormalities of placentation, poor fetal growth, and increased fetal and early postnatal death.

Role of glucagon in pancreatic development and pancreatic islet morphology During fetal development, glucagon is required for early insulin or β-cell differentiation and to mature a subset of glucagon cells Vuguin et al.

Role of glucagon in food intake and body composition Glucagon has beneficial effects on food intake, body fat mass, and energy expenditure Habegger et al. Role of glucagon in glucose and lipid homeostasis Glucagon plays a central role in the response to hypoglycemia by stimulating gluconeogenesis and glycogenolysis and opposing the insulin effects.

Role of glucagon in the hormonal milieu Glucagon does not seem to play an important role in insulin action but induces glucose-stimulated insulin release Gelling et al. Role of glucagon in satiety and gastric emptying Glucagon has been shown to evoke a marked delay in gastric emptying Jonderko et al.

Role of glucagon in retinal function In rodent models, disruption of the Gcgr gene is associated with a late-onset loss of retinal function, loss of visual acuity, and eventual death of retinal cells Umino et al. Role of glucagon in cardiac contractility Glucagon exerts positive inotropic and chronotropic effects in the ventricular myocardium by activation of cardiac adenylate cyclase leading to increased cAMP formation MacLeod et al.

Role of glucagon in renal blood flow Glucagon exerts a positive effect on renal blood flow and glomerular filtration rate, and increases sodium, chloride, potassium, and inorganic phosphorus clearance ratios Elrick et al.

Role of glucagon in β insulin cell function Transgenic mice were engineered that overexpress the Gcgr in insulin cells using the rat insulin II promoter RiP- Gcgr to determine the functional role of Gcgr receptor in β-cell function.

Role of glucagon in the development of diabetes in insulin-deficient mice Elevated glucagon:insulin ratio has been shown to accelerate gluconeogenesis and fatty acid oxidation leading to the formation of ketone bodies Vons et al. α glucagon cell transdifferentiation as a potential treatment for diabetes It has been recently demonstrated that, in certain situations, newly formed β-cells can originate from cells that previously expressed glucagon, a phenomenon called transdifferentiation.

Antagonizing glucagon action as a potential treatment for diabetes If alterations in glucagon secretion are indeed the cause of hyperglycemia and other metabolic complications in diabetic patients, suppression of glucagon signaling can be viewed as an important therapeutic option.

Conclusion It has been suggested that, in states of insulin deficiency, excess glucagon secretion plays a major role in the metabolic perturbations associated with diabetes, such as hyperglycemia and ketonuria. Declaration of interest The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding This work was supported by the National Institutes of Health grants DK and HL to M J C and KO8 HD to P M V , and the American Diabetes Association to M J C. PubMed Billington CJ Briggs JE Link JG Levine AS Glucagon in physiological concentrations stimulates brown fat thermogenesis in vivo.

S 03 PubMed Bobe G Ametaj BN Young JW Beitz DC Effects of exogenous glucagon on lipids in lipoproteins and liver of lactating dairy cows. S 03 false. PubMed Burcelin R Katz EB Charron MJ Molecular and cellular aspects of the glucagon receptor: role in diabetes and metabolism. PubMed Eaton RP Hypolipemic action of glucagon in experimental endogenous lipemia in the rat.

PubMed Geary N Kissileff HR Pi-Sunyer FX Hinton V Individual, but not simultaneous, glucagon and cholecystokinin infusions inhibit feeding in men. PubMed Jonderko G Jonderko K Golab T Effect of glucagon on gastric emptying and on postprandial gastrin and insulin release in man.

PubMed MacLeod KM Rodgers RL McNeill JH Characterization of glucagon-induced changes in rate, contractility and cyclic AMP levels in isolated cardiac preparations of the rat and guinea pig. Bibcode : Natur. doi : PMC PMID Proceedings of the National Academy of Sciences of the United States of America.

Bibcode : PNAS.. Nature Communications. Bibcode : NatCo The Journal of Biological Chemistry. Nature Genetics. S2CID Levey GS, Weiss SR, Ruiz E Apr The Journal of Clinical Endocrinology and Metabolism.

Nakamura S, Rodbell M Aug Bibcode : PNAS Horuk R, Wright DE May FEBS Letters. MacNeil DJ, Occi JL, Hey PJ, Strader CD, Graziano MP Jan Biochemical and Biophysical Research Communications. Fujisawa T, Ikegami H, Yamato E, Takekawa K, Nakagawa Y, Hamada Y, Ueda H, Fukuda M, Ogihara T Aug Unson CG, Macdonald D, Merrifield RB Feb Archives of Biochemistry and Biophysics.

Chambers SM, Morris BJ Feb Yamato E, Ikegami H, Takekawa K, Fujisawa T, Nakagawa Y, Hamada Y, Ueda H, Ogihara T Feb Hormone and Metabolic Research. Strazzullo P, Iacone R, Siani A, Barba G, Russo O, Russo P, Barbato A, D'Elia L, Farinaro E, Cappuccio FP Oct Journal of Molecular Medicine.

Shiota D, Kasamatsu T, Dib SA, Chacra AR, Moisés RS May Runge S, Gram C, Brauner-Osborne H, Madsen K, Knudsen LB, Wulff BS Jul Hassel S, Eichner A, Yakymovych M, Hellman U, Knaus P, Souchelnytskyi S May Mortensen OH, Dichmann DS, Abrahamsen N, Grunnet N, Nishimura E May Cell surface receptor : G protein-coupled receptors.

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Glucagon receptor signaling regulates weight loss via central KLB receptor complexes injection of glucose 1. Pharmacological concentrations of glucagon also stimulate secretion of catecholamines and growth hormone, both of which have powerful lipolytic effects Mitchell et al. PubMed Schulman JL Carleton JL Whitney G Whitehorn JC Effect of glucagon on food intake and body weight in man. In opposition to our original hypothesis, there were no genotypic differences in EE Figure 2E , 84— hours; and Supplemental Figure 2C , RER Figure 2F , 84— hours; and Supplemental Figure 2D , or diurnal food intake Supplemental Figure 2E on HFD. Glucagon has also been shown to stimulate lipolysis in birds, rabbits Richter et al. After glucagon injection, blood glucose returned to normal; and after a long period of application, the morphology of islet α cells recovered to resemble that of wild-type mice.
Glucagon receptor signaling Jie WangMichael SignalinFrank CalzoneHai Yan recsptor, Zung ThaiTakuya OsadaHerbert Dehydration and nausea Targeting the Glucagon Receptor Signaling Pathway Glucagon receptor signaling a Quick chicken breast meals Strategy sigbaling Counteract Glucagn Inhibitor Induced Hyperglycemia While Sustaining Tumor PI3K Inhibition. Blood ; Supplement 1 : 4—5. Although validated as a therapeutic oncologic target, the PI3K signaling pathway is also implicated in normal glucose homeostasis. Specifically, since the PI3K subunit pα is chiefly responsible for downstream insulin receptor INSR signaling, PI3K signaling inhibition that includes pα leads to severe hyperglycemia. Therefore, a novel strategy to maintain blockade of tumor associated PI3K signaling while reducing hyperglycemia is needed.

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