Glucagon Receptor Signaling and Glucagon Resistance

Hundred years after the discovery of glucagon, its biology remains enigmatic. Accurate measurement of glucagon has been essential for uncovering its pathological hypersecretion that underlies various metabolic diseases including not only diabetes and liver diseases but also cancers (glucagonomas). The suggested key role of glucagon in the development of diabetes has been termed the bihormonal hypothesis. However, studying tissue-specific knockout of the glucagon receptor has revealed that the physiological role of glucagon may extend beyond blood-glucose regulation. Decades ago, animal and human studies reported an important role of glucagon in amino acid metabolism through ureagenesis. Using modern technologies such as metabolomic profiling, knowledge about the effects of glucagon on amino acid metabolism has been expanded and the mechanisms involved further delineated. Glucagon receptor antagonists have indirectly put focus on glucagon’s potential role in lipid metabolism, as individuals treated with these antagonists showed dyslipidemia and increased hepatic fat. One emerging field in glucagon biology now seems to include the concept of hepatic glucagon resistance. Here, we discuss the roles of glucagon in glucose homeostasis, amino acid metabolism, and lipid metabolism and present speculations on the molecular pathways causing and associating with postulated hepatic glucagon resistance.

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Integrated Metabolomics and Lipidomics Analysis Reveal Remodeling of Lipid Metabolism and Amino Acid Metabolism in Glucagon Receptor–Deficient Zebrafish

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.605979 ◽

2021 ◽

Vol 8 ◽

Author(s):

Xuanxuan Bai ◽

Jianxin Jia ◽

Qi Kang ◽

Yadong Fu ◽

You Zhou ◽

...

Keyword(s):

Lipid Metabolism ◽

Amino Acid ◽

Metabolic Network ◽

Amino Acid Metabolism ◽

Acid Metabolism ◽

Cholesterol Metabolism ◽

Transcriptional Level ◽

Omics Data ◽

Glucagon Receptor ◽

Physiological Functions

The glucagon receptor (GCGR) is activated by glucagon and is essential for glucose, amino acid, and lipid metabolism of animals. GCGR blockade has been demonstrated to induce hypoglycemia, hyperaminoacidemia, hyperglucagonemia, decreased adiposity, hepatosteatosis, and pancreatic α cells hyperplasia in organisms. However, the mechanism of how GCGR regulates these physiological functions is not yet very clear. In our previous study, we revealed that GCGR regulated metabolic network at transcriptional level by RNA-seq using GCGR mutant zebrafish (gcgr−/−). Here, we further performed whole-organism metabolomics and lipidomics profiling on wild-type and gcgr−/− zebrafish to study the changes of metabolites. We found 107 significantly different metabolites from metabolomics analysis and 87 significantly different lipids from lipidomics analysis. Chemical substance classification and pathway analysis integrated with transcriptomics data both revealed that amino acid metabolism and lipid metabolism were remodeled in gcgr-deficient zebrafish. Similar to other studies, our study showed that gcgr−/− zebrafish exhibited decreased ureagenesis and impaired cholesterol metabolism. More interestingly, we found that the glycerophospholipid metabolism was disrupted, the arachidonic acid metabolism was up-regulated, and the tryptophan metabolism pathway was down-regulated in gcgr−/− zebrafish. Based on the omics data, we further validated our findings by revealing that gcgr−/− zebrafish exhibited dampened melatonin diel rhythmicity and increased locomotor activity. These global omics data provide us a better understanding about the role of GCGR in regulating metabolic network and new insight into GCGR physiological functions.

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Interactive effects of aging and aerobic capacity on energy metabolism–related metabolites of serum, skeletal muscle, and white adipose tissue

GeroScience ◽

10.1007/s11357-021-00387-1 ◽

2021 ◽

Author(s):

Haihui Zhuang ◽

Sira Karvinen ◽

Timo Törmäkangas ◽

Xiaobo Zhang ◽

Xiaowei Ojanen ◽

...

Keyword(s):

Adipose Tissue ◽

Amino Acid ◽

White Adipose Tissue ◽

Aerobic Capacity ◽

Amino Acid Metabolism ◽

Acid Metabolism ◽

Disease Risk ◽

Whole Body ◽

Whole Body Metabolism

AbstractAerobic capacity is a strong predictor of longevity. With aging, aerobic capacity decreases concomitantly with changes in whole body metabolism leading to increased disease risk. To address the role of aerobic capacity, aging, and their interaction on metabolism, we utilized rat models selectively bred for low and high intrinsic aerobic capacity (LCRs/HCRs) and compared the metabolomics of serum, muscle, and white adipose tissue (WAT) at two time points: Young rats were sacrificed at 9 months of age, and old rats were sacrificed at 21 months of age. Targeted and semi-quantitative metabolomics analysis was performed on the ultra-pressure liquid chromatography tandem mass spectrometry (UPLC-MS) platform. The effects of aerobic capacity, aging, and their interaction were studied via regression analysis. Our results showed that high aerobic capacity is associated with an accumulation of isovalerylcarnitine in muscle and serum at rest, which is likely due to more efficient leucine catabolism in muscle. With aging, several amino acids were downregulated in muscle, indicating more efficient amino acid metabolism, whereas in WAT less efficient amino acid metabolism and decreased mitochondrial β-oxidation were observed. Our results further revealed that high aerobic capacity and aging interactively affect lipid metabolism in muscle and WAT, possibly combating unfavorable aging-related changes in whole body metabolism. Our results highlight the significant role of WAT metabolism for healthy aging.

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Purification and properties of glutamate-phenylpyruvate aminotransferase from the ruminal protozoan Entodinium caudatum

Australian Journal of Agricultural Research ◽

10.1071/ar04050 ◽

2004 ◽

Vol 55 (9) ◽

pp. 991

Author(s):

Md. Ruhul Amin ◽

Ryoji Onodera ◽

R. Islam Khan ◽

R. John Wallace ◽

C. Jamie Newbold

Keyword(s):

Amino Acid ◽

Amino Acid Metabolism ◽

Acid Metabolism ◽

Maximum Activity ◽

Purification And Properties ◽

Sds Page ◽

Wide Range ◽

S 100 ◽

A Cell

Entodinium species are important in catabolic protein metabolism by the mixed ruminal microbial population. This study was conducted to purify, and investigate properties of one of the enzymes involved in amino acid metabolism by Entodinium caudatum, glutamate-phenylpyruvate aminotransferase (GPA; EC 2.6.1.64). GPA was purified 74-fold from a cell-free extract by ammonium sulfate precipitation and column chromatography with phenyl-superose, DEAE-Toyopearl 650M, Sephacryl S-100 HR, and Sephadex G-100. The molecular mass of GPA was estimated by SDS–PAGE to be 65.0 kDa. The optimum pH was 6.0 and it was found to be reactive over a wide range of pH from 5.0 to 10.5. Maximum activity of GPA occurred at 45°C and the activity declined at temperatures over 55°C. GPA was stable below 60°C. Aminooxyacetate and phenylhydrazine were highly inhibitory, and SDS, EDTA, and some heavy metal ions also inhibited activity. The purification and characterisation of the enzyme will help to isolate the gene and ultimately to understand the role of GPA in both anabolic and catabolic amino acid metabolism by Entodinium caudatum.

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Amino acid metabolism in the thermophilic phototroph, Chloroflexus aurantiacus: properties and metabolic role of two l-threonine (l-serine) dehydratases

Archives of Microbiology ◽

10.1007/bf00422013 ◽

1988 ◽

Vol 149 (3) ◽

pp. 249-254 ◽

Cited By ~ 10

Author(s):

Gisela Laakmann-Ditges ◽

Jobst-Heinrich Klemme

Keyword(s):

Amino Acid ◽

Amino Acid Metabolism ◽

Acid Metabolism ◽

Chloroflexus Aurantiacus ◽

Metabolic Role

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Glucagon receptor signaling is not required for N-carbamoyl glutamate- and l-citrulline-induced ureagenesis in mice

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00294.2019 ◽

2020 ◽

Vol 318 (5) ◽

pp. G912-G927

Author(s):

Katrine D. Galsgaard ◽

Jens Pedersen ◽

Sasha A. S. Kjeldsen ◽

Marie Winther-Sørensen ◽

Elena Stojanovska ◽

...

Keyword(s):

Amino Acid ◽

Amino Acid Metabolism ◽

Acid Metabolism ◽

Urea Cycle ◽

Receptor Signaling ◽

Glucagon Receptor ◽

Acetylglutamate Synthase

Hepatic ureagenesis is essential in amino acid metabolism and is importantly regulated by glucagon, but the exact mechanism is unclear. With the aim to identify the steps whereby glucagon both acutely and chronically regulates ureagenesis, we here show, contrary to our hypothesis, that glucagon receptor-mediated activation of ureagenesis is not required when N-acetylglutamate synthase activity and/or N-acetylglutamate levels are sufficient to activate the first step of the urea cycle in vivo.

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The role of amino acid metabolism during abiotic stress release

Plant Cell & Environment ◽

10.1111/pce.13518 ◽

2019 ◽

Vol 42 (5) ◽

pp. 1630-1644 ◽

Cited By ~ 30

Author(s):

Willian Batista‐Silva ◽

Björn Heinemann ◽

Nils Rugen ◽

Adriano Nunes‐Nesi ◽

Wagner L. Araújo ◽

...

Keyword(s):

Abiotic Stress ◽

Amino Acid ◽

Amino Acid Metabolism ◽

Acid Metabolism ◽

Stress Release

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Glucose and amino acid metabolism in mice depend mutually on glucagon and insulin receptor signaling

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00410.2018 ◽

2019 ◽

Vol 316 (4) ◽

pp. E660-E673 ◽

Cited By ~ 10

Author(s):

Katrine D. Galsgaard ◽

Marie Winther-Sørensen ◽

Jens Pedersen ◽

Sasha A. S. Kjeldsen ◽

Mette M. Rosenkilde ◽

...

Keyword(s):

Amino Acids ◽

Amino Acid ◽

Insulin Receptor ◽

Amino Acid Metabolism ◽

Acid Metabolism ◽

Receptor Signaling ◽

Cell Secretion ◽

Glucagon Receptor ◽

Insulin Receptor Signaling ◽

Glucagon And Insulin

Glucagon and insulin are important regulators of blood glucose. The importance of insulin receptor signaling for alpha-cell secretion and of glucagon receptor signaling for beta-cell secretion is widely discussed and of clinical interest. Amino acids are powerful secretagogues for both hormones, and glucagon controls amino acid metabolism through ureagenesis. The role of insulin in amino acid metabolism is less clear. Female C57BL/6JRj mice received an insulin receptor antagonist (IRA) (S961; 30 nmol/kg), a glucagon receptor antagonist (GRA) (25-2648; 100 mg/kg), or both GRA and IRA (GRA + IRA) 3 h before intravenous administration of similar volumes of saline, glucose (0.5 g/kg), or amino acids (1 µmol/g) while anesthetized with isoflurane. IRA caused basal hyperglycemia, hyperinsulinemia, and hyperglucagonemia. Unexpectedly, IRA lowered basal plasma concentrations of amino acids, whereas GRA increased amino acids, lowered glycemia, and increased glucagon but did not influence insulin concentrations. After administration of GRA + IRA, insulin secretion was significantly reduced compared with IRA administration alone. Blood glucose responses to a glucose and amino acid challenge were similar after vehicle and GRA + IRA administration but greater after IRA and lower after GRA. Anesthesia may have influenced the results, which otherwise strongly suggest that both hormones are essential for the maintenance of glucose homeostasis and that the secretion of both is regulated by powerful negative feedback mechanisms. In addition, insulin limits glucagon secretion, while endogenous glucagon stimulates insulin secretion, revealed during lack of insulin autocrine feedback. Finally, glucagon receptor signaling seems to be of greater importance for amino acid metabolism than insulin receptor signaling.

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