Amino Acid Metabolism Is Regulated by Glucagon Receptor Signaling in Mice

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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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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Disruption of glucagon receptor signaling causes hyperaminoacidemia exposing a possible liver-alpha-cell axis

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00198.2017 ◽

2018 ◽

Vol 314 (1) ◽

pp. E93-E103 ◽

Cited By ~ 33

Author(s):

Katrine D. Galsgaard ◽

Marie Winther-Sørensen ◽

Cathrine Ørskov ◽

Hannelouise Kissow ◽

Steen S. Poulsen ◽

...

Keyword(s):

Amino Acids ◽

Amino Acid ◽

Amino Acid Metabolism ◽

Acid Metabolism ◽

Alpha Cell ◽

Alpha Cells ◽

Receptor Signaling ◽

Cell Hyperplasia ◽

Glucagon Receptor ◽

Pancreatic Alpha Cells

Glucagon secreted from the pancreatic alpha-cells is essential for regulation of blood glucose levels. However, glucagon may play an equally important role in the regulation of amino acid metabolism by promoting ureagenesis. We hypothesized that disruption of glucagon receptor signaling would lead to an increased plasma concentration of amino acids, which in a feedback manner stimulates the secretion of glucagon, eventually associated with compensatory proliferation of the pancreatic alpha-cells. To address this, we performed plasma profiling of glucagon receptor knockout ( Gcgr−/−) mice and wild-type (WT) littermates using liquid chromatography-mass spectrometry (LC-MS)-based metabolomics, and tissue biopsies from the pancreas were analyzed for islet hormones and by histology. A principal component analysis of the plasma metabolome from Gcgr−/− and WT littermates indicated amino acids as the primary metabolic component distinguishing the two groups of mice. Apart from their hyperaminoacidemia, Gcgr−/− mice display hyperglucagonemia, increased pancreatic content of glucagon and somatostatin (but not insulin), and alpha-cell hyperplasia and hypertrophy compared with WT littermates. Incubating cultured α-TC1.9 cells with a mixture of amino acids (Vamin 1%) for 30 min and for up to 48 h led to increased glucagon concentrations (~6-fold) in the media and cell proliferation (~2-fold), respectively. In anesthetized mice, a glucagon receptor-specific antagonist (Novo Nordisk 25–2648, 100 mg/kg) reduced amino acid clearance. Our data support the notion that glucagon secretion and hepatic amino acid metabolism are linked in a close feedback loop, which operates independently of normal variations in glucose metabolism.

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Glucagon Receptor Signaling and Glucagon Resistance

International Journal of Molecular Sciences ◽

10.3390/ijms20133314 ◽

2019 ◽

Vol 20 (13) ◽

pp. 3314 ◽

Cited By ~ 18

Author(s):

Janah ◽

Kjeldsen ◽

Galsgaard ◽

Winther-Sørensen ◽

Stojanovska ◽

...

Keyword(s):

Lipid Metabolism ◽

Amino Acid ◽

Amino Acid Metabolism ◽

Acid Metabolism ◽

Metabolic Diseases ◽

Physiological Role ◽

Glucagon Receptor ◽

Metabolomic Profiling ◽

Hepatic Fat

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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Deleterious mutation V369M in the mouse GCGR gene causes abnormal plasma amino acid levels indicative of a possible liver-α-cell axis

Bioscience Reports ◽

10.1042/bsr20210758 ◽

2021 ◽

Author(s):

Qiaofeng Liu ◽

Guangyao Lin ◽

Yan Chen ◽

Wenbo Feng ◽

Yingna Xu ◽

...

Keyword(s):

Amino Acid ◽

Amino Acid Metabolism ◽

Acid Metabolism ◽

Glucagon Secretion ◽

Plasma Amino Acid ◽

Cell Hyperplasia ◽

Cell Axis ◽

Glucagon Receptor ◽

A Cell ◽

Amino Acid Levels

Glucagon plays an important role in glucose homeostasis and amino acid metabolism. It regulates plasma amino acid levels which in turn modulate glucagon secretion from the pancreatic a-cell, thereby establishing a liver-α-cell axis described recently. We reported previously that the knock-in mice bearing homozygous V369M substitution (equivalent to a naturally occurring mutation V368M in the human glucagon receptor, GCGR) led to hypoglycemia with improved glucose tolerance. They also exhibited hyperglucagonemia, pancreas enlargement and α-cell hyperplasia. Here, we investigated the effect of V369M/V368M mutation on glucagon-mediated amino acid metabolism. It was found that GcgrV369M+/+ mice displayed increased plasma amino acid levels in general, but significant accumulation of the ketogenic/glucogenic amino acids was observed in animals fed with a high fat diet, resulting in deleterious metabolic consequence characteristic of α-cell proliferation and hyperglucagonemia.

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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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