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

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.

scholarly journals Glucagon Receptor Signaling and Glucagon Resistance

2019 ◽  
Vol 20 (13) ◽  
pp. 3314 ◽  
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.

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

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.

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

2019 ◽  
Vol 316 (4) ◽  
pp. E660-E673 ◽  
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.

scholarly journals Hypoxic Adaptation of Mitochondrial Metabolism in Rat Cerebellum Decreases in Pregnancy

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 139 ◽  
Author(s):  
Anastasia Graf ◽  
Lidia Trofimova ◽  
Alexander Ksenofontov ◽  
Lyudmila Baratova ◽  
Victoria Bunik
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Metabolic Network ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Amino Acid Pool ◽  
Pregnant Rats ◽  
Acid Pool ◽  
Rat Cerebellum ◽  
Amino Acid Levels

Function of brain amino acids as neurotransmitters or their precursors implies changes in the amino acid levels and/or metabolism in response to physiological and environmental challenges. Modelling such challenges by pregnancy and/or hypoxia, we characterize the amino acid pool in the rat cerebellum, quantifying the levels and correlations of 15 amino acids and activity of 2-oxoglutarate dehydrogenase complex (OGDHC). The parameters are systemic indicators of metabolism because OGDHC limits the flux through mitochondrial TCA cycle, where amino acids are degraded and their precursors synthesized. Compared to non-pregnant state, pregnancy increases the cerebellar content of glutamate and tryptophan, decreasing interdependence between the quantified components of amino acid metabolism. In response to hypoxia, the dependence of cerebellar amino acid pool on OGDHC and the average levels of arginine, glutamate, lysine, methionine, serine, phenylalanine, and tryptophan increase in non-pregnant rats only. This is accompanied by a higher hypoxic resistance of the non-pregnant vs. pregnant rats, pointing to adaptive significance of the hypoxia-induced changes in the cerebellar amino acid metabolism. These adaptive mechanisms are not effective in the pregnancy-changed metabolic network. Thus, the cerebellar amino acid levels and OGDHC activity provide sensitive markers of the physiology-dependent organization of metabolic network and its stress adaptations.

scholarly journals Elucidation of salt stress defense and tolerance mechanisms of marine red yeast Sporobolomyces pararoseus NGR using transcriptomic and metabolomic profiling

2019 ◽  
Author(s):  
Chunji Li ◽  
Die Zhao ◽  
Ning Zhang ◽  
Bingxue Li
Keyword(s):  
Salt Stress ◽  
Lipid Metabolism ◽  
Amino Acid ◽  
Network Analysis ◽  
Transcriptome Analysis ◽  
Metabolic Profiling ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Salt Tolerant ◽  
Tolerance Mechanisms

Background. Salinity stress is one of the most environmental stresses in agricultural regions worldwide. Salinity inhibits shoot and root growth of various crops, which culminate in reductions in the quality and yield. It is of crucial to understand the molecular biological mechanisms of salt stress responses and defenses in order to enhance crops salt-tolerance. Sporobolomyces pararoseus is a member of marine red yeasts. Since marine red yeast has been naturally selected for its long-term survival in high-salt marine ecosystems, some unique salt-tolerant mechanism has been developed. Little research has conducted so far by considering S. pararoseus as model microorganisms to study salt stress tolerance mechanisms. A better understanding of the mechanisms mediating salt stress of S. pararoseus NGR will provide valuable information for enhancing the crops salt-tolerant via genetic engineering. Methods. S. pararoseus NGR (CGMCC 2.5280) cultures were treated with initial NaCl concentrations of 0.75 M throughout 3 days of growth period. Transcriptome analysis was performed using RNA-seq to study the differentially expressed genes (DEGs) between the NaCl-treated cells and the control cells. Metabolome analysis was performed using the LC-MS/MS untargeted metabolic profiling to study the differentially accumulated metabolites between the NaCl-treated cells and the control cells. Co-expression network analysis was carried out using the screening parameters of correlation coefficient = 0.99 and p-value = 0.01. Transcriptome analysis results were confirmed by real-time quantitative PCR (RT-qPCR). Results. After sequencing, de novo assembly and quantitative assessment, 9,533 unigenes were finally generated with an average length of 1,538 bp. A total of 3,849 DGEs were identified in NaCl-treated cultures, including 2,019 up-regulated genes and 1,830 down-regulated genes. Screening of metabolite features with untargeted metabolic profiling of all samples in NaCl-treated and control group, we characterized 4,862 compounds from the LC–MS/MS-based dataset. An integrated analysis of transcriptome and metabolome indicated that amino acid metabolism, carbohydrate metabolism, and lipid metabolism is significantly enriched in response to salt stress. Co-expression network analysis showed that 28 genes and 8 metabolites played an important role in the response of S. pararoseus NGR and defense against salt stress, which provides valuable clues for subsequent validation. Together, our results suggested that the most primary salt-tolerant mechanism of the S. pararoseus NGR is the biosynthesis of carotenoids, and torulene showed the dominated effect among them. Moreover, amino acid metabolism, carbohydrate metabolism and lipid metabolism act as its secondary salt-tolerant mechanism.

scholarly journals Transcriptomic Responses Induced in Muscle and Adipose Tissues of Growing Pigs by Intravenous Infusion of Sodium Butyrate

Biology ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 559
Author(s):  
He Zhang ◽  
Erdu Ren ◽  
Rongying Xu ◽  
Yong Su
Keyword(s):  
Adipose Tissue ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Amino Acid ◽  
Carbohydrate Metabolism ◽  
Muscle Tissue ◽  
Sodium Butyrate ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Growing Pigs

Butyrate has a central function in the regulation of energy metabolism as a metabolite of bacterial fermentation. This study evaluated the effects of intravenous sodium butyrate (SB) administration on the transcriptome of muscle and adipose tissue of pigs. Twelve crossbred barrows (Duroc × Landrace × Large White) were fitted with a medical polyethylene cannula via the internal jugular vein and were daily infused with 10 mL SB (200 mmol/L) or the same volume of physiological saline. Muscle transcriptome showed 11 DEGs related to carbohydrate metabolism, 28 DEGs related to lipid metabolism, and 10 DEGs related to amino acid metabolism. Among these, carbohydrate catabolic process-related genes (PPP1R3B, PRPS2, ALDOC), fatty acid synthase (FASN), and lipolysis-related genes (PLIN1) were upregulated, while the carbohydrate biosynthetic process-related genes (PCK1) and most amino acid metabolism-related genes were downregulated. Adipose transcriptome showed 12 DEGs related to carbohydrate metabolism, 27 DEGs related to lipid metabolism, and 10 DEGs related to amino acid metabolism. Among these, carbohydrate metabolism-related genes (IGF1, LEP, SLC2A4) and lipolysis-related genes (LPL) were upregulated, while lipolysis-related genes (ANGPTL4) and most amino acid metabolism-related genes were downregulated. The results suggest that short-term intravenous SB infusion could modulate the muscle and adipose tissue metabolism at the transcriptional level by decreasing amino acid metabolism pathways. Additionally, intravenous SB increased the glucose catabolism in muscle tissue and decreased the glucose utilization in adipose tissue. Intravenous SB increased the fatty acid synthesis, decreased the lipolysis in muscle tissue, and increased the lipolysis in adipose tissue. This suggests that systemic butyrate may display discriminative metabolic regulation in different tissues of barrows.

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

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.

Amino Acid Metabolism Is Regulated by Glucagon Receptor Signaling in Mice

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 43-OR ◽  
Author(s):  
MARIE WINTHER-SOERENSEN ◽  
KATRINE D. GALSGAARD ◽  
RUNE E. KUHRE ◽  
JENS PEDERSEN ◽  
NICOLAI J. WEWER ALBRECHTSEN ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Receptor Signaling ◽  
Glucagon Receptor

Stoffwechsel Des Neugeborenen (Metabolism of the Newborn), edited by Prof. Dr. med. G. Joppich and Prof. Dr. med. H. Wolf. Stuttgart, W. Germany: Hippokrates Verlag, 1970, 447 pp., no price given

PEDIATRICS ◽  
1971 ◽  
Vol 47 (3) ◽  
pp. 642-643
Author(s):  
Ekkehard W. Reimold
Keyword(s):  
Lipid Metabolism ◽  
Amino Acid ◽  
Broad Spectrum ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Postnatal Period ◽  
West Germany ◽  
Newborn Period

Behind the ambitious title "Metabolism of the Newborn" one finds the transcript of a symposium held in October, 1968 in West Germany. At this meeting a broad spectrum of interesting topics of neonatal metabolism was presented and discussed. There are, for instance, three papers on metabolic and acidbase changes in the fetus, three presentations on protein and amino acid metabolism in the pre- and postnatal period, four papers on the problems of lipid metabolism, and three papers on some hormonal aspects of the newborn period.

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

2018 ◽  
Vol 314 (1) ◽  
pp. E93-E103 ◽  
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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