Ontology highlight
ABSTRACT:
PROVIDER: PRJNA281885 | ENA |
REPOSITORIES: ENA
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Project description:Decreasing glucagon action lowers blood glucose and may be a useful therapeutic approach for diabetes. However, interrupted glucagon signaling in mice leads to hyperglucagonemia and α-cell hyperplasia. We show using islet transplantation, mouse and zebrafish models, an in vitro islet culture assay that a hepatic-derived, circulating factor in mice with interrupted glucagon signaling stimulates α-cell proliferation, which was dependent on mTOR signaling and the FoxP transcription factors. α-cells of transplanted human islets also proliferated in response to this signal in mice. A combination of liver transcriptomics and serum fractionation with proteomics/metabolomics found changes in hepatic gene expression relating to amino acid catabolism predicting the observed increase in serum amino acid levels. Amino acid concentrations that mimicked the levels in mice with interrupted glucagon signaling, specifically L-glutamine, stimulated α-cell proliferation. These results indicate a hepatic-α-islet cell axis where glucagon regulates serum amino acid availability and L-glutamine regulates α-cell proliferation via mTOR-dependent nutrient sensing.
2017-03-31 | GSE89035 | GEO
Project description:Glucagon supports glucose homeostasis by stimulating hepatic gluconeogenesis, in part by promoting the uptake and conversion of amino acids into gluconeogenic precursors. Genetic disruption or pharmacologic inhibition of glucagon signaling results in elevated plasma amino acids, and compensatory glucagon hypersecretion involving expansion of pancreatic α-cell mass. Regulation of pancreatic α- and β-cell growth has drawn a lot of attention because of potential therapeutic implications. Recent findings indicate that hyperaminoacidemia triggers pancreatic α-cell proliferation via an mTOR-dependent pathway. We confirm and extend these findings by demonstrating that glucagon pathway blockade selectively increases expression of the sodium-coupled neutral amino acid transporter Slc38a5 in a subset of highly proliferative α-cells, and that Slc38a5 is critical for the pancreatic response to glucagon pathway blockade; most notably, mice deficient in Slc38a5 exhibit markedly decreased α-cell hyperplasia to glucagon pathway blockade-induced hyperaminoacidemia. These results show that Slc38a5 is a key component of the feedback circuit between glucagon receptor signaling in the liver and amino acid-dependent regulation of pancreatic α-cell mass in mice.
2017-05-01 | GSE89636 | GEO
Project description:Glucagon supports glucose homeostasis by stimulating hepatic gluconeogenesis, in part by promoting the uptake and conversion of amino acids into gluconeogenic precursors. Genetic disruption or pharmacologic inhibition of glucagon signaling results in elevated plasma amino acids and compensatory glucagon hypersecretion involving expansion of pancreatic a cell mass. Recent findings indicate that hyperaminoacidemia triggers pancreatic a cell proliferation via an mTOR-dependent pathway. We confirm and extend these findings by demonstrating that glucagon pathway blockade selectively increases expression of the sodium-coupled neutral amino acid transporter Slc38a5 in a subset of highly proliferative a cells and that Slc38a5 controls the pancreatic response to glucagon pathway blockade; most notably, mice deficient in Slc38a5 exhibit markedly decreased a cell hyperplasia to glucagon pathway blockade-induced hyperaminoacidemia. These results show that Slc38a5 is a key component of the feedback circuit between glucagon receptor signaling in the liver and amino-acid-dependent regulation of pancreatic a cell mass in mice.
2017-06-21 | GSE90116 | GEO
Project description:Glucagon is a key regulator of glucose homeostasis, amino acid catabolism, and lipid metabolism. Glucagon receptor knock-out (GcgrKO) mice have slightly reduced blood glucose levels whereas plasma levels of amino acids are vastly increased reflecting disruption of hepatic amino acid catabolism. To dissect the molecular mechanisms underlying this effect, RNA sequencing of livers from male GcgrKO mice and wild-type littermates were performed. The mice were 10 weeks of age and were subjected to a short-term fast of 4 h before anesthesia with 2.5% isoflurane.
2022-10-11 | E-MTAB-12060 | biostudies-arrayexpress
Project description:Chronic glucagon receptor activation with a long-acting glucagon analogue increases amino acid catabolism, and to dissect the molecular mechanism underlying this effect, RNA sequencing of liver biopsies from female mice treated for eight weeks with GCGA or PBS were performed.
2022-10-11 | E-MTAB-12040 | biostudies-arrayexpress
Project description:Chronic glucagon receptor inhibition with a glucagon receptor antibody decreases amino acid catabolism and ureagenesis, while increasing plasma triglyceride concentrations, plasma very-low density lipoprotein cholesterol concentrations, and liver triglyceride concentrations. To dissect the molecular mechanism underlying these effects, RNA sequencing of liver biopsies from female mice treated for eight weeks with the glucagon receptor antibody, REGN1193, or a control antibody, REGN1945, were performed.
2022-10-09 | E-MTAB-12048 | biostudies-arrayexpress
Project description:The hormone glucagon plays a crucial role in maintaining normal blood glucose levels and recently has also been found with synergistic effects on liver lipid catabolism in both clinic and basic research studies. However, the mechanisms by which glucagon signaling synchronizes glucose and lipid metabolism in the liver are not yet fully understood. Here, we report that hepatic androgen receptor (AR) functions as a critical mediator of glucagon signaling, contributing to sexual dimorphism in hepatic glucagon sensitivity. The inhibition of AR, either through chemical or genetic means, impairs glucagon stimulation of gluconeogenesis and lipid catabolism in hepatocytes. Notably, female mouse hepatocytes express up to four times more AR than their male littermates, and consistently respond to glucagon to a much greater extent in producing glucose and catabolizing lipid. Moreover, liver-specific AR knockout impairs glucagon induction of blood glucose and increases liver fat deposit, especially in female mice. Mechanistically, we demonstrate that hepatic AR drives a PGC1α/ERRα-mitochondria axis to promote lipid catabolism for liver glucose production in response to glucagon treatment. Overall, our findings shed light on the role of hepatic AR in mediating glucagon signaling to orchestrate glucose and lipid metabolism, particularly in female mice, which may help elucidate the factors responsible for sex differences in glucagon sensitivity and the development of fatty liver diseases.
2025-01-01 | GSE236551 | GEO
Project description:Blockade of the glucagon receptor (GCGR) has been shown to improve glycemic control. However, this therapeutic approach also brings side effects, such as α-cell hyperplasia and hyperglucagonemia, and the mechanisms underlying these side effects remain elusive. Here, we conduct single-cell transcriptomic sequencing of islets from male GCGR knockout (GCGR-KO) mice. Our analysis confirms the elevated expression of Gcg in GCGR-KO mice, along with enhanced glucagon secretion at single-cell level. Notably, Vgf (nerve growth factor inducible) is specifically upregulated in α cells of GCGR-KO mice. Inhibition of VGF impairs the formation of glucagon immature secretory granules and compromises glucagon maturation, lead to reduced α-cell hypersecretion of glucagon. We further demonstrate that activation of both mTOR-STAT3 and ERK-CREB pathways, induced by elevated circulation amino acids, is responsible for upregulation of Vgf and Gcg expression following glucagon receptor blockade. Thus, our findings elucidate a previously unappreciated molecular mechanism underlying hyperglucagonemia in GCGR blockade.
2025-02-11 | GSE253271 | GEO
Project description:The hormone glucagon, which is primarily recognized for its ability to raise blood glucose levels, may also have a significant role in regulating liver fat content by increasing lipid breakdown. This topic has been extensively investigated in both clinical and basic research studies, generating considerable interest and discussion.Using both chemical and genetic means, we uncovered the unexpected role of hepatic androgen receptor in mediating glucagon response. AR regulated transcriptome in hepatocyes was for the first time defined through RNAseq analysis. Sex difference in response to glucagon was shown at different level in both primary hepatocytes and mice. AR direct regulation on PGC1α/ERRα axis was proved through co-immunoprecipitation assay.Androgn receptor has been found to regulate glucagon function in both gluconeogenesis and lipid catabolism through moludation of basal mitochondrial respiration. Notably, female mouse hepatocytes express up to three times more AR than their male littermates. Consequently, they respond to glucagon to a much greater extent in terms of glucose production and lipid catabolism outcomes. Moreover, liver-specific AR knockout impairs the effect of glucagon in inducing blood glucose production, especially in female mice. Mechanistically, we demonstrate that hepatic AR drives a PGC1α/ERRα-mitochondria axis to promote lipid catabolism for liver glucose production in response to glucagon treatment. Together, our study sheds light on the role of hepatic AR in mediating glucagon activity in orchestrating glucose and lipid metabolism, and sex-differentiated AR expression contributes to sexual dimorphism in hepatic glucagon sensitivity.
2025-01-01 | GSE261197 | GEO
Project description:Amino acid catabolism fuels microalgal lipogenesis
| PRJNA324164 | ENA