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:Amino acid catabolism fuels microalgal lipogenesis
| PRJNA324164 | ENA
Project description:Excessive hepatic glucose production is a major contributor to the hyperglycemia observed in Type 2 diabetes mellitus. It is widely accepted that it is due to an increase in hepatic gluconeogenesis. While much attention has been devoted to the transcriptional regulation of key gluconeogenic enzymes, much less is known about the regulation of amino acid catabolism that provides gluconeogenic substrates. Here, we emphasize a novel role of LKB1 in this regulation. We show that mice with a hepatocyte-specific deletion of Lkb1 have increased hepatic amino acid catabolism for gluconeogenesis. This occurred during fasting, as well as during the postprandial period, identifying Lkb1 as a critical suppressor of hepatic postprandial gluconeogenesis. Hepatic Lkb1 deletion was also associated with severe alterations in whole body metabolism leading to decreased lean body mass deposition on MRI analysis and, at a longer term, cachexia and sarcopenia as a consequence of the diversion of amino acids for liver metabolism at the expense of muscle. Using genetic and pharmacological approaches, we identified the aminotransferases and Agxt and as critical effectors of the suppressor function of Lkb1 in amino acid-driven gluconeogenesis.
2020-12-01 | PXD013478 | Pride
Project description:Non-oxidative pentose phosphate pathway (PPP) is a crucial gatekeeper of glucose catabolism in metabolic tissues. However, its role in regulatory T cells (Tregs) remains unknown. Here we report deleting transketolase (TKT), an indispensable enzyme of non-oxidative PPP, in Tregs caused a fatal auto-immune disease in mice. TKT deletion impaired suppressive capability without disturbing Treg cell number. Mechanistically, TKT deficiency caused Treg metabolic remodeling with decreased glucose catabolism, activated fatty acid and amino acid catabolism and uncontrolled oxidative phosphorylation. Moreover, excessive ammonia from deregulated amino acid catabolism impaired mitochondrial fitness while reduced α-ketoglutarate/succinate ratio led to DNA hypermethylation, limiting functional gene expression and suppressive activity of TKT-deficient Tregs. Therefore, our study identifies non-oxidative PPP as a new pathway for controlling Treg function.
2022-03-31 | GSE172047 | GEO
Project description:Non-oxidative pentose phosphate pathway (PPP) is a crucial gatekeeper of glucose catabolism in metabolic tissues. However, its role in regulatory T cells (Tregs) remains unknown. Here we report deleting transketolase (TKT), an indispensable enzyme of non-oxidative PPP, in Tregs caused a fatal auto-immune disease in mice. TKT deletion impaired suppressive capability without disturbing Treg cell number. Mechanistically, TKT deficiency caused Treg metabolic remodeling with decreased glucose catabolism, activated fatty acid and amino acid catabolism and uncontrolled oxidative phosphorylation. Moreover, excessive ammonia from deregulated amino acid catabolism impaired mitochondrial fitness while reduced α-ketoglutarate/succinate ratio led to DNA hypermethylation, limiting functional gene expression and suppressive activity of TKT-deficient Tregs. Therefore, our study identifies non-oxidative PPP as a new pathway for controlling Treg function.
2022-03-31 | GSE171675 | GEO