Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Glucagon-receptor signaling regulates energy metabolism via hepatic Farnesoid X Receptor and Fibroblast Growth Factor 21

ABSTRACT: Glucagon, an essential regulator of glucose and lipid metabolism, also promotes weight loss, in part through potentiation of fibroblast-growth factor 21 (FGF21) secretion. However, FGF21 is only a partial mediator of metabolic actions ensuing from GcgR-activation, prompting us to search for additional pathways. Intriguingly, chronic GcgR agonism increases plasma bile acid levels. We hypothesized that GcgR agonism regulates energy metabolism, at least in part, through farnesoid X receptor (FXR). To test this hypothesis, we studied whole body and liver-specific FXR knockout (FXR∆liver) mice. Chronic GcgR agonist (IUB288) administration in diet-induced obese (DIO) Gcgr, Fgf21 and Fxr whole body or liver-specific knockout (∆liver) mice failed to reduce body weight (BW) when compared to wildtype (WT) mice. IUB288 increased energy expenditure and respiration in DIO WT mice, but not FXR∆liver mice. GcgR agonism increased [14C]-palmitate oxidation in hepatocytes isolated from WT mice in a dose-dependent manner, an effect blunted in hepatocytes from FXR∆liver mice. Our data clearly demonstrate that control of whole body energy expenditure by GcgR agonism requires intact FXR signaling in the liver. This heretofore-unappreciated aspect of glucagon biology has implications for the use of GcgR agonism in the therapy of metabolic disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE135881 | GEO | 2019/08/16

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

BI 456906: a dual glucagon-like peptide-1/glucagon agonist promoting bodyweight reduction

Project description:Glucagon and glucagon-like peptide-1 (GLP-1) are hormones involved in energy homeostasis. GLP-1 receptor (GLP-1R) agonism reduces food intake and delays gastric emptying, and glucagon receptor (GCGR) agonism increases energy expenditure by thermogenesis. BI 456906 is a subcutaneous, once-weekly injectable dual GLP-1R/GCGR agonist in development for the treatment of obesity or non-alcoholic steatohepatitis. Here we show that BI 456906 is a potent dual agonist with an extended half-life in human plasma. Key GLP-1R-mediated mechanisms of reduced food intake, delayed gastric emptying and improved glucose tolerance were confirmed in GLP-1R knockout mice. GCGR activity was confirmed by reduced plasma amino acids, increased hepatic expression of nicotinamide N-methyltransferase and increased energy expenditure. BI 456906 produced greater bodyweight reductions than maximally efficacious semaglutide doses and modulated gene expression, including genes involved in amino acid metabolism. BI 456906 is a potent dual agonist that produces bodyweight-lowering effects through both GLP-1R and GCGR agonism.

2022-12-09 | GSE211105 | GEO

Chronic treatment with glucagon-like peptide-1/glucagon receptor co-agonist causes weight-loss independent improvements in hepatic steatosis

Project description:Co-agonists at the glucagon-like peptide-1/glucagon receptors (GLP1R/GCGR) show promise as treatments for metabolic dysfunction-associated steatotic liver disease (MASLD). Unlike GLP1, glucagon directly acts on the liver to reduce fat content. To date most metabolic studies have looked at heavily GLP1R-biased co-agonists and have not distinguished weight-loss versus weight loss-independent effects. We demonstrate that 24 days’ treatment with Dicretin, a GLP1/GCGR co-agonist with high potency at the GCGR, in mice with hepatic steatosis secondary to diet-induced obesity leads to superior reduction of hepatic lipid content when compared to Semaglutide or equivalent weight loss by calorie restriction. Hepatic transcriptomic and metabolomic profiling demonstrated many changes that were unique to Dicretin-treated mice: some known targets of glucagon signalling and others with as yet unclear physiological significance. Our study supports the development of GLP1/GCGR co-agonists for treatment of MASLD and related conditions.

2024-06-11 | GSE243681 | GEO

Glucagon receptor deficient liver during postnatal development

Project description:Glucagon receptor deficient liver during postnatal development: fig S5a-S5c in Solloway et al. livers from ko and wt GCGR mice at various developmental stages

2015-06-02 | GSE68141 | GEO

Glucagon receptor signaling in GCGR KO mice

Project description:GCGR wt and ko mice Glucagon receptor signaling in GCGR KO mice: fig 2a in Solloway et al.

2015-06-02 | GSE68143 | GEO

Disruption of glucagon receptor increase α-cell glucagon expression and secretion beyond hyperplasia in zebrafish

Project description:Glucagon receptor (GCGR) is a potential target for diabetes therapy. Several emerging GCGR antagonism-based therapies are under pre-clinical and clinical development. However, the GCGR antagonism as well as GCGR deficient animal accompanied with α-cell hyperplasia and hyperglucagonemia, which may limit the application of GCGR antagonism. To better understand the physiological changes in the α cells during the GCGR disruption, we performed the single cell sequencing of α cells isolated from control and gcgr-/- zebrafish. We found that α cells in gcgr-/- zebrafish dramatically increased glucagon (both gcga and gcgb) expression, we also found that several transcriptional factors that regulate glucagon expression were also increased. Based on the sequencing data, we further experimentally confirmed that gcgr-/- up-regulated glucagon mRNA level by in situ hybridization, and the gcgr-/- increased glucagon promoter activity indicated by reporter line Tg(gcga: GFP). Moreover, our results also revealed that α cells increased glucagon granule population and glucagon level in gcgr-/- zebrafish. These data suggested that hyperglucagonemia in the organism of GCGR antagonism not only contributed by the α-cell hyperplasia but also contributed by the increased glucagon expression and secretion from α cells. Our study provided more comprehensive understanding of physiological changes of α-cell during the GCGR disruption.

2022-10-26 | GSE179894 | GEO

Transcription profiling of liver from farnesoid X receptor knockout mice

Project description:Expression profiling of whole body (WB) FXR knockout (KO) mice (FXR WB KO), liver-specific FXR KO mice (AFXR Cre+) and enterocyte specific FXR KO mice (VFXR Cre+) on a C57BL/6J genetic background Whole body (WB) FXR knockout (KO) mice (FXR WB KO), liver-specific FXR KO mice (AFXR Cre+) and enterocyte specific FXR KO mice (VFXR Cre+) on a C57BL/6J genetic background were bred and maintained in the laboratory animal research facility at the University of Kansas Medical Center in rooms under a 12-hour light-dark cycle. All experiments used 10-16 week-old male mice. FXR was activated by treatment with the FXR synthetic agonist, GW4064, at 150 mg/kg. GW4064 or vehicle was administered by oral gavage at 6 p.m., followed by a second administration at 8 a.m. the next morning. Two hours later, the liver was harvested.

2014-01-31 | E-GEOD-54557 | biostudies-arrayexpress

Transcription profiling of liver from farnesoid X receptor knockout mice

2014-01-31 | GSE54557 | GEO

Mus musculus

Project description:Glucagon receptor signaling in GCGR KO mice

| PRJNA282087 | ENA

Farnesoid X Receptor alters adipose tissue architecture in mice and limits its storage capacity leading to metabolic derangements

Project description:The bile acid-activated nuclear receptor Farnesoid X receptor (FXR, NR1H4) has been implicated in the control of lipid and energy metabolism, but its role in fat tissue, where it is moderately expressed, is not understood. In view of the recent development of FXR-targeting therapeutics for treatment of human metabolic diseases, understanding the tissue-specific actions of FXR is essential. We show that transgenic mice expressing human FXR specifically in adipose tissue (aP2-hFXR) have markedly enlarged adipocytes and show extensive extracellular matrix remodelling. Ageing and exposure to obesogenic conditions revealed a strongly limited capacity for adipose expansion and development of fibrosis in adipose tissues of aP2-hFXR transgenic mice. This was associated with impaired lipid storage capacity, leading to elevated plasma free fatty acids, ectopic fat deposition in liver and muscle as well as whole-body insulin resistance. These studies establish that adipose FXR is a determinant of adipose tissue architecture and contributes to whole-body lipid homeostasis.

2020-04-13 | GSE37248 | GEO

Dietary protein defends lean mass and maintains metabolic benefits of glucagon receptor agonist G108 in mice

Project description:Glucagon has long been proposed as a component of multi-agonist obesity therapeutics due to its ability to induce energy expenditure and cause weight loss. However, chronic glucagon-receptor agonism has been associated with a reduction in circulating amino acids and loss of lean mass. Importantly, it is currently not known whether the metabolic benefits of glucagon can be maintained in contexts that permit the defence of lean mass.

2024-09-09 | GSE273658 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data