Anti-Fibrotic Effects Of A Novel Long-Acting Fgf21 Analogue Zalfermin
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1110280 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR28995900.fastq.gz | Fastqsanger.gz | |||
| SRR28995901.fastq.gz | Fastqsanger.gz | |||
| SRR28995905.fastq.gz | Fastqsanger.gz | |||
| SRR28995906.fastq.gz | Fastqsanger.gz |
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Project description:The potential clinical benefits of FGF21 analogues for the treatment of MASH has evolved significantly within the last years. However, despite clinical meaningful effect on MASH resolution and fibrosis the body weight loss in humans have been less impressive. Thus, a combination of an FGF21 analogue with a GLP-1 receptor agonist may add additional benefit to the treatment of MASH due to complimentary mode of action compared to stand alone therapies
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Project description:FGF21 analogs tested in clinical trials in metabolic diseases i.e. type 2 diabetes mellitus and non-alcoholic fatty liver disease are generally well-tolerated. FGF21 is a peptide hormone that is primarily secreted by the liver, but it also crosses the blood-brain barrier. The bulk of literature on this subject has raised the possibility that FGF21 administration could affect alcohol use and reward behaviors. Our recent study showed that FGF21 levels were associated with recent alcohol consumption. Furthermore, our data also suggest that the effects of FGF21 in the induced pluripotent stem cell (iPSC)-derived 3D-brain organoids are associated, at least in part, with the regulation of catecholamines, neurotransmitters that play a crucial role in reward pathways. These observations potentially open the way to pharmacologic manipulation of FGF21, which in turn could have significant implications for catecholamines, and alcohol use. Current in vitro models designed to study drug action in the human brain are limited. Therefore, we used iPSC-derived neurons as a novel "cell-line based" approach to advance our understanding of drug action in the brain. Since the half-life of the naïve form of FGF21 is about 0.5-2 hours, it is not suitable for clinical use due to poor pharmacokinetic and biophysical properties . As a result, the present study was designed to identify molecular mechanisms for both the naïve form of FGF21 and a long-acting FGF21 molecule (PF-05231023) which was developed by conjugating two molecules of modified FGF21 (dHis/Ala129Cys) to an antibody scaffold.
2023-09-27 | GSE223173 | GEO
Project description:Chronic stress leads post-traumatic stress disorder (PTSD) and to metabolic complications, including fatty liver. It is feasible, that stress immediately initiates molecular mechanisms to alter energy metabolism and glucose homeostasis which interfere with hepatic lipid accumulation after stress recovery. We aim to elucidate these molecular mechanisms of long term stress effects on metabolism and focus on physiological adaptation and the role of FGF21, which is protective in hepatic lipid accumulation. Methods FGF21 knockout and control mice were exposed to chronic variable stress (Cvs) and recovered for 3 months to simulate PTSD. We determined in vivo and ex vivo energy metabolism, mitochondrial function by extracellular flux analysis, alterations in DNA modifying enzymes and gene regulation immediately after stress and after the recovery period to determine long term alterations. Results Chronic stress leads to reduced insulin sensitivity and hepatic lipid accumulation with increased fatty acid uptake (FAU), stress-induced lipolysis, and reduction in NAD+/NAD ratio and Sirt activity. Immediately after stress, PPARa and SREBP-1 target genes are differentially regulated and are involved in the development of stress-induced fatty liver. After recovery, insulin sensitivity increases but insulin-induced de novo lipogenesis (DNL) is reduced and FAU is increased. HDAC and MT activity are suppressed, whereas HAT activity increases, linking metabolic adjustments to transcriptional regulators. Thus, key metabolic genes are differentially regulated and secreted proteins indicate the activation of liver disease by Cvs only in FGF21WT. GR binding to the Cd36 promoter is altered. After stress recovery, serum FGF21 is increased and protects against lipid accumulation. FGF21 interacts by attenuating DNL, increasing FAU and HAT activity, and balancing mitochondrial activity. Higher long-term stress-induced activation and binding of GR to the FGF21 promoter may contribute to the prolonged FGF21 release. Conclusions We show that previous stress exposure determines predisposition to fatty liver disease is regulated by FGF21. Immediately after Cvs, altered gene regulation and activity of DNA-modifying enzymes determine the metabolic late effects seen in PTSD. FGF21 functions after chronic stress exposure i) to protect against hepatic lipid accumulation, ii) to maintain mitochondrial capacity, and iii) to mediate in the modulation of DNA-modifying enzymes. These findings highlight the protective role of FGF21 even in stress-induced hepatic lipid accumulation.
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Project description:Chronic glucagon receptor activation induced by a long-acting glucagon analogue causes thickening of the parietal layer of Bowman’s capsule, causes mesangial area expansion, and formation of albuminuria. To dissect the molecular mechanism underlying these effects, RNA sequencing of kidney biopsies from female mice treated for eight weeks with either the long-acting glucagon analogue, NNC9204-0043, or PBS were performed
2023-12-01 | E-MTAB-12520 | biostudies-arrayexpress
Project description:The potential clinical benefits of FGF21 analogues for the treatment of NASH has evolved significantly within the last years. However, despite clinical meaningful effect on NASH resolution and fibrosis the body weight loss in humans have been less impressive. Thus, a combination of an FGF21 analogue with a GLP-1 receptor agonist may add additional benefit to the treatment of NASH due to complimentary mode of action compared to stand alone therapies
2025-02-01 | GSE256063 | GEO
Project description:FGF21 is a novel secreted protein with robust anti-diabetic, anti-obesity, and anti-atherogenic activities in preclinical species. In the current study, we investigated the signal transduction pathways downstream of FGF21 following acute administration of the growth factor to mice. Focusing on adipose tissues, we identified FGF21-mediated downstream signaling events and target engagement biomarkers. Specifically, RNA profiling of adipose tissues and phosphoproteomic profiling of adipocytes, following FGF21 treatment revealed several specific changes in gene expression and post-translational modifications, specifically phosphorylation, in several relevant proteins. Affymetrix microarray analysis of white adipose tissues isolated from both C57BL/6 (fed either regular chow or HFD) and db/db mice identified over 150 robust potential RNA transcripts and over 50 potential secreted proteins that were changed greater than 1.5 fold by FGF21 acutely. Phosphoprofiling analysis identified over 130 phosphoproteins that were modulated greater than 1.5 fold by FGF21 in 3T3-L1 adipocytes. Bioinformatic analysis of the combined gene and phosphoprotein profiling data identified a number of known metabolic pathways such as glucose uptake, insulin receptor signaling, Erk/Mapk signaling cascades, and lipid metabolism. Moreover, a number of novel events with hitherto unknown links to FGF21 signaling were observed at both the transcription and protein phosphorylation levels following treatment. We conclude that such a combined "omics" approach can be used not only to identify robust biomarkers for novel therapeutics but can also enhance our understanding of downstream signaling pathways; in the example presented here, novel FGF21-mediated signaling events in adipose tissue have been revealed that warrant further investigation. Three mouse strains (C57BL6 on chow diet, C57BL6 on high fat diet, and db/db on chow diet) were treated with either vehicle, wild-type FGF21, or pegylated FGF21 acutely or for several days and three white adipose tissues (IWAT, EWAT, RPWAT) and brown adipose tissue (BAT) were profiled on custom Affymetrix microarrays. The primary goal was to identify robust and consistent acute target engagement biomarkers of FGF21 activation in white adipose tissues.
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Project description:To elucidate the signalling network responsible for mediating the effects of FGF21, we quantified the dynamic phosphoproteome of adipocytes following acute exposure to this hormone. A major FGF21-regulated signalling node was mTORC1/S6K. In contrast to insulin, we find that FGF21 activates mTORC1 via MAPK signalling rather than through the canonical PI3K/AKT pathway. This study provides a systems view of FGF21 signalling and reveals a new role for mTORC1 in maintaining nutrient homeostasis.
2016-08-15 | PXD003631 | Pride
Project description:Fibroblast growth factor 21 (FGF21) is a key metabolic regulator which was recently discovered as stress-induced myokine and common denominator of muscle mitochondrial disease. However, its precise function and pathophysiological relevance remains unknown. Here we demonstrate that white adipose tissue (WAT) is the major target of muscle mitochondrial stress-induced FGF21. Strikingly, substantial browning and metabolic remodeling of subcutaneous WAT, together with the reduction of circulating triglycerides and cholesterol are fully FGF21 dependent. Unexpectedly and in contrast to prior expectations, we found a negligible role of FGF21 in muscle stress-related improved glycemic control, obesity resistance and hepatic lipid homeostasis. Furthermore, we show that the protective muscle mitohormesis and metabolic stress adaptation does not require FGF21 action. Taken together, our data imply that although FGF21 drives WAT remodeling, this effect and FGF21 as stress hormone per se may not be essential for the adaptive response under muscle mitochondrial stress conditions. Wildtype male mice and FGF21-knockout male mice, together with muscle specific UCP1-transgenic male animals, and double cross of FGF21-KO with UCP1-Tg male mice, were kept on a standardized low fat diet for 40 weeks. After sacrifice, subcutaneous white adipose tisseu (scWAT) was rapidly removed, weighed, and snap frozen in liquid nitrogen and used for RNA isolation and whole genome gene expression microarray hybridisation using Agilent arrays.
2016-01-07 | E-GEOD-71749 | biostudies-arrayexpress
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2025-02-28 | GSE267618 | GEO
Project description:Fibroblast Growth Factor (FGF) 21 is a hormone produced mainly by the liver but also other organs, including the heart. FGF21 analogs are used for treating obesity and metabolic syndrome in humans. In this study, we explored involvement of FGF21 in cardiac hypertrophy. Our mouse studies in wild type mice as well as in mice with either hepatocyte-specific or cardiomyocyte-specific FGF21 ablation demonstrated an interorgan liver-heart crosstalk mechanism, which is controlled by initial hepatic FGF21 release followed by induction of cardiomyocyte FGF21 expression. Conclusively, a hepato-cardiac FGF21-based signaling axis governs cardiac hypertrophy.
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