Therapeutic effects of FGF21 mimetic bFKB1 on MASH and atherosclerosis in Ldlr-/-.Leiden mice
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ABSTRACT:
PROVIDER: PRJNA1074673 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27911600_1.fastq.gz | Fastqsanger.gz | |||
| SRR27911600_2.fastq.gz | Fastqsanger.gz | |||
| SRR27911601_1.fastq.gz | Fastqsanger.gz | |||
| SRR27911601_2.fastq.gz | Fastqsanger.gz | |||
| SRR27911602_1.fastq.gz | Fastqsanger.gz |
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Project description:Fibroblast growth factor 21 (FGF21) is a promising target for treatment of obesity-associated diseases including metabolic dysfunction-associated steatohepatitis (MASH) and atherosclerosis. We evaluated the effects of the bispecific anti-FGF21-β klotho (KLB) agonist antibody bFKB1 in a preclinical model of MASH and atherosclerosis. Low-density lipoprotein receptor knockout (Ldlr−/−).Leiden mice received a high-fat diet for 20 weeks, followed by treatment with an isotype control antibody or bFKB1 for 12 weeks. Effects on plasma risk markers and (histo)pathology of liver, adipose tissue, and heart were evaluated alongside hepatic transcriptomics analysis. bFKB1 lowered body weight (−21%) and adipose tissue mass (−22%) without reducing food intake. The treatment also improved plasma insulin (−80%), cholesterol (−48%), triglycerides (−76%), alanine transaminase (ALT: −79%), and liver weight (−43%). Hepatic steatosis and inflammation were strongly reduced (macrovesicular steatosis −34%; microvesicular steatosis −100%; inflammation −74%) and while the total amount of fibrosis was not affected, bFKB1 did decrease new collagen formation (−49%). Correspondingly, hepatic transcriptomics and pathway analysis revealed the mechanistic background underlying these histological improvements, demonstrating broad inactivation of inflammatory and profibrotic transcriptional programs by bFKB1. In epididymal white adipose tissue, bFKB1 reduced adipocyte size (−16%) and inflammation (−52%) and induced browning, signified by increased uncoupling protein-1 (UCP1) protein expression (8.5-fold increase). In the vasculature, bFKB1 had anti-atherogenic effects, lowering total atherosclerotic lesion area (−38%). bFKB1 has strong beneficial metabolic effects associated with a reduction in hepatic steatosis, inflammation, and atherosclerosis. Analysis of new collagen formation and profibrotic transcriptional programs indicate that bFKB1 treatment may have antifibrotic potential in a longer treatment duration as well.
2025-01-01 | GSE255321 | GEO
Project description:Fibroblast growth factor 21 (FGF21) is a promising target for treatment of obesity-associated diseases including metabolic dysfunction-associated steatohepatitis (MASH) and atherosclerosis. We evaluated the effects of the bispecific anti-FGF21-β klotho (KLB) agonist antibody bFKB1 in a preclinical model of MASH and atherosclerosis. Low-density lipoprotein receptor knockout (Ldlr-/-).Leiden mice received a high-fat diet for 20 weeks, followed by treatment with an isotype control antibody or bFKB1 for 12 weeks. Effects on plasma risk markers and (histo)pathology of liver, adipose tissue, and heart were evaluated alongside hepatic transcriptomics analysis. bFKB1 lowered body weight (-21%) and adipose tissue mass (-22%) without reducing food intake. The treatment also improved plasma insulin (-80%), cholesterol (-48%), triglycerides (-76%), alanine transaminase (ALT: -79%), and liver weight (-43%). Hepatic steatosis and inflammation were strongly reduced (macrovesicular steatosis -34%; microvesicular steatosis -100%; inflammation -74%) and while the total amount of fibrosis was not affected, bFKB1 did decrease new collagen formation (-49%). Correspondingly, hepatic transcriptomics and pathway analysis revealed the mechanistic background underlying these histological improvements, demonstrating broad inactivation of inflammatory and profibrotic transcriptional programs by bFKB1. In epididymal white adipose tissue, bFKB1 reduced adipocyte size (-16%) and inflammation (-52%) and induced browning, signified by increased uncoupling protein-1 (UCP1) protein expression (8.5-fold increase). In the vasculature, bFKB1 had anti-atherogenic effects, lowering total atherosclerotic lesion area (-38%). bFKB1 has strong beneficial metabolic effects associated with a reduction in hepatic steatosis, inflammation, and atherosclerosis. Analysis of new collagen formation and profibrotic transcriptional programs indicate that bFKB1 treatment may have antifibrotic potential in a longer treatment duration as well.
| S-EPMC11580715 | biostudies-literature
Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), represent a growing public health burden with limited therapeutic options. Recent studies have revealed that fibroblast growth factor 21 (FGF21)-based analogs can significantly improve MASH, but the mechanisms for this effect are not well understood. Here, we demonstrate that the beneficial metabolic effects of FGF21 to reverse MASH are mediated through distinct mechanisms to independently lower hepatic triglyceride and cholesterol levels. Specifically, FGF21 signaling directly to glutamatergic neurons in the central nervous system (CNS) stimulates hepatic triglyceride reduction and reversal of fibrosis, whereas FGF21 signaling directly to hepatocytes is necessary and sufficient to reduce hepatic cholesterol levels in mice. Mechanistically, we show that FGF21 acts in the CNS to increase sympathetic nerve activity to the liver which suppresses hepatic de novo lipogenesis. These results provide critical insights into a promising pharmacological target to treat MASH.
2025-05-13 | GSE295343 | GEO
Project description:Abstract. Background and aims: Semaglutide, a glucagon-like peptide-1 receptor agonist, is an antidiabetic medication that has recently been approved for treatment of obesity as well. Semaglutide is also postulated to be a promising candidate for treatment of non-alcoholic steatohepatitis (NASH). Here, we evaluated the effects of semaglutide in a translational diet-induced model with advanced NASH and fibrosis. Methods: Ldlr-/-.Leiden mice received a fast food diet (FFD) for 25 weeks, followed by another 12 weeks on FFD with daily subcutaneously injections of semaglutide or vehicle (control). Plasma parameters were evaluated, livers and hearts were examined and hepatic transcriptome analysis was performed. Results: In the liver, semaglutide significantly reduced macrovesicular steatosis (-74%, p<0.001), inflammation (-73%, p<0.001) and completely abolished microvesicular steatosis (-100%, p<0.001). Histological and biochemical assessment of hepatic fibrosis showed no significant effects of semaglutide. However, digital pathology revealed significant improvements in the degree of collagen fiber reticulation (-12%, p<0.001). Semaglutide did not affect atherosclerosis relative to controls. Additionally, we compared the transcriptome profile of FFD-fed Ldlr-/-.Leiden mice with a human gene set that differentiates human NASH patients with severe fibrosis from those with mild fibrosis. In FFD-fed Ldlr-/-.Leiden control mice, this gene set was upregulated as well, while semaglutide predominantly reversed this gene expression. Conclusions: Using a translational model with advanced NASH, we demonstrated that semaglutide is a promising candidate with particular potential for treatment of hepatic steatosis and inflammation, while for reversal of advanced fibrosis, combinations with other NASH agents may be necessary.
2023-08-01 | GSE226496 | GEO
Project description:Abstract Obesity has been linked to vascular dysfunction, cognitive impairment and neurodegenerative diseases. However, experimental models that recapitulate brain pathology in relation to obesity and vascular dysfunction are still lacking. In this study we performed the histological and histochemical characterization of brains from Ldlr-/-.Leiden mice, an established model for obesity and associated vascular disease. 18 week-old and 50 week-old Ldlr-/-.Leiden male mice were compared with age-matched C57BL/6J mice. We then assessed the effect of high-fat diet (HFD)-induced obesity on brain pathology in Ldlr-/-.Leiden mice and tested whether a treatment with an anti-complement component 5 antibody, a terminal complement pathway inhibitor recently shown to reduce vascular disease, can attenuate neurodegeneration and neuroinflammation. Histological analyses were complemented with Next Generation Sequencing (NGS) analyses of the hippocampus to unravel molecular pathways underlying brain histopathology. We show that Ldlr-/-.Leiden mice have more severe neurodegeneration and show an age-dependent astrogliosis that is not observed in age-matched C57BL/6J controls. This was substantiated by pathway enrichment analysis using the NGS data which showed that oxidative phosphorylation, EIF2 signaling and mitochondrial dysfunction pathways, all associated with neurodegeneration, were significantly altered in the hippocampus of Ldlr-/-.Leiden mice compared with controls. Obesity-inducing HFD-feeding did not aggravate neurodegeneration and astrogliosis. However, brains from HFD-fed Ldlr-/-.Leiden mice showed reduced IBA-1 immunoreactivity and increased CD68 immunoreactivity compared with chow-fed controls, indicating an altered overall microglial immunophenotype by HFD feeding. The systemic administration of an anti-C5 treatment partially restored the HFD effect on microglial immunophenotype. In addition, NGS data of hippocampi from Ldlr-/-.Leiden mice showed that HFD affected multiple molecular pathways: HFD notably inactivated synaptogenesis and activated neuroinflammation pathways. The anti-C5 treatment restored the HFD-induced effect on molecular pathways to a large extent. This study shows that the Ldlr-/-.Leiden mouse model is suitable to study brain histopathology and associated biological processes in a context of obesity and provides evidence of the potential therapeutic value of anti-complement therapy against obesity-induced neuroinflammation.
2023-06-18 | GSE234425 | GEO
Project description:- Background: Obesity in mid-adulthood has been suggested to promote brain aging and is associated with progressive cognitive impairment later in life. However, the structural and functional alterations that underlie obesity-related cognitive dysfunction are still poorly understood, partly owing to the lack of translational models replicating age- and obesity-related brain pathology. - Methods: The effect of age and high-fat diet (HFD)-induced obesity was investigated in adult Ldlr-/-.Leiden mice, an established translational model for obesity and its comorbidities. During mid-adulthood, from three to eight months of age, brain structure and function (hippocampal volume, cortical thickness, white matter integrity, cerebral blood flow (CBF), resting-state functional connectivity) were monitored with brain magnetic resonance imaging, and cognitive function was evaluated using cognitive tests. Brain pathology was further examined with histopathological and gene expression analyses. - Results: Ldlr-/-.Leiden mice showed age-related decreases in cortical thickness, CBF, brain connectivity, and neurogenesis along with the development of neuroinflammation and (short-term) memory impairments. On HFD feeding, Ldlr-/-.Leiden mice exhibited similar features, but memory deficits started at a younger age than in chow-fed mice. HFD-fed mice additionally showed a rise in CBF with concomitant decline in fractional anisotropy in white matter tracts. Analyses of hippocampal gene expression further revealed an age-related suppression of processes related to metabolic and neuronal function while HFD feeding strongly activated neuroinflammatory pathways. - Conclusions: Ldlr-/-.Leiden mice show similar critical age-related changes in brain structure and function as observed in humans. In this mouse model, HFD feeding particularly trigger disturbances in brain blood perfusion and white matter tract integrity, which may underlie an accelerated cognitive decline in obesity.
2025-04-30 | GSE294054 | GEO
Project description:Title: White adipose tissue inflammation and gut permeability develop prior to NASH development, associated with increased oxidative stress, intrahepatic diacylglycerol and proinflammatory chemokines in the liver of diet-induced obese and hyperinsulinemic Ldlr-/-.Leiden mice Abstract: NAFLD progression from simple steatosis to NASH and fibrosis is driven by an intricate interplay between molecular and cellular mechanisms. These drivers are not limited to the liver itself but also white adipose tissue and gut may contribute. Current knowledge on these drivers is mostly based on studies that investigate these at a single time point (typically end-stage disease). However, such studies provide no insight into the temporal dynamics and chronology, which therefore remain poorly understood. Ldlr-/-.Leiden mice were fed a high-fat diet (HFD) to induce obesity-associated NAFLD and compared to lean controls fed chow. Groups of mice were sacrificed after 8, 16, 28 and 38 weeks to study liver, white adipose tissue, gut and circulating factors to investigate the sequence of pathogenic events in these critical metabolically active organs as well as organ-crosstalk during NAFLD development. Ldlr-/-.Leiden mice on a HFD develop obesity, dyslipidemia and insulin resistance, essentially as observed in obese NASH patients, in this translational context WAT and gut dysfunction precede the development of NASH and liver fibrosis.
2023-03-20 | GSE209762 | GEO
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
2025-06-01 | GSE267229 | GEO
Project description:Study gene expression changes in M1 and M2 macrophages and APs in visceral adipose tissue in diet-induced obese mice following cold exposure or administration of FGF21-mimetic antibody
2018-12-31 | GSE112396 | GEO
Project description:Semaglutide has beneficial effects on non-alcoholic steatohepatitis in Ldlr-/-.Leiden mice
| PRJNA940436 | ENA