Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA358510 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Early drivers of Type 2 diabetes mellitus (T2D) include ectopic fat accumulation, especially in the liver, that significantly impairs insulin sensitivity. In a T2D setting, GLP-1R/GCGR dual agonists have been shown to reduce glycaemia, body weight and hepatic steatosis. We utilized cotadutide, a well characterized GLP-1R/GCGR dual-agonist, to demonstrate improved insulin sensitivity during hyperinsulinemic euglycemic clamp following sub-chronic dosing in male, diet-induced obese mice. Phosphoproteomic analyses of insulin stimulated liver from cotadutide treated diet-induced obese (DIO) mice identified novel phosphorylation sites on key insulin signalling pathway proteins associated with improved insulin sensitivity. Cotadutide or GCGR monoagonist treatment also resulted in specific increased brown adipose tissue (BAT) insulin-stimulated glucose uptake, while GLP-1R monoagonist only showed a weak effect. BAT from cotadutide treated mice had induction of UCP-1 protein, increased mitochondrial area and a transcriptomic profile of increased fat oxidation and mitochondrial activity. Finally, the cotadutide-induced improvement in insulin sensitivity was associated with reduced insulin secretion from isolated pancreatic islet β-cells indicating reduced insulin secretory demand. Thus, GLP-1R/GCGR dual agonism provides multimodal efficacy to decrease hepatic steatosis and consequently improve insulin sensitivity, in concert with recovery of endogenous β-cell function and reduced insulin demand. This substantiates GLP-1R/GCGR dual-agonism as a novel and effective T2D treatment
2025-03-28 | PXD057744 | Pride
Project description:Metabolic dysfunction-associated fatty liver disease (MASLD), the hepatic manifestation of obesity and type 2 diabetes (T2D), can progress to metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis. MASLD is characterized by elevated hepatic lipid accumulation (steatosis) and insulin resistance. Ketogenic diet (KD), a high-fat, low-carbohydrate diet, induces hepatic insulin resistance and steatosis in animal models through unknown mechanisms. Our studies demonstrate the importance of adipose tissue-liver crosstalk in mediating MASLD progression and identify adipocyte IL-6-gp130 as a potential therapeutic target.
2025-08-07 | GSE294746 | GEO
Project description:Alcohol’s impairment of both hepatic lipid metabolism and insulin resistance (IR) are key drivers of alcoholic steatosis, the initial stage of alcoholic liver disease (ALD). Pharmacologic reduction of lipotoxic ceramide prevents alcoholic steatosis and glucose intolerance in mice, but potential off-target effects limit its strategic utility. Here, we employed a hepatic-specific acid-ceramidase (ASAH) overexpression model to reduce hepatic ceramides in a Lieber-DeCarli model of experimental alcoholic steatosis. We examined effects of alcohol on hepatic lipid metabolism, body composition, energy homeostasis and insulin sensitivity as measured by hyperinsulinemic-euglycemic clamp. Our results demonstrate that hepatic ceramide reduction ameliorates the effects of alcohol on hepatic lipid droplet accumulation by promoting VLDL secretion and lipophagy, the latter of which involves ceramide cross-talk between the lysosomal and lipid droplet compartments. We additionally demonstrate that hepatic ceramide reduction prevents alcohol’s inhibition of hepatic insulin signaling. These effects on the liver are associated with a reduction in oxidative stress markers and are relevant to humans, as we observe peri-lipid droplet ASAH expression in human ALD. Together, our results suggest a potential role for hepatic ceramide inhibition in preventing ALD.
2020-07-08 | GSE139015 | GEO
Project description:Growth differentiation factor 15 (GDF15) is strongly associated with metabolic dysfunction-associated steatohepatitis (MASH), yet whether it drives disease or protects against liver injury remains unresolved. Using thermoneutral mouse models that closely mimic human MASH, we show that loss of GDF15 or its receptor GFRAL selectively worsens hepatic inflammation and fibrosis independently of steatosis or insulin resistance. Conversely, recombinant GDF15 suppressed liver inflammation and fibrosis more effectively than matched caloric restriction despite equivalent reductions in food intake, body weight, and steatosis. Spatial transcriptomics and bulk RNA-seq revealed that GDF15 remodels the hepatic immune-fibrotic niche by suppressing pro-inflammatory macrophages, plasma B cells, and activated stellate cells while promoting pro-resolving immune programs. These effects required GFRAL but occurred independently of β-adrenergic signaling. In a steatosis-free CCl₄ model, GDF15 retained potent anti-inflammatory effects and activated hypothalamic-pituitary-adrenal (HPA) axis and hepatic glucocorticoid receptor (GR) signaling, which were blunted by GR antagonism. Together, these findings identify GDF15 as an endogenous neuroimmune regulator that restrains liver inflammation and fibrosis independently of weight loss or steatosis through a GFRAL–HPA–GR signaling axis.
2026-08-25 | PXD083028 | Pride
Project description:Early drivers of Type 2 diabetes mellitus (T2D) include ectopic fat accumulation, especially in the liver, that significantly impairs insulin sensitivity. In a T2D setting, GLP-1R/GCGR dual agonists have been shown to reduce glycaemia, body weight and hepatic steatosis. We utilized cotadutide, a well characterized GLP-1R/GCGR dual-agonist, to demonstrate improved insulin sensitivity during hyperinsulinemic euglycemic clamp following sub-chronic dosing in male, diet-induced obese mice. Cotadutide or GCGR monoagonist treatment resulted in specific increased brown adipose tissue (BAT) insulin-stimulated glucose uptake, while GLP-1R monoagonist only showed a weak effect. BAT from cotadutide treated mice had induction of UCP-1 protein, increased mitochondrial area and a transcriptomic profile of increased fat oxidation and mitochondrial activity. Thus, GLP-1R/GCGR dual agonism provides multimodal efficacy to decrease hepatic steatosis and consequently improve insulin sensitivity, in concert with recovery of endogenous β-cell function and reduced insulin demand. This substantiates GLP-1R/GCGR dual-agonism as a novel and effective T2D treatment.
2025-03-06 | GSE284233 | GEO
Project description:We comprehensively searched for the factors that may attribute to hepatic insulin sensitivity in the patients with NAFLD. Forty-three NAFLD patients were assessed for putative biomarkers in blood and urine, body composition, tissue lipid content, tissue insulin sensitivity by hyperinsulinemic-euglycemic clamp, hepatic histology and gene expressions using liver biopsies, and life styles. In results, the higher levels of plasma adiponectin, muscle insulin sensitivity, and adipose tissue insulin sensitivity positively, but the higher levels of HbA1c, ALT, and log converted high-sensitive CRP negatively correlated with hepatic insulin sensitivity. Interestingly, whole liver volume and hepatic lean volume corrected by body surface area (cm3/m2) showed significant negative correlation with hepatic insulin sensitivity, specifically in patients with T2DM.
2019-07-18 | GSE134438 | GEO
Project description:Growth differentiation factor 15 (GDF15) is strongly associated with metabolic dysfunction-associated steatohepatitis (MASH), yet whether it promotes or protects against liver injury remains unclear. Using thermoneutral mouse models that closely resemble human MASH, genetic deletion of GDF15 or its receptor GFRAL selectively worsened hepatic inflammation and fibrosis without altering steatosis or insulin resistance. Conversely, recombinant GDF15 reduced liver inflammation and fibrosis more effectively than matched caloric restriction despite identical reductions in food intake, body weight, and steatosis, demonstrating weight loss-independent hepatoprotection. These effects required GFRAL but were independent of β-adrenergic signaling. Instead, GDF15 activated the hypothalamic-pituitary-adrenal (HPA) axis, increasing circulating corticosterone and hepatic glucocorticoid receptor signaling. Spatial transcriptomics and RNA sequencing demonstrated that GDF15 remodeled the hepatic immune-fibrotic niche by suppressing inflammatory macrophages, plasma B cells, and activated stellate cells while promoting pro-resolving immune programs. Together, these findings identify a GDF15-GFRAL-HPA axis that restrains liver inflammation independently of weight loss.
2026-08-10 | GSE337623 | GEO
Project description:Growth differentiation factor 15 (GDF15) is strongly associated with metabolic dysfunction-associated steatohepatitis (MASH), yet whether it promotes or protects against liver injury remains unclear. Using thermoneutral mouse models that closely resemble human MASH, genetic deletion of GDF15 or its receptor GFRAL selectively worsened hepatic inflammation and fibrosis without altering steatosis or insulin resistance. Conversely, recombinant GDF15 reduced liver inflammation and fibrosis more effectively than matched caloric restriction despite identical reductions in food intake, body weight, and steatosis, demonstrating weight loss-independent hepatoprotection. These effects required GFRAL but were independent of β-adrenergic signaling. Instead, GDF15 activated the hypothalamic-pituitary-adrenal (HPA) axis, increasing circulating corticosterone and hepatic glucocorticoid receptor signaling. Spatial transcriptomics and RNA sequencing demonstrated that GDF15 remodeled the hepatic immune-fibrotic niche by suppressing inflammatory macrophages, plasma B cells, and activated stellate cells while promoting pro-resolving immune programs. Together, these findings identify a GDF15-GFRAL-HPA axis that restrains liver inflammation independently of weight loss.
2026-08-10 | GSE337622 | GEO
Project description:Background Metabolic associated fatty liver disease (MAFLD) was recently proposed to replace non-alcoholic fatty liver disease (NAFLD), which is defined as ectopic fat deposition in the liver. Hepatic steatosis is an independent predictor for insulin resistance and cardiovascular risk and hence mortality. The aim of present study was to investigate the urine molecular pattern and potential urine biomarker to distinguish healthy control, mild and severe hepatic steatosis in MAFLD patients using proteomic data. Method Hepatic steatosis was measured by Magnetic resonance imaging (MRI) that measure the proton density fat fraction (MRI-PDFF). Proteomic measurements of urine samples were done by mass spectrometry. Linear regression analyses were used to detect significant associations between the biomarkers and clinical parameters. Western blot and Elisa were performed for validation. Results Multiple pathways have been compromised in MAFLD, including the carbohydrate derivative catabolic process, glycosaminoglycan process, aminoglycan metabolic process, inflammatory response, insulin-like growth factor receptor and GTPase complex. Alpha-1-acid glycoprotein 1 (ORM1) and ceruloplasmin were finally identified to be potential urine biomarkers to detect mild/severe hepatic steatosis.
2022-08-12 | PXD026333 | Pride
Project description:We report that a high affinity, selective, small molecule Gpr120 agonist (cpdA), exerts potent anti-inflammatory effects on macrophages in vitro, and in obese mice in vivo. Gpr120 agonist treatment of high fat diet (HFD)/obese mice causes improved glucose tolerance, decreased hyperinsulinemia, increased insulin sensitivity and decreased hepatic steatosis. This suggests that Gpr120 agonists could become new insulin sensitizing drugs for the treatment of Type 2 diabetes and other human insulin resistant states in the future. Examination of effects of DHA and compound A on primary macrophages stimulated by LPS, 3 replicates for each condition
2014-06-07 | E-GEOD-58282 | biostudies-arrayexpress