Ontology highlight
ABSTRACT:
PROVIDER: PRJNA369731 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Immune checkpoint inhibitor (ICI) therapies are associated with an increased risk of metabolic syndrome; the underlying mechanisms remain elusive. We show here that anti-PD-1 antibody targets macrophage PD-1 to reduce energy expenditure without affecting food intake, leading to an augmented susceptibility of mice to high-fat diet (HFD)-induced obesity, and systemic metabolic disorders. Mechanistically, LPS activates Unc-51-like autophagy activating kinase 1 (ULK1) via Mechanistic target of rapamycin (mTOR)-dependent manner. Activated ULK1 phosphorylates PD-1 at Thr250 to inhibit FBXO38-mediated PD-1 ubiquitination and degradation by disrupting FBXO38-PD-1 binding. Phosphorylated PD-1 interacts with inositol-requiring enzyme 1α (IRE1α) and attenuates IRE1α autophosphorylation to suppress ER stress-mediated inflammatory responses. Inhibition or IRE1α knockout alleviates HFD-induced metabolic disorders in macrophage-specific PD-1 knockout mice by rescuing the reduced energy expenditure. Our findings highlight the critical role of macrophage PD-1 in the intersection of immune checkpoint blockade, energy expenditure, and metabolic dysfunction. The underscored moonlighting function of macrophage PD-1 in protecting against ER stress-driven systemic inflammation may provide new rational for combating both ICI therapy- and HFD-induced metabolic diseases.
2025-10-26 | GSE304734 | GEO
Project description:Insulin is a potent pleiotropic hormone that affects processes such as cellular growth, differentiation, apoptosis, ion flux, energy expenditure, and carbohydrate, lipid, and protein metabolism. We used microarrays to detail the global programme of gene expression underlying the influence of insulin in human skeletal muscle collected from different human individuals including 20 insulin sensitive, 20 insulin resistant and 15 diabetic patients. We identified distinct classes of up-regulated and down-regulated genes during these processes. The pathophysiology of obesity represents an imbalance between a high energy intake and/or low energy expenditure. Resting energy expenditure (REE) comprises 60-75% of total energy expenditure. The respiratory quotient (RQ) is used to estimate fuel partitioning between fat and carbohydrate as preferred substrates for energy generation, and fuel preferences to generate REE also exhibit individual variation. Genes influencing REE and RQ could represent candidate genes for obesity, Metabolic Syndrome, and Type 2 Diabetes due to the involvement of these traits in energy balance and substrate oxidation. We used microarrays to explore the molecular bases for individual variation in REE and fuel partitioning as reflected by RQ. We performed microarray studies in human vastus lateralis muscle biopsies from 40 healthy subjects with measured REE and RQ values. We identified genes significantly correlated with REE and RQ, respectively. Human skeletal muscle samples were biopsied from different individuals before and after insulin treatment for RNA extraction and hybridization on Affymetrix microarrays.
2010-07-08 | E-GEOD-22309 | biostudies-arrayexpress
Project description:Cancer cells exploit adaptive responses such as endoplasmic reticulum (ER) stress to support their survival. ER stress response is mediated in part by the ER-localized transmembrane sensor IRE1α endoribonuclease and its substrate XBP1 to regulate XBP1 target gene expression. However, the mechanism that controls the IRE1α/XBP1 pathway remains poorly understood. CARM1 is an oncogene that is often overexpressed in a number of cancer types including ovarian cancer. Here we report that CARM1 determines ER stress response by controlling the IRE1α/XBP1 pathway. Genome-wide profiling revealed that CARM1 regulates XBP1 target gene expression during ER stress response. CARM1 directly interacts with XBP1. Inhibition of the IRE1α/XBP1 pathway was effective in ovarian cancer in a CARM1-dependent manner both in vitro and in vivo in orthotopic and patient-derived xenograft models. In addition, IRE1α inhibitor B-I09 synergizes with immune checkpoint blockade anti-PD1 antibody in an immunocompetent CARM1-expressing ovarian cancer model.
2021-08-11 | GSE157117 | GEO
Project description:Cancer cells exploit adaptive responses such as endoplasmic reticulum (ER) stress to support their survival. ER stress response is mediated in part by the ER-localized transmembrane sensor IRE1α endoribonuclease and its substrate XBP1 to regulate XBP1 target gene expression. However, the mechanism that controls the IRE1α/XBP1 pathway remains poorly understood. CARM1 is an oncogene that is often overexpressed in a number of cancer types including ovarian cancer. Here we report that CARM1 determines ER stress response by controlling the IRE1α/XBP1 pathway. Genome-wide profiling revealed that CARM1 regulates XBP1 target gene expression during ER stress response. CARM1 directly interacts with XBP1. Inhibition of the IRE1α/XBP1 pathway was effective in ovarian cancer in a CARM1-dependent manner both in vitro and in vivo in orthotopic and patient-derived xenograft models. In addition, IRE1α inhibitor B-I09 synergizes with immune checkpoint blockade anti-PD1 antibody in an immunocompetent CARM1-expressing ovarian cancer model.
2021-08-11 | GSE157116 | GEO
Project description:Obesity results from a caloric imbalance between energy intake, absorption and expenditure. In both rodents and humans, diet-induced thermogenesis contributes to energy expenditure and involves the activation of brown adipose tissue (BAT). We hypothesized that environmental toxicants commonly used as food additives or pesticides might reduce BAT thermogenesis through suppression of uncoupling protein 1 (UCP1) and this may contribute to the development of obesity. Using a step-wise screening approach, we discovered that the organophosphate insecticide chlorpyrifos suppresses UCP1 and mitochondrial respiration in BAT at concentrations as low as 1 pM. In mice housed at thermoneutrality and fed a high-fat diet, chlorpyrifos impaired BAT mitochondrial function and diet-induced thermogenesis, promoting greater obesity, non-alcoholic fatty liver disease (NAFLD) and insulin resistance. This was associated with reductions in cAMP; activation of p38MAPK and AMPK; protein kinases critical for maintaining UCP1 and mitophagy, respectively in BAT. These data indicate that the commonly used pesticide chlorpyrifos, suppresses diet-induced thermogenesis and the activation of BAT, suggesting its use may contribute to the obesity epidemic.
2021-07-19 | GSE178366 | GEO
Project description:It remains unknown whether ER stress response signaling has a metabolic regulatory role in ECs. Here, in mice with high-fat diet-induced obesity, we found that EC-specific ablation of IRE1α selectively impaired the compensatory adaptation of pancreatic islet function in response to metabolic stress. Loss of IRE1α in ECs resulted in significantly lower intra-islet angiogenesis, accompanied by defects in the compensatory growth of pancreatic islets and their capacity of glucose-stimulated insulin secretion, consequently leading to hyperglycemia. Mechanistically, IRE1α could downregulate the intra-islet EC expression of the mRNA encoding thrombospondin-1 (THBS1/TSP1), an endogenous anti-angiogenic factor implicated in islet function regulation and prediabetes, through its RIDD activity. Importantly, EC-specific depletion of THBS1 completely corrected these islet dysfunctions arising from IRE1α deficiency in ECs. Together, our findings demonstrate a critical role of the endothelial IRE1α suppression of THBS1 in governing the vascular support that enables the homeostatic adaptation of pancreatic islets to cope with overnutrition-associated metabolic stress.
2025-11-29 | GSE263586 | GEO
Project description:Obesity is an energy balance disorder in which nutrient intake chronically exceeds energy expenditure, resulting in the accumulation of white adipose tissue. Increased adiposity is due to increases in the number and size of adipocytes, which leads to increased body fat and metabolic consequences. Adipocytes induce insulin resistance by promoting lipotoxicity and modulating adipokine secretion. Therefore, a thorough understanding of the mechanisms that regulate adipogenesis could have clinical relevance in preventing and treating obesity and the metabolic syndrome. In this study, we performed miRNA array to measure miRNA profiles of undifferentiated and differentiated 3T3-L1 adipocytes using Agilent(r) miRNA array. We show that miRNA profile changes during adipogenesis. Thus, this data would be useful to find the distinct role of miRNAs for the regulation of adipogenesis.
2013-08-07 | E-MTAB-1783 | biostudies-arrayexpress
Project description:Inflammation plays a key role in the pathogenesis of obesity. Chronic overfeeding leads to macrophage infiltration in the adipose tissue, resulting in pro-inflammatory cytokine production. Both microbial and endogenous danger signals trigger assembly of the intracellular innate immune sensor Nlrp3 [NLR family, pyrin domain containing 3] resulting in caspase-1 activation and production of pro-inflammatory cytokines interleukin (IL)-1beta and IL-18. Here, we showed that mice deficient in Nlrp3, ASC [apoptosis-associated speck-like protein containing a CARD; a.k.a PYCARD (PYD and CARD domain containing)] and caspase-1 were resistant to the development of high fat diet-induced obesity, which correlated with protection from obesity-induced insulin resistance. Detailed metabolic and molecular phenotyping demonstrated that the inflammasome controls energy expenditure and adipogenic gene expression during chronic overfeeding. These findings reveal a critical function of the inflammasome in obesity and insulin resistance and suggest inhibition of the inflammasome as a potential therapeutic strategy. Keywords: Expression profiling by array Wild-type (WT), ASC-null and Casp1-null mice were subjected to high fat diet feeding for 16 weeks. After the diet intervention period, the animals were killed and epididymal white adipose tissue was removed. Total RNA was isolated and subjected to gene expression profiling.
2011-08-20 | E-GEOD-25205 | biostudies-arrayexpress
Project description:KDM4B (lysine demethylase 4B) in adipose tissues plays a critical role in energy balance, oxidation, lipolysis and thermogenesis. Loss of KDM4B in mice resulted in obesity associated with reduced energy expenditure and impaired adaptive thermogenesis. Mechanistically, we determined that KDM4B directly controls the expression of multiple metabolic genes.
2019-05-22 | GSE102289 | GEO
Project description:Transfer RNA-derived fragments have specific biological roles. However, it is still not characterized what factors are responsible for generation of 5′-tRHs in certain conditions, such as metabolic disease and maturation of reproductive cells. Here, we report that Inositol-requiring enzyme 1α (IRE1α), a major ER stress sensor protein, cleaves specifically anticodon stem-loop region of tRNAGly(GCC) and produces 5′-tRHs. Using an RNA-seq-based approach, we identified cleavage sites in tRNAGly(GCC), generating 5′-tRHs in KGN cells (human ovarian granulosa cells) in an IRE1α-expression dependent manner. In vitro cleavage analyses further supported that IRE1α generates 5′-tRHs from tRNAGly(GCC) (5′-tRH-GlyGCC) with highly selective target discrimination. The production of 5′-tRH-GlyGCC was promoted upon endoplasmic reticulum (ER) stress, which induced IRE1α expression, in KGN cells as well as other cancer cell lines such as HeLa and HepG. In addition, transfection of synthetic 5′-tRH-GlyGCC mimics promoted survival of KGN and HeLa cells; this effect required expression of HNRNPM and HNRNPH2, which were identified as binding proteins of 5′-tRH-GlyGCC.
2024-10-30 | PXD013798 | Pride