Ehmt2’s transcriptional coactivation restricts glucocorticoid-induced insulin resistance in a study with male mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE179180 | GEO | 2023/04/07
REPOSITORIES: GEO
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Project description:Ehmt2’s transcriptional coactivation restricts glucocorticoid-induced insulin resistance in a study with male mice
| PRJNA742661 | ENA
Project description:Glucocorticoids play a key role in metabolic adaptation during stress, such as fasting and starvation. Excess and/or chronic glucocorticoid exposure, however, cause metabolic disorders that include insulin resistance dyslipidemia and hepatic steatosis. We previously showed that chronic glucocorticoid treatment elevates hepatic production of ceramides and sphingosine-1-phosphate (S1P). Ceramides are converted to sphingosine that is further converted to S1P. We showed that ceramide-initiated signaling in turn inhibits insulin signaling and increases lipogenic program in hepatocytes. However, the role of S1P, a signaling molecule that modulates physiological responses through membrane S1P receptors (S1PRs), in glucocorticoid actions is unclear. Here we found that inhibiting S1PR2 activity, but not S1PR1 and S1PR3, resulted in improved glucocorticoid-induced insulin resistance. Similarly, reducing hepatic S1PR2 expression showed similar results. Interestingly, reducing S1PR2 expression did not affect the ability of glucocorticoids to modify insulin signaling. Instead, glucocorticoids enhanced gluconeogenesis was reduced. Moreover, glucocorticoid-induced dyslipidemia and fatty liver was also compromised in mice with reduced hepatic S1PR2 expression. Indeed, RNA sequencing analysis showed that lipogenic, gluconeogenic and glycolytic genes are significantly lower in glucocorticoid-treated hepatic S1PR2 knockdown mice than those of glucocorticoid-treated hepatic scramble small hairpin RNA (shRNA) expressing mice (Control). Overall, our studies highlight the importance role of S1PR2 signaling in the mediating glucocorticoid regulation on gluconeogenesis and hepatic lipid homeostasis.
2023-05-13 | GSE150626 | GEO
Project description:In metabolic control, GC signaling acts as a major counter-regulatory system against insulin action, and aberrantly elevated GC activity is tightly linked to major components of the so-called Metabolic Syndrome, including obesity, insulin resistance, hyperglycemia, and systemic dyslipidemia. Here we identify the hepatic induction of the conserved microRNA (miR)-379/410 genomic cluster as a key component of GC/GR-driven metabolic dysfunction in M-bM-^@M-^\diabesityM-bM-^@M-^] Microarray data were utilized to screened for differentially regulated miRNAs between wt and db/db and between wt and GR Knockdown mice For wt vs. db/db: mice were fasted for 24 hours and refed for 6 hours; For GR-dependent miRNAs: mice were treated with rAAV delivering either control or GR-directed miRNA for the knockdown of the GR specifically in the liver.
2014-10-15 | E-GEOD-55245 | biostudies-arrayexpress
Project description:In metabolic control, GC signaling acts as a major counter-regulatory system against insulin action, and aberrantly elevated GC activity is tightly linked to major components of the so-called Metabolic Syndrome, including obesity, insulin resistance, hyperglycemia, and systemic dyslipidemia. Here we identify the hepatic induction of the conserved microRNA (miR)-379/410 genomic cluster as a key component of GC/GR-driven metabolic dysfunction in “diabesity” Microarray data were utilized to screened for differentially regulated miRNAs between wt and db/db and between wt and GR Knockdown mice
2014-10-15 | GSE55245 | GEO
Project description:GRBATKO_BAT_COLDEXPOSURE Aberrant activity of the glucocorticoid (GC)/glucocorticoid receptor (GR) endocrine system has been linked to obesity-related metabolic dysfunction. Traditionally, the GC/GR axis has been believed to play a crucial role in adipose tissue formation and function in both, white (WAT) and brown adipose tissue (BAT). While recent studies have challenged this notion for WAT, the contribution of GC/GR signaling to BAT-dependent energy homeostasis remained unknown. Here, we have generated and characterized a BAT-specific GR knockout mouse (GRBATKO), for the first time allowing to genetically interrogate the metabolic impact of BAT GR. The HPA axis in GRBATKO mice was intact, as was the ability of mice to adapt to cold. BAT GR was dispensable for the adaptation to fasting-feeding cycles and the development of diet-induced obesity. In obesity, glucose and lipid metabolism, insulin sensitivity, and food intake remained unchanged, aligning with the absence of changes in thermogenic gene expression. Together, we demonstrate that the GR in UCP1-positive BAT adipocytes plays a negligible role in systemic metabolism and BAT function, thereby opposing a long-standing paradigm in the field.
2019-08-26 | GSE135544 | GEO
Project description:The Euchromatic Histone Methyl Transferase Protein 2 (EHMT2), also known as G9a, deposits transcriptionally repressive chromatin marks that play pivotal roles in the maturation and homeostasis of multiple organs.Recently, we have shown that Ehmt2 inactivation in the mouse pancreas alters growth and immune gene expression networks, antagonizing Kras-mediated pancreatic cancer initiation and promotion. Here, we elucidate the essential role of Ehmt2 in maintaining a transcriptional landscape that protects organs from inflammation. Comparative RNA-seq studies between normal postnatal and young adult pancreatic tissue from Ehmt2 conditional knockout animals (Ehmt2 fl/fl ) targeted to the exocrine pancreatic epithelial cells (Pdx1-Cre and P48 Cre/+ ), reveal alterations in gene expression networks in the whole organ related to injury-inflammationrepair, suggesting an increased predisposition to damage. Thus, we induced an inflammation repair response in the Ehmt2 fl/fl pancreas and used a data science-based approach to integrate RNA-seq-derived pathways and networks, deconvolution digital cytology, and spatial transcriptomics. We also analyzed the tissue response to damage at the morphological, biochemical, and molecular pathology levels. The Ehmt2 fl/fl pancreas displays an enhanced injury-inflammation-repair response, offering insights into fundamental molecular and cellular mechanisms involved in this process. More importantly, these data show that conditional Ehmt2 inactivation in exocrine cells reprograms the local environment to recruit mesenchymal and immunological cells needed to mount an increased inflammatory response. Mechanistically, this response is an enhanced injury-inflammationrepair reaction with a small contribution of specific Ehmt2-regulated transcripts. Thus, this new knowledge extends the mechanisms underlying the role of the Ehmt2- mediated pathway in suppressing pancreatic cancer initiation and modulating inflammatory pancreatic diseases.
2024-06-06 | GSE269251 | GEO
Project description:The Euchromatic Histone Methyl Transferase Protein 2 (EHMT2), also known as G9a, deposits transcriptionally repressive chromatin marks that play pivotal roles in the maturation and homeostasis of multiple organs.Recently, we have shown that Ehmt2 inactivation in the mouse pancreas alters growth and immune gene expression networks, antagonizing Kras-mediated pancreatic cancer initiation and promotion. Here, we elucidate the essential role of Ehmt2 in maintaining a transcriptional landscape that protects organs from inflammation. Comparative RNA-seq studies between normal postnatal and young adult pancreatic tissue from Ehmt2 conditional knockout animals (Ehmt2 fl/fl ) targeted to the exocrine pancreatic epithelial cells (Pdx1-Cre and P48 Cre/+ ), reveal alterations in gene expression networks in the whole organ related to injury-inflammationrepair, suggesting an increased predisposition to damage. Thus, we induced an inflammation repair response in the Ehmt2 fl/fl pancreas and used a data science-based approach to integrate RNA-seq-derived pathways and networks, deconvolution digital cytology, and spatial transcriptomics. We also analyzed the tissue response to damage at the morphological, biochemical, and molecular pathology levels. The Ehmt2 fl/fl pancreas displays an enhanced injury-inflammation-repair response, offering insights into fundamental molecular and cellular mechanisms involved in this process. More importantly, these data show that conditional Ehmt2 inactivation in exocrine cells reprograms the local environment to recruit mesenchymal and immunological cells needed to mount an increased inflammatory response. Mechanistically, this response is an enhanced injury-inflammationrepair reaction with a small contribution of specific Ehmt2-regulated transcripts. Thus, this new knowledge extends the mechanisms underlying the role of the Ehmt2-mediated pathway in suppressing pancreatic cancer initiation and modulating inflammatory pancreatic diseases.
2024-06-06 | GSE269256 | GEO
Project description:Glucocorticoids play central roles in the regulation of energy metabolism by shifting it toward catabolism, while AMPK is the master regulator of energy homeostasis, sensing energy depletion and stimulating pathways of increasing fuel uptake and saving on peripheral supplies. We showed here that AMPK regulates glucocorticoid actions on carbohydrate metabolism by targeting the glucocorticoid receptor (GR) and modifying transcription of glucocorticoid-responsive genes in a tissue- and promoter-specific fashion. Activation of AMPK in rats reversed glucocorticoid-induced hepatic steatosis and suppressed glucocorticoid-mediated stimulation of glucose metabolism. Transcriptomic analysis in the liver suggested marked overlaps between the AMPK and glucocorticoid signaling pathways directed mostly from AMPK to glucocorticoid actions. AMPK accomplishes this by phosphorylating serine 211 of the human GR indirectly through phosphorylation and consequent activation of p38 MAPK and by altering attraction of transcriptional coregulators to DNA-bound GR. In human peripheral mononuclear cells, AMPK mRNA expression positively correlated with that of glucocorticoid-responsive GILZ, which correlated also positively with the body mass index of subjects. These results indicate that the AMPK-mediated energy control system modulates glucocorticoid action at target tissues. Since increased action of glucocorticoids is associated with development of metabolic disorders, activation of AMPK could be a promising target for developing pharmacologic interventions to these pathologies. We tested the hypothesis by treateing rats with the synthetic glucocorticoid dexamethasone and the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-d-ribonucleoside (AICAR).
2010-07-30 | E-GEOD-22647 | biostudies-arrayexpress
Project description:We report the genome-wide occupancy of EHMT2/G9a in the RD18 embryonal rhabdomyosarcoma cell line.
2020-12-16 | GSE125960 | GEO
Project description:The Glucocorticoid Receptor (GR) is a potent metabolic regulator and a major drug target. While GR was shown to play various important roles in circadian biology, its rhythmic genomic actions have never been studied. Here we mapped GR’s genome-wide chromatin occupancy in mouse livers throughout the day/night cycle. We show how GR partitions metabolic processes during fasting (cellular maintenance, gluconeogenesis) and feeding (lipid and amino acid metabolism) by time-dependent binding and target gene regulation. Highlighting the dominant role GR plays in synchronizing circadian pathways, we find that the majority of oscillating genes harbor GR binding sites and depend on GR for amplitude stability . Surprisingly, this rhythmic pattern is altered by exposure to high fat diet in a ligand-independent manner. We show how the remodeling of oscillatory gene expression and GR binding result from a concomitant increase with Stat5 co-occupancy in obese mice, and that loss of GR reduces circulating glucose and triglycerides differentially during feeding and fasting. Altogether, our findings highlight GR’s fundamental role in the rhythmic orchestration of hepatic metabolism.
2019-10-24 | PXD014030 | Pride