Cannabinoid receptor 1 deficiency alters expression of stress-related genes in microglia
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE152266 | GEO | 2021/12/31
REPOSITORIES: GEO
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Project description:Although the cannabinoid CB1 receptor has been implicated in atherosclerosis, its cellspecific effects in this disease are not well understood. Here, we report that male mice with myeloid-specific Cnr1 deficiency on atherogenic background developed smaller lesions and necrotic cores than controls, while only minor genotype differences were observed in females. Male Cnr1 deficient mice showed reduced arterial monocyte recruitment and macrophage proliferation with less inflammatory phenotype. The sexspecific differences in proliferation were dependent on estrogen receptor (ER)α estradiol signaling. Kinase activity profiling revealed a CB1-dependent regulation of p53 and cyclin-dependent kinases. Transcriptomic profiling further unveiled chromatin modifications, mRNA processing and mitochondrial respiration among the key processes affected by CB1 signaling, which was supported by metabolic flux assays. Chronic administration of the peripherally-restricted CB1 antagonist JD5037 inhibited plaque progression and macrophage proliferation, but only in male mice. Finally, CNR1 expression was detectable in human carotid endarterectomy plaques and inversely correlated with proliferation, oxidative metabolism and inflammatory markers, hinting to a possible implication of CB1-dependent regulation in human pathophysiology. In conclusion, impaired macrophage CB1 signaling is atheroprotective by limiting their arterial recruitment, proliferation and inflammatory reprogramming. The importance of macrophage CB1 signaling seems to be more pronounced in male mice.
2023-12-07 | GSE249503 | GEO
Project description:Peripherally restricted cannabinoid CB1 receptor antagonists without central side effects hold promise for treating metabolic disorders including diabetes and obesity. In atherosclerosis, the specific effects of peripheral CB1 signaling in vascular endothelial cells (ECs) remain incompletely understood.We performed en face in situ hybridization of Cnr1 in murine aortas, revealing a significantly increased expression of the CB1 encoding gene in ECs within atheroprone compared to atheroresistant regions. In vitro, CNR1 was upregulated by oscillatory shear stress in human aortic endothelial cells (HAoECs). Endothelial CB1 deficiency (Cnr1EC-KO) in female mice on atherogenic background resulted in pronounced endothelial phenotypic changes, with reduced vascular inflammation and permeability. This translated into attenuated plaque development with reduced lipid content as well as reduced white and brown adipose tissue mass and liver steatosis. Ex vivo imaging of carotid arteries via two-photon microscopy revealed less DIL-LDL uptake in Cnr1EC-KO. This was accompanied by a significant reduction of aortic endothelial caveolin-1 (CAV1) expression, a key structural protein involved in lipid transcytosis in female Cnr1EC-KO mice. In vitro, pharmacological blocking with CB1 antagonist AM281 reproduced the inhibition of CAV1 expression and LDL uptake in response to atheroprone shear stress in human aortic endothelial cells (HAoECs), which was dependent on cAMP-mediated PKA activation. Conversely, the CB1 agonist ACEA increased DIL-LDL uptake and CAV1 expression in HAoECs. Finally, treatment of atherosclerotic mice with the peripheral CB1 antagonist JD-5037 reduced plaque progression, CAV1 and endothelial adhesion molecule expression in female mice. These results confirm an essential role of endothelial CB1 to the pathogenesis of atherosclerosis.
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Project description:FKBP51, also known as FK506-binding protein 51, is a molecular chaperone and scaffolding protein with significant roles in regulating hormone signaling and stress responding. Genetic variants in FKBP5, which encodes FKBP51, have been implicated in a growing number of neuropsychiatric disorders, which has spurred efforts to target FKBP51 therapeutically. However, the molecular mechanisms by which FKBP51 influences the pathways affected in these disorders are not fully understood. Protein changes in Fkbp5 KO mice, as measured by histology and proteomics, revealed alterations in a brain region- and sex-dependent manner.
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Project description:Adolescent cannabis use increases the risk for cognitive impairments and psychiatric disorders. Cannabinoid receptor type 1 (Cnr1) is expressed not only in neurons and astrocytes, but also in microglia, which shape synaptic connections during adolescence. Nonetheless, until now, the role of microglia in mediating the adverse cognitive effects of delta-9-tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis, has been unexplored. Here, we report that adolescent THC exposure produces microglial apoptosis in the medial prefrontal cortex (mPFC), which was exacerbated in the mouse model of 16p11.2 duplication, a representative copy number variation (CNV) risk factor for psychiatric disorders. These effects are mediated by microglial Cnr1, leading to reduction in the excitability of mPFC pyramidal-tract neurons and deficits in social memory in adulthood. Our findings highlight the importance of microglial Cnr1 to produce the adverse effect of cannabis exposure in genetically vulnerable individuals.
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Project description:Glucocorticoid excess is linked to central obesity, adipose tissue insulin resistance and type 2 diabetes mellitus. The aim of our study was to investigate the effects of dexamethasone on gene expression in human subcutaneous and omental adipose tissue, in order to identify potential novel mechanisms and biomarkers for glucocorticoid-induced insulin resistance in adipose tissue. Dexamethasone changed the expression of 527 genes in both subcutaneous and omental adipose tissue. FKBP5 and CNR1 were the most responsive genes in both depots (~7-fold increase). Dexamethasone increased FKBP5 gene and protein expression in a dose-dependent manner in both depots, but FKBP5 protein levels were 10-fold higher in omental than subcutaneous adipose tissue. FKBP5 gene expression in subcutaneous adipose tissue was positively correlated with serum insulin, HOMA-IR and subcutaneous adipocyte diameter, while fold change in gene expression by dexamethasone was negatively correlated with clinical markers of insulin resistance, i.e. HbA1c, BMI, HOMA-IR and serum insulin. Only one gene, SERTM1, clearly differed in response to dexamethasone between the two depots. Dexamethasone at high concentrations, influences gene expression in both subcutaneous and omental adipose tissue in a similar pattern and promotes gene expression of FKBP5, a gene that may be implicated in glucocorticoid-induced insulin resistance. Paired human subcutaneous (sc) and omental (om) adipose tissue samples obtained from 4 non-diabetic adipose tissue donors (4 M; BMI: 20.8-27.5 Kg/m2) were incubated without (Ctr) or with dexamethasone (Dex, 3 M-NM-<M) for 24 h.
2014-08-18 | E-GEOD-42902 | biostudies-arrayexpress
Project description:Psychological stress is a risk factor for several diseases. In particular, stressor exposure has been linked with various psychiatric disorders. Since the hypothalamic-pituitary-adrenal (HPA) axis plays a central role in the regulation of stress responses, it has been implicated in the etiology of stress related disorders such as PTSD. The HPA axis regulate synthesis and release of glucocorticoids and its dysregulation cause abnormal response to stress. FK506-binding protein 51 (FKBP5) is a co chaperone of HSP90 in the glucocorticoid receptor (GR) molecular complex and a key regulator of the sensitivity of GR. In this study, we profiled the miRNAs in the prefrontal cortex of FKBP5 knock out mice compared to the wild type. Subsequently, we profiled target mRNAs for differentially expressed miRNAs in the FKBP5 deficient mice using several tools for sequence-based miRNA target prediction such as miRDB, DIANA tool, miRmap and TargetScan. Gene ontology analysis suggested that differentially expressed miRNAs in the brain of FKBP5 deficient mice may be involved in neuron development, cell motion, endocytosis, and cell-cell adhesion. These results suggest that Nfasc could be a new target for understanding of the pathophysiology of PTSD.
2020-10-31 | GSE139502 | GEO
Project description:Fkbp5 encodes the FK506 binding protein 5, a glucocorticoid receptor (GR) binding protein which is an important factor in stress responses that form coping behavior. However, the results of previous studies have been controversial about the relationships between variants in Fkbp5 and stress have been controversial. To clarify the effects of the loss of Fkbp5 on the stress response, we conducted behavior test with mice following chronic restraint stress with homozygous wild type (WT) and knock-out (KO) genotypes. WT mice showed anhedonia, one of depressive-like behaviors, but KO mice did not show this symptom in sucrose preference test (SPT). To examine the molecular mechanism of this stress resilience, we performed RNAseq analysis. The results of differentially expressed gene (DEG) analysis showed that diverse biological processes related with cell-cell communication are changed by chronic stress. Weighted gene co-expression network analysis detected 60 gene modules which show varied correlation patterns with stress or Fkbp5 genotype. The expression pattern of M55 module correlated with SPT results and the gene ontology (GO) enrichment analysis in this module revealed that the genes in this module are involved in nervous system development, gland morphogenesis and inflammatory response. We identify the role of Fkbp5 KO in stress response and the transcriptome study provide insight into stress-related biological processes.
2019-11-06 | GSE138240 | GEO
Project description:We evaluated cutaneous contact hypersensitivity (CHS) in Cnr1-/-/Cnr2-/- animals using the obligate contact allergen 2,4-dinitrofluorobenzene (DNFB), which generates a specific cutaneous T-cell mediated allergic response upon repeated allergen contact. Allergic contact dermatitis affects about 5% of men and 11% of women in industrialized countries and is one of the leading causes for occupational diseases. In an animal model for cutaneous contact hypersensitivity we show that mice lacking both known cannabinoid receptors display exacerbated allergic inflammation. In contrast, fatty acid amide hydrolase deficient mice, which have increased levels of the endocannabinoid anandamide, displayed reduced allergic responses in the skin. Cannabinoid receptor antagonists exacerbated whereas receptor agonists attenuated allergic inflammation. These results demonstrate a protective role of the endocannabinoid system in contact allergy in the skin, and suggest a novel target for therapeutic intervention. Experiment Overall Design: Three wildtype mice (Wt) and three Cnr1-/-/Cnr2-/- (Ko) mice were used. Contact hypersensitivity was determined always at the right ears, which therefore were treated with DNFB (Tr). Left ears of mice were kept untreated and served as control ears (C). A total of 12 hybridizations were performed (2 strains x 2 treatments X 3 biological replicates) in this experiment.
2009-04-23 | E-GEOD-7694 | biostudies-arrayexpress
Project description:Glucocorticoid excess is linked to central obesity, adipose tissue insulin resistance and type 2 diabetes mellitus. The aim of our study was to investigate the effects of dexamethasone on gene expression in human subcutaneous and omental adipose tissue, in order to identify potential novel mechanisms and biomarkers for glucocorticoid-induced insulin resistance in adipose tissue. Dexamethasone changed the expression of 527 genes in both subcutaneous and omental adipose tissue. FKBP5 and CNR1 were the most responsive genes in both depots (~7-fold increase). Dexamethasone increased FKBP5 gene and protein expression in a dose-dependent manner in both depots, but FKBP5 protein levels were 10-fold higher in omental than subcutaneous adipose tissue. FKBP5 gene expression in subcutaneous adipose tissue was positively correlated with serum insulin, HOMA-IR and subcutaneous adipocyte diameter, while fold change in gene expression by dexamethasone was negatively correlated with clinical markers of insulin resistance, i.e. HbA1c, BMI, HOMA-IR and serum insulin. Only one gene, SERTM1, clearly differed in response to dexamethasone between the two depots. Dexamethasone at high concentrations, influences gene expression in both subcutaneous and omental adipose tissue in a similar pattern and promotes gene expression of FKBP5, a gene that may be implicated in glucocorticoid-induced insulin resistance.
2014-08-18 | GSE42902 | GEO
Project description:Role of myeloid cannabinoid CB1 receptor in atherosclerosis
| PRJNA1049407 | ENA