Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA287125 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR2064181_1.fastq.gz | Fastqsanger.gz | |||
| SRR2064181_2.fastq.gz | Fastqsanger.gz | |||
| SRR2064182_1.fastq.gz | Fastqsanger.gz | |||
| SRR2064182_2.fastq.gz | Fastqsanger.gz | |||
| SRR2064183_1.fastq.gz | Fastqsanger.gz |
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Project description:Activated brown adipose tissue contributes to control of energy and glucose homeostasis in rodents and humans. Defining cell-autonomous processes underlying BAT differentiation and activation may thus reveal novel therapeutic targets for obesity and type 2 diabetes mellitus intervention. Here we show that ageing- and obesity-associated demises in BAT function coincide with down-regulation of mature microRNAs in BAT in the presence of reduced expression of the critical microRNA processing enzyme Dicer1. To mimic this partial down-regulation of microRNA processing in obesity and ageing, we inactivated one allele of Dicer1 selectively in BAT of mice. BAT- restricted heterozygosity of Dicer1 caused glucose intolerance in lean mice and aggravated diet-induced-obesity (DIO)-evoked deterioration of glucose homeostasis. Using combinatorial analyses of altered microRNA-expression in BAT during in vitro preadipocyte commitment and mouse models of progeria, longevity and DIO, we identified 23 microRNAs dysregulated among these conditions. Of these, we identified miR-328 as a novel regulator of BAT differentiation. miR-328 over-expression promotes BAT-differentiation and impairs muscle progenitor commitment, while reducing miR-328 expression blocks BAT specification. We validated the ß-Secretase Bace1 as a target of miR-328, which is consequently over-expressed in BAT of obese and premature ageing mice. Reducing Bace1 expression enhances brown adipocyte, while impairing myogenic differentiation in vitro. In vivo small-molecule Bace1 inhibition in obese mice delayed DIO-induced weight gain, ameliorated obesity-associated deterioration of glucose metabolism and improved insulin sensitivity. Collectively, these experiments reveal reduced Dicer1-miR-328-Bace1 axis in presence of generalized impairment of microRNA processing in ageing and obesity as a novel determinant of ageing- and obesity-associated decline in BAT function. This may define in vivo Bace1-inhibition as an innovative therapeutic approach to not only target age-related neurodegenerative diseases but at the same time improving age-related impairment of BAT-function and metabolism. C57BL/6 mice ( 4 weeks of age) were treated with a calory-rich, high-sugar high-fat diet (HFD) for a course of 4 weeks. Then groups were stratified and one group continued to receive HFD (BAT13-15) or HFD supplemented with an experimental small-molecule Bace 1 inhibitor (BAT17, 33, 35).
2015-06-17 | E-GEOD-69913 | biostudies-arrayexpress
Project description:Activated brown adipose tissue contributes to control of energy and glucose homeostasis in rodents and humans. Defining cell-autonomous processes underlying BAT differentiation and activation may thus reveal novel therapeutic targets for obesity and type 2 diabetes mellitus intervention. Here we show that ageing- and obesity-associated demises in BAT function coincide with down-regulation of mature microRNAs in BAT in the presence of reduced expression of the critical microRNA processing enzyme Dicer1. To mimic this partial down-regulation of microRNA processing in obesity and ageing, we inactivated one allele of Dicer1 selectively in BAT of mice. BAT- restricted heterozygosity of Dicer1 caused glucose intolerance in lean mice and aggravated diet-induced-obesity (DIO)-evoked deterioration of glucose homeostasis. Using combinatorial analyses of altered microRNA-expression in BAT during in vitro preadipocyte commitment and mouse models of progeria, longevity and DIO, we identified 23 microRNAs dysregulated among these conditions. Of these, we identified miR-328 as a novel regulator of BAT differentiation. miR-328 over-expression promotes BAT-differentiation and impairs muscle progenitor commitment, while reducing miR-328 expression blocks BAT specification. We validated the ß-Secretase Bace1 as a target of miR-328, which is consequently over-expressed in BAT of obese and premature ageing mice. Reducing Bace1 expression enhances brown adipocyte, while impairing myogenic differentiation in vitro. In vivo small-molecule Bace1 inhibition in obese mice delayed DIO-induced weight gain, ameliorated obesity-associated deterioration of glucose metabolism and improved insulin sensitivity. Collectively, these experiments reveal reduced Dicer1-miR-328-Bace1 axis in presence of generalized impairment of microRNA processing in ageing and obesity as a novel determinant of ageing- and obesity-associated decline in BAT function. This may define in vivo Bace1-inhibition as an innovative therapeutic approach to not only target age-related neurodegenerative diseases but at the same time improving age-related impairment of BAT-function and metabolism.
2015-06-17 | GSE69913 | GEO
Project description:A persistent influx of energy due to intake over expenditure leads to obesity. Increasing energy expenditure through activation of brown fat thermogenesis is a promising therapeutic strategy for the treatment of obesity. Epigenetic regulation has emerged as a key player in regulating brown fat development and thermogenic program. Here we aimed to study the role of DNA methyltransferase 3b (Dnmt3b), a DNA methyltransferase involved in de novo DNA methylation, in the regulation of brown fat function and energy homeostasis during diet-induced obesity (DIO). We have generated a genetic model with Dnmt3b deletion in brown fat-skeletal lineage precursor cells (3bKO mice) by crossing Dnmt3b-floxed (fl/fl) mice with Myf5-Cre mice. Female 3bKO mice were prone to diet-induced obesity and were insulin resistant. This was associated with decreased energy expenditure, which may largely account for the obese phenotype as there was no difference in food intake and locomotor activity between 3bKO and fl/fl mice. Dnmt3b deficiency impaired mitochondrial and thermogenic program in brown fat. Surprisingly, further RNA-seq analysis revealed a profound up-regulation of myogenic markers in the brown fat of 3bKO mice, suggesting a myocyte-like remodeling in brown fat, which may explain the impaired thermogenic program in brown fat. Further motif enrichment and pyrosequencing analysis suggested myocyte enhancer factor 2C (Mef2c) as a mediator for the myogenic alteration in Dnmt3b-deficient brown fat as indicated by decreased methylation at its promoter. Our data demonstrate that brown fat Dnmt3b is a key regulator of brown fat development, energy metabolism and obesity in female mice.
2021-12-01 | GSE173765 | GEO
Project description:Brown fat dissipates energy as heat and protects against obesity. Here, we identified nuclear factor I-A (NFIA) as a novel transcriptional regulator of brown fat by a genome-wide open chromatin analysis of murine brown and white fat followed by motif analysis of brown-fat-specific open chromatin regions. NFIA and the adipogenic master regulator, PPARγ, co-localize at the brown-fat-specific enhancers. Moreover, the binding of NFIA precedes and facilitates the binding of PPARγ, leading to increased chromatin accessibility and active transcription. Introduction of NFIA into myoblasts results in brown adipocyte differentiation. Conversely, the brown fat of NFIA knockout mice displays impaired expression of the brown-fat-specific genes and reciprocal elevation of muscle genes. Finally, expression of NFIA and the brown-fat-specific genes is positively correlated in human brown fat. These results indicate that NFIA is a key transcriptional regulator of brown fat and exerts its effects by co-localizing with PPARγ at cell-type-specific enhancers.
2017-08-14 | GSE83762 | GEO
Project description:Brown fat dissipates energy as heat and protects against obesity. Here, we identified nuclear factor I-A (NFIA) as a novel transcriptional regulator of brown fat by a genome-wide open chromatin analysis of murine brown and white fat followed by motif analysis of brown-fat-specific open chromatin regions. NFIA and the adipogenic master regulator, PPARgamma, co-localize at the brown-fat-specific enhancers. Moreover, the binding of NFIA precedes and facilitates the binding of PPARgamma, leading to increased chromatin accessibility and active transcription. Introduction of NFIA into myoblasts results in brown adipocyte differentiation. Conversely, the brown fat of NFIA knockout mice displays impaired expression of the brown-fat-specific genes and reciprocal elevation of muscle genes. Finally, expression of NFIA and the brown-fat-specific genes is positively correlated in human brown fat. These results indicate that NFIA is a key transcriptional regulator of brown fat and exerts its effects by co-localizing with PPARg at cell-type-specific enhancers.
2017-08-14 | GSE83757 | GEO
Project description:Brown adipocytes are specialized for heat generation and energy expenditure as a defense against cold and obesity. Recent studies demonstrate that brown adipocytes arise in vivo from a Myf5-positive, myoblastic progenitor by the action of PRDM16. Here, we identified a brown fat-enriched miRNA cluster mir-193b-365 as a key regulator of brown fat development. Blocking miR-193b and/or miR-365 in primary brown preadipocytes dramatically impaired brown adipocyte adipogenesis whereas myogenic markers were significantly induced. Forced expression of miR-193b and/or miR-365 in C2C12 myoblasts blocked the entire program of myogenesis, and miR-193b induced myoblasts to differentiate into brown adipocytes. Mir-193b-365 was upregulated by PRDM16. Our results demonstrate that mir-193b-365 serves as an essential regulator for brown fat differentiation, in part by repressing myogenesis. To study if miR-193b-365 is required for brown adipocyte adipogenesis, mRNAs from cultured primary brown adipocytes (Day 4) transfected with each locked nucleic acid (LNA) miRNA inhibitor or Control inhibitor were analyzed by microarray analysis.
2011-05-02 | E-GEOD-27614 | biostudies-arrayexpress
Project description:Brown adipocytes are specialized for heat generation and energy expenditure as a defense against cold and obesity. Recent studies demonstrate that brown adipocytes arise in vivo from a Myf5-positive, myoblastic progenitor by the action of PRDM16. Here, we identified a brown fat-enriched miRNA cluster mir-193b-365 as a key regulator of brown fat development. Blocking miR-193b and/or miR-365 in primary brown preadipocytes dramatically impaired brown adipocyte adipogenesis whereas myogenic markers were significantly induced. Forced expression of miR-193b and/or miR-365 in C2C12 myoblasts blocked the entire program of myogenesis, and miR-193b induced myoblasts to differentiate into brown adipocytes. Mir-193b-365 was upregulated by PRDM16. Our results demonstrate that mir-193b-365 serves as an essential regulator for brown fat differentiation, in part by repressing myogenesis.
2011-05-02 | GSE27614 | GEO
Project description:Beige fat is specialized for energy expenditure and has therefore been proposed to function as a defense against obesity. The loss of beige fat is associated with the age-dependent decline in metabolism. In this study, we isolated a subpopulation of adipogenic progenitors (Sca-1+/CD45−/Mac1−; referred to as Sca- 1+ progenitor cells, ScaPCs) residing in subcutaneous white fat from young and aged mice to determine the gene signature of aging.
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2022-12-31 | E-MTAB-10954 | biostudies-arrayexpress
Project description:Brown fat generates heat via the mitochondrial uncoupling protein UCP1, defending against hypothermia and obesity. Recent data suggest that there are two distinct types of brown fat: classical brown fat derived from a myf-5 cellular lineage and UCP1-positive cells that emerge in white fat from a non-myf-5 lineage. Here, we report the isolation of “beige” cells from murine white fat depots.
2012-07-24 | GSE39562 | GEO