Adipocyte-Specific Ablation Of PU.1 Promotes Energy Expenditure and Ameliorates Metabolic Syndrome In Aging Mice
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ABSTRACT:
PROVIDER: PRJNA779077 | ENA |
REPOSITORIES: ENA
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Project description:Here, we investigated the role of adipocyte PU.1 in the development of age-associated metabolic syndrome. We generated mice with adipocyte specific PU.1 knockout, assessed metabolic changes in young and aged PU.1fl/fl (control) and AdipoqCre PU.1fl/fl(aPU.1KO) mice, including body weight, body composition, energy expenditure and glucose homeostasis. We also performed transcriptional analyses using RNA-Sequencing of adipocytes from these mice.
2022-01-06 | GSE188497 | GEO
Project description:Objective: Although PU.1/Spi1 is known as a master regulator for macrophage development and function, we have reported previously that it is also expressed in adipocytes and is transcriptionally induced in obesity. Here, we investigated the role of adipocyte PU.1 in the development of the age-associated metabolic syndrome. Methods: We generated mice with adipocyte-specific PU.1 knockout, assessed metabolic changes in young and older adult PU.1fl/fl (control) and AdipoqCre PU.1fl/fl (aPU.1KO) mice, including body weight, body composition, energy expenditure, and glucose homeostasis. We also performed transcriptional analyses using RNA-Sequencing of adipocytes from these mice. Results: aPU.1KO mice have elevated energy expenditure at a young age and decreased adiposity and increased insulin sensitivity in later life. Corroborating these observations, transcriptional network analysis indicated the existence of validated, adipocyte PU.1-modulated regulatory hubs that direct inflammatory and thermogenic gene expression programs. Conclusion: Our data provide evidence for a previously uncharacterized role of PU.1 in the development of age-associated obesity and insulin resistance.
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Project description:Ten-eleven translocation (TET) proteins oxidize 5-methylcytosine in DNA to 5- hydroxymethylcytosine and further oxidized derivatives. Here we show that TET proteins are key epigenetic suppressors of adipocyte thermogenesis and energy expenditure in both white and brown adipose tissues in vivo. Tet expression in adipocytes decreases upon cold or adrenergic stimulation but increases following high-fat diet (HFD) consumption. Mice with triple deletion of all three Tet genes in adipocytes have higher energy expenditure due to enhanced fat browning and thermogenesis. They also show significantly enhanced lipolysis because of elevated expression of Adrb3 and key lipases including Atgl and Hsl. Consequently, the knockout mice display improved cold tolerance and are substantially resistant to obesity, inflammation, and associated metabolic complications including insulin resistance. Mechanistically, TET deficiency substantially prevents the HFD-induced transcriptional alterations in adipose tissues. TET proteins recruit histone deacetylases (HDACs) to the key thermogenic gene loci including Adrb3, Ppargc1a, and Ucp1, leading to transcriptional repression through histone deacetylation. Thus, the TET-HDAC axis may be therapeutically targeted to treat obesity and related metabolic diseases.
2021-11-01 | GSE178762 | GEO
Project description:Ablation of TET proteins in adipocytes protects against adiposity and metabolic dysfunction by potentiating energy expenditure
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Project description:Exercise benefits M2 macrophage polarization, energy homeostasis and protects against obesity partially through exercise-induced circulating factors. Here, by unbiased quantitative proteomics on serum samples from sedentary and exercised mice, we identify parvalbumin as a circulating factor suppressed by exercise. Parvalbumin functions as a non-competitive CSF1R antagonist to inhibit M2 macrophage activation and energy expenditure in adipose tissue. More importantly, serum concentrations of parvalbumin positively correlate with obesity in mouse and human, while treating mice with a recombinant parvalbumin blocker prevents its interaction with CSF1R and promotes M2 macrophage polarization and ameliorates diet-induced obesity. Thus, although further studies are required to assess the significance of parvalbumin in mediating the effects of exercise, our results implicate parvalbumin as a potential therapeutic strategy against obesity.
2022-05-10 | PXD033582 | Pride
Project description:Master transcription factors are the gatekeepers of lineage identity. As such, they have been a major focus of efforts to manipulate cell fate for therapeutic purposes. The ETS transcription factor PU.1 has a potent ability to confer macrophage phenotypes on cells already committed to a different lineage, but how it overcomes the presence of other master regulators is not known. The nuclear receptor PPARγ is the master regulator of the adipose lineage, and its genomic binding pattern is well characterized in adipocytes. Here, we show that when expressed at macrophage levels in mature adipocytes, PU.1 bound a large fraction of its macrophage sites, where it induced chromatin opening and the expression of macrophage target genes. Strikingly, PU.1 markedly reduced the genomic binding of PPARγ without changing its abundance. PU.1 expression repressed genes with nearby adipocyte-specific PPARγ binding sites, while a common macrophage-adipocyte gene expression program was retained. Together, these data reveal unexpected lability within the adipocyte PPARγ cistrome and show that even in terminally differentiated cells, PU.1 can remodel the cistrome of another master regulator. Microarray expression profiling was performed on 3T3-L1 adipocytes from two treatment groups: (1) adipocytes transduced with a control adenovirus expressing beta-galactosidase (LACZ-Ads) and (2) adipocytes transduced with an adenovirus expressing full-length murine PU.1 cDNA (PU.1-Ads). Each sample group consists of four biological replicates which are here defined as separate differentiations of mature 3T3-L1 adipocytes and adenoviral infections. Each replicate was hybridized to an individual array for a total of eight arrays.
2013-06-27 | E-GEOD-48344 | biostudies-arrayexpress
Project description:"Master" transcription factors are the gatekeepers of lineage identity. As such, they have been a major focus of efforts to manipulate cell fate for therapeutic purposes. The ETS transcription factor PU.1 has a potent ability to confer macrophage phenotypes on cells already committed to a different lineage, but how it overcomes the presence of other master regulators is not known. The nuclear receptor PPARM-NM-3 is the master regulator of the adipose lineage, and its genomic binding pattern is well characterized in adipocytes. Here, we show that when expressed at macrophage levels in mature adipocytes, PU.1 bound a large fraction of its macrophage sites, where it induced chromatin opening and the expression of macrophage target genes. Strikingly, PU.1 markedly reduced the genomic binding of PPARM-NM-3 without changing its abundance. PU.1 expression repressed genes with nearby adipocyte-specific PPARM-NM-3 binding sites, while a common macrophage-adipocyte gene expression program was retained. Together, these data reveal unexpected lability within the adipocyte PPARM-NM-3 cistrome and show that even in terminally differentiated cells, PU.1 can remodel the cistrome of another master regulator. ChIP-seq was performed on 3T3-L1 adipocytes from two treatment groups: (1) adipocytes transduced with a control adenovirus expressing beta-galactosidase (LACZ-Ads) and (2) adipocytes transduced with an adenovirus expressing full-length murine PU.1 cDNA (PU.1-Ads). Nuclear lysates from each group were used for PPARg ChIP. For PU.1-Ads, PU.1 ChIP was also performed. To generate chromatin for ChIP-seq, DNA from three immunoprecipitations per condition was pooled. This process was repreated from a second set of L1 adipocytes to generate two biological replicates for sequencing. Genomic input DNA was sequenced from the first biological replicate only.
2013-06-27 | E-GEOD-48343 | biostudies-arrayexpress
Project description:Gray but not white matter astroglia-specific connexin 43 ablation ameliorates neuroinflammation
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Project description:Mechanisms to coordinately regulate oxidative metabolism and glucose transport into cells are not well described. In muscle and fat, insulin mobilizes GLUT4 glucose transporters to the cell surface in part by stimulating the site-specific endoproteolytic cleavage of TUG proteins. Here, we show that the TUG C-terminal cleavage product enters the nucleus, binds the transcriptional 30 regulators PGC-1a and PPARg, and increases oxidative metabolism, thermogenic protein expression, and energy expenditure. The PPARg2 Pro12Gly polymorphism, which confers reduced diabetes risk, enhances TUG binding. The TUG cleavage product stabilizes PGC-1a, so that both proteins are susceptible to an Ate1 arginyltransferase -dependent degradation mechanism. We conclude that TUG cleavage coordinates energy expenditure with glucose 35 uptake, and that alterations in this pathway may contribute to metabolic disease.
2020-07-23 | GSE134846 | GEO
Project description:Gray but not white matter astroglia-specific connexin 43 ablation ameliorates neuroinflammation [Agilent]
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