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ABSTRACT:
PROVIDER: PRJNA665140 | ENA |
REPOSITORIES: ENA
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Project description:Beige adipocytes in mammalian white adipose tissue (WAT) can reinforce fat catabolism and energy expenditure. Promoting beige adipocyte biogenesis is a tantalizing tactic for combating obesity and its associated metabolic disorders. Here, we report that a previously unidentified phosphorylation pattern (Thr166) in the DNA-binding domain of PPARg regulates the inducibility of beige adipocytes. This unique posttranslational modification (PTM) pattern influences allosteric communication between PPARg and DNA or coactivators, which impedes the PPARg-mediated transactivation of beige cell-related gene expression in WAT. The genetic mutation mimicking T166 phosphorylation (p-T166) hinders the inducibility of beige adipocytes. In contrast, genetic or chemical intervention in this PTM pattern favors beige cell formation. Moreover, inhibition of p-T166 attenuates metabolic dysfunction in obese mice. Our results uncover a mechanism involved in beige cell fate determination. Moreover, our discoveries provide a promising strategy for guiding the development of novel PPARg agonists for the treatment of obesity and related metabolic disorders.
2022-10-28 | GSE158615 | GEO
Project description:Macrophages exhibit a reparative phenotype that supports tissue repair and remodeling in response to tissue injury. However, the metabolic requirements that support this process have remained incompletely understood. Here, we showed that posttranslational modification (PTM) of peroxisome proliferator-activated receptor g (PPARg) regulated lipid synthesis in response to wound microenvironmental cues and that metabolic rewiring orchestrated the function of reparative macrophages. In injured tissues, repair signaling attenuated macrophage PPARg threonine 166 (T166) phosphorylation, which induced a partially active PPARg program with increased binding activity to the regulator regions of lipid synthesis-associated genes, thereby activating lipogenesis. The accumulated lipids served as signaling molecules, triggering signal transducer and activator of transcription 3 (STAT3)-mediated growth factor expression, and supporting the synthesis of phospholipids for the expansion of the endoplasmic reticulum (ER), which is required for the secretion of proteins. Genetic or pharmacological inhibition of PPARg T166 phosphorylation promoted the reparative function of macrophages and facilitated tissue regeneration. In summary, we identified that PPARg T166-regulated lipid biosynthesis was essential for the anabolic demands of the activation and function of macrophages and provided a rationale for therapeutic targeting of tissue repair.
2024-07-30 | GSE269832 | GEO
Project description:Macrophages exhibit a reparative phenotype that supports tissue repair and remodeling in response to tissue injury. However, the metabolic requirements that support this process have remained incompletely understood. Here, we showed that posttranslational modification (PTM) of peroxisome proliferator-activated receptor g (PPARg) regulated lipid synthesis in response to wound microenvironmental cues and that metabolic rewiring orchestrated the function of reparative macrophages. In injured tissues, repair signaling attenuated macrophage PPARg threonine 166 (T166) phosphorylation, which induced a partially active PPARg program with increased binding activity to the regulator regions of lipid synthesis-associated genes, thereby activating lipogenesis. The accumulated lipids served as signaling molecules, triggering signal transducer and activator of transcription 3 (STAT3)-mediated growth factor expression, and supporting the synthesis of phospholipids for the expansion of the endoplasmic reticulum (ER), which is required for the secretion of proteins. Genetic or pharmacological inhibition of PPARg T166 phosphorylation promoted the reparative function of macrophages and facilitated tissue regeneration. In summary, we identified that PPARg T166-regulated lipid biosynthesis was essential for the anabolic demands of the activation and function of macrophages and provided a rationale for therapeutic targeting of tissue repair.
2024-07-30 | GSE252900 | GEO
Project description:Macrophages exhibit a reparative phenotype that supports tissue repair and remodeling in response to tissue injury. However, the metabolic requirements that support this process have remained incompletely understood. Here, we showed that posttranslational modification (PTM) of peroxisome proliferator-activated receptor g (PPARg) regulated lipid synthesis in response to wound microenvironmental cues and that metabolic rewiring orchestrated the function of reparative macrophages. In injured tissues, repair signaling attenuated macrophage PPARg threonine 166 (T166) phosphorylation, which induced a partially active PPARg program with increased binding activity to the regulator regions of lipid synthesis-associated genes, thereby activating lipogenesis. The accumulated lipids served as signaling molecules, triggering signal transducer and activator of transcription 3 (STAT3)-mediated growth factor expression, and supporting the synthesis of phospholipids for the expansion of the endoplasmic reticulum (ER), which is required for the secretion of proteins. Genetic or pharmacological inhibition of PPARg T166 phosphorylation promoted the reparative function of macrophages and facilitated tissue regeneration. In summary, we identified that PPARg T166-regulated lipid biosynthesis was essential for the anabolic demands of the activation and function of macrophages and provided a rationale for therapeutic targeting of tissue repair.
2024-07-30 | GSE252899 | GEO
Project description:The winged helix protein FOXA2 and the nuclear receptor PPARg are highly conserved, regionally-expressed transcription factors that regulate networks of genes controlling complex metabolic functions. Cistrome analysis for FOXA2 in mouse liver and PPARg in mouse adipocytes has previously produced consensus binding sites that are nearly identical to those used by the factors in human cells. Despite this conservation of the canonical binding motif, we report here that the great majority of specific binding regions for FOXA2 in human liver and for PPARg in human adipocytes are not in the orthologous locations to the mouse genome. Nevertheless, gene-centric analysis reveals strong shared transcription factor occupancy near genes in tissue-specific metabolic pathways that are functionally conserved across species. Genes with only species-specific binding sites fail to show enrichment for these pathways. Thus, the biological functions of transcription factors that control specific metabolic functions are highly shared across species. Two TFs, FOXA2 and PPARg, were studied for genome-wide conservation of binding between mouse and human in specific tissues/cell-types (liver for FOXA2, adipocytes for PPARg). The number of replicates for each TF was chosen to obtain a comparable number of reads between the TFs and species. Human FOXA2 ChIP-seq was performed on two biological replicates of human liver samples, in three technical replicates each. Input DNA was also collected and sequenced from both biological samples. Mouse FOXA2 ChIP-seq was performed on four biological replicates of mouse liver samples. The ChIP and sequencing were repeated on two of these biological replicates to create technical replicates for additional sequence reads. Input DNA was sequenced from three additional mouse livers. Human PPARg ChIP-seq was performed on a human adipocyte cell-line (SGBS) differentiated in two replicate cultures. Input DNA was also collected and sequenced from one culture. Mouse PPARg ChIP-seq was performed on 3T3-L1 cells differentiated into adipocytes in culture in a single replicate, and this sequence data was pooled with existing data previously generated by the same lab, already available in GEO (GSE21314). A standard pool of input DNA sample sequence from multiple mouse tissue was used for analyzing the Mouse PPARg ChIP-seq data.
2011-04-06 | E-GEOD-25836 | biostudies-arrayexpress
Project description:The discreteness of cell fates is an inherent and fundamental feature of multicellular organisms. Here we show that cross-antagonistic mechanisms of actions of MyoD and PPARg, which are the master regulators of muscle and adipose differentiation, respectively, confer the robustness to the integrity of cell differentiation. Simultaneous expression of MyoD and PPARg in mesenchymal stem/stromal cells led to the generation of a mixture of multinucleated myotubes and lipid-filled adipocytes. Interestingly, hybrid cells, i.e., lipid-filled myotubes, were not generated, suggesting that these differentiation programs are mutually exclusive. Mechanistically, while exogenously expressed MyoD was rapidly degraded in adipocytes through ubiquitin-proteasome pathways, exogenously expressed PPARg was not down-regulated in myotubes. In PPARg-expressing myotubes, PPARg-dependent histone hyperacetylation was inhibited in a subset of adipogenic gene loci, including that of C/EBPa, an essential effector of PPARg. Thus, the cross-repressive interactions between MyoD- and PPARg-induced differentiation programs ensure the discrete cell fate decisions. To gain insights into the mechanisms by which adipogenic differentiation is inhibited in PPARg-expressing myotubes, we performed microarray analysis to compare gene expression profiles of the myotube-enriched (M) fraction and the adipocyte-enriched (A) fraction. M fraction and A fraction were obtained by fractionating a mixture of myotubes and adipocytes, which was generated by simultaneous expression of MyoD and PPARg, according to cell size.
2014-05-08 | GSE56082 | GEO
Project description:Examination of PPARg occupancy (GSE41481) and DNA hypersensitive sites (GSE122453) in in vitro differentiatied adipocytes isolated from epididymal and inguinal white adipose tissues, as well as brown adipose tissue.
2018-11-13 | GSE122453 | GEO
Project description:The discreteness of cell fates is an inherent and fundamental feature of multicellular organisms. Here we show that cross-antagonistic mechanisms of actions of MyoD and PPARg, which are the master regulators of muscle and adipose differentiation, respectively, confer the robustness to the integrity of cell differentiation. Simultaneous expression of MyoD and PPARg in mesenchymal stem/stromal cells led to the generation of a mixture of multinucleated myotubes and lipid-filled adipocytes. Interestingly, hybrid cells, i.e., lipid-filled myotubes, were not generated, suggesting that these differentiation programs are mutually exclusive. Mechanistically, while exogenously expressed MyoD was rapidly degraded in adipocytes through ubiquitin-proteasome pathways, exogenously expressed PPARg was not down-regulated in myotubes. In PPARg-expressing myotubes, PPARg-dependent histone hyperacetylation was inhibited in a subset of adipogenic gene loci, including that of C/EBPa, an essential effector of PPARg. Thus, the cross-repressive interactions between MyoD- and PPARg-induced differentiation programs ensure the discrete cell fate decisions. To gain insights into the mechanisms by which adipogenic differentiation is inhibited in PPARg-expressing myotubes, we performed microarray analysis to compare gene expression profiles of the myotube-enriched (M) fraction and the adipocyte-enriched (A) fraction. M fraction and A fraction were obtained by fractionating a mixture of myotubes and adipocytes, which was generated by simultaneous expression of MyoD and PPARg, according to cell size. Microarray analysis was performed using mRNA isolated from C3H10T1/2 cells. We used five samples: non-infected cells, control lentivirus-infected cells, HA-PPARg-infected cells, and cells co-infected with Myc-MyoD and HA-PPARg and then fractionated accroding to cell size (M-fraction and A-fraction). Total RNA was prepared using the RNeasy Mini Kit (Qiagen) according to the manufacturer’s instruction. Other procedures including hybridization to the Mouse Gene 1.0 ST array (Affymetrix) were performed according to Affymetrix protocols. The affymetrix outputs (CEL files) were imported into GeneSpring GX 11.0.2 (Agilent Technologies) microarray analysis software for presentation of the expression profiles. Probe intensities were normalized, and expression signals of all genes (probe sets) were calculated using RMA (robust multi-array analysis, as implemented in GeneSpring GX).
2014-05-08 | E-GEOD-56082 | biostudies-arrayexpress
Project description:The winged helix protein FOXA2 and the nuclear receptor PPARg are highly conserved, regionally-expressed transcription factors that regulate networks of genes controlling complex metabolic functions. Cistrome analysis for FOXA2 in mouse liver and PPARg in mouse adipocytes has previously produced consensus binding sites that are nearly identical to those used by the factors in human cells. Despite this conservation of the canonical binding motif, we report here that the great majority of specific binding regions for FOXA2 in human liver and for PPARg in human adipocytes are not in the orthologous locations to the mouse genome. Nevertheless, gene-centric analysis reveals strong shared transcription factor occupancy near genes in tissue-specific metabolic pathways that are functionally conserved across species. Genes with only species-specific binding sites fail to show enrichment for these pathways. Thus, the biological functions of transcription factors that control specific metabolic functions are highly shared across species.
2011-04-06 | GSE25836 | GEO
Project description:We conducted extensive transcriptome profiling studies to characterize 70 SPPARgMs and seven PPARg full agonists in 3T3-L1 adipocytes, and a subset of these ligands in adipose tissue of diabetic db/db mice. In both cases, the SPPARgMs generated attenuated gene regulatory responses, and their gene expression signatures were more enriched in metabolic pathways that are likely to mediate anti-diabetic efficacy than those of PPARg full agonists. More importantly, our profiling results demonstrated that in both 3T3-L1 adipocytes and db/db mice, SPPARgMs regulate the expression of anti-diabetic efficacy-associated genes to a greater extent than that of adverse effect-associated genes, while PPARg full agonists regulate both gene sets proportionally. We conducted 10 independent batches of profiling experiments. Within each batch, drug treatment and pool of vehicle controls were hybridized to the Agilent two channel microarray. Generally 2-3 biological replicates for each condition.
2012-06-29 | E-GEOD-31222 | biostudies-arrayexpress