Isoform-specific functions of PPARγ in gene regulation and metabolism

Hu, Wenxiang; Jiang, Chunjie; Kim, Mindy; Xiao, Yang; Richter, Hannah; Guan, Dongyin; Zhu, Kexin; Krusen, Brianna M.; Roberts, Arielle N; Miller, Jessica; Steger, David J.; Lazar, Mitchell A.

doi:10.1101/gad.349232.121

Cited by 19 publications

(18 citation statements)

References 60 publications

(77 reference statements)

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“…These results are consistent with the fact that PPARγ2 is almost exclusively expressed in adipose tissue, while PPARγ1 is also expressed in various other tissues . Similar to our findings, a recent study revealed that both PPARγ1 and PPARγ2 regulated many different genes in mouse adipose tissue and PPARγ1 had far more target genes than PPARγ2 …”

Section: Discussionsupporting

confidence: 93%

“…All these phenomena could possibly be explained by the additional amino acids at the N terminus of PPARγ2, which may affect protein–protein interaction, DNA–protein interaction, and receptor–ligand interaction, leading to the change in downstream target genes. Our previous study and the published data had showed that PPARγ1 and PPARγ2 had differential transcriptional activities, , protein–protein interaction, , and DNA binding affinities . To better understand the differential roles of PPARγ1 and PPARγ2 in adipogenesis, it is necessary to identify the PPARγ isoform-specific target genes in adipogenesis.…”

Section: Discussionmentioning

confidence: 99%

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Knockout and Restoration Reveal Differential Functional Roles of PPARγ1 and PPARγ2 in Chicken Adipogenesis

Yang

Xing

et al. 2022

J. Agric. Food Chem.

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Peroxisome proliferator-activated receptor γ (PPARγ) is the master regulator of adipogenesis and is expressed as two isoforms, PPARγ1 and PPARγ2. Our previous lentiviral overexpression study showed that PPARγ1 and PPARγ2 differentially regulated proliferation, differentiation, and apoptosis of the immortalized chicken preadipocyte cell line (ICP2). However, we cannot rule out the possibility that the endogenous expression of PPARγ isoforms may compromise our findings. In this study, using the dual sgRNA-directed CRISPR/Cas9 system, we generated PPARγ (PPARγ–/–) and PPARγ2-specific knockout (PPARγ2 –/–) ICP2 cell lines and investigated the differences in proliferation and differentiation among PPARγ–/–, PPARγ2 –/–, and wild-type ICP2 cells. EdU proliferation assay showed that both PPARγ2-specific and PPARγ knockouts significantly increased the proliferation rates. Consistently, real-time RT-PCR analysis showed that both PPARγ2-specific and PPARγ knockouts significantly upregulated the expression of proliferation marker genes PCNA and cyclinD1. FACS analysis revealed that PPARγ knockout significantly increased the number of cells accumulating in the S phase and decreased the number of cells accumulating in the G1/G0 phase. Oil Red O staining and gene expression analysis showed both PPARγ2-specific and PPARγ knockouts dramatically reduced capacity for adipogenic differentiation. To corroborate our previous findings, PPARγ1 and PPARγ2 expression were restored in PPARγ –/– cells by using the lentiviruses expressing chicken PPARγ1 (LV-PPARγ1) and PPARγ2 (LV-PPARγ2), respectively. Subsequent assays showed that restoration of expression of either PPARγ1 or PPARγ2 suppressed proliferation and stimulated differentiation of the PPARγ –/– cells. By comparison, PPARγ2 had stronger anti-proliferative and pro-adipogenic effects than PPARγ1. To understand the molecular mechanism underlying their differential effects on differentiation of the PPARγ –/– cells, we performed RNA-seq in the PPARγ –/– cells in which individual PPARγ isoform expression was restored at 72 h of differentiation. Transcriptomic analysis revealed that restoring PPARγ1 expression caused far more differentially expressed genes (DEGs) than restoring PPARγ2 expression. GO and KEGG pathway enrichment analyses indicated that PPARγ1 and PPARγ2 had distinct and overlapping functions in adipogenesis. Taken together, our results clearly indicate that PPARγ1 and PPARγ2 differentially impact chicken adipogenesis.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Knockout and Restoration Reveal Differential Functional Roles of PPARγ1 and PPARγ2 in Chicken Adipogenesis

Yang

Xing

et al. 2022

J. Agric. Food Chem.

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“…Numerous studies showed that cancer cells have evolved adaptive metabolic patterns different from normal cells, to meet the needs of tumor growth, maintain a balanced REDOX cell environment, and influence cell communication ( Hu et al, 2021 ; Hu et al, 2022 ). Cancer cells can also change the tumor microenvironment through reprogramming metabolic patterns and affect the related metabolic activity of tumor cells.…”

Section: Resultsmentioning

confidence: 99%

Multidimensional difference analysis in gastric cancer patients between high and low latitude

et al. 2022

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Genetic variation has been shown to affect tumor growth and progression, and the temperature at different latitudes may promote the evolution of genetic variation. Geographical data with latitudinal information is of importance to understand the interplay between genetic variants and environmental influence, such as the temperature, in gastric cancer (GC). In this study, we classified the GC samples from The Cancer Genome Atlas database into two groups based on the latitudinal information of patients and found that GC samples with low-latitude had better clinical outcomes. Further analyses revealed significant differences in other clinical factors such as disease stage and grade between high and low latitudes GC samples. Then, we analyzed the genomic and transcriptomic differences between the two groups. Furthermore, we evaluated the activity score of metabolic pathways and infiltrating immune cells in GC samples with different latitudes using the single-sample gene set enrichment analysis algorithm. These results showed that GC samples at low-latitude had lower tumor mutation burden and subclones as well as higher DNA repair activities. Meanwhile, we found that most immune cells were associated with the prognosis of low-latitude GC patients. At last, we constructed and validated an immune-related prognostic model to evaluate the prognosis of GC samples at different latitudes. This study has provided a further understanding of the geographical contribution to GC at the multiomic level and may benefit the individualized treatment of GC patients at different latitudes.

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“…Ligand-mediated PPARγ activation has been shown to induce skipping of exon 5 which by itself lacks ligand-dependent transactivation ability, and thus acts as a dominant negative form of PPARγ [ 32 ]. In particular, recent evidence points towards distinct roles of γ1 vs. γ2 variant of PPARγ governing specific and separate gene expression and metabolic functions at different stages in adipocytes [ 70 ], as well as between adipocytes and macrophages [ 38 ]. In the current study, analysis of the podocyte vs. adipocyte specific expression of genes downstream of PPARγ containing putative or identified PPREs informs us that these downstream effects in podocytes are likely directed by the PPARγ1 splice variant, distinct from the adipocyte-regulatory γ2 variant ( Figure 3 and Figure 4 ).…”

Section: Discussionmentioning

confidence: 99%

Alternatively Spliced Landscape of PPARγ mRNA in Podocytes Is Distinct from Adipose Tissue

Bryant

Webb

Banks

et al. 2022

Cells

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Podocytes are highly differentiated epithelial cells, and their structural and functional integrity is compromised in a majority of glomerular and renal diseases, leading to proteinuria, chronic kidney disease, and kidney failure. Traditional agonists (e.g., pioglitazone) and selective modulators (e.g., GQ-16) of peroxisome-proliferator-activated-receptor-γ (PPARγ) reduce proteinuria in animal models of glomerular disease and protect podocytes from injury via PPARγ activation. This indicates a pivotal role for PPARγ in maintaining glomerular function through preservation of podocytes distinct from its well-understood role in driving insulin sensitivity and adipogenesis. While its transcriptional role in activating adipokines and adipogenic genes is well-established in adipose tissue, liver and muscle, understanding of podocyte PPARγ signaling remains limited. We performed a comprehensive analysis of PPARγ mRNA variants due to alternative splicing, in human podocytes and compared with adipose tissue. We found that podocytes express the ubiquitous PPARγ Var 1 (encoding γ1) and not Var2 (encoding γ2), which is mostly restricted to adipose tissue and liver. Additionally, we detected expression at very low level of Var4, and barely detectable levels of other variants, Var3, Var11, VartORF4 and Var9, in podocytes. Furthermore, a distinct podocyte vs. adipocyte PPAR-promoter-response-element containing gene expression, enrichment and pathway signature was observed, suggesting differential regulation by podocyte specific PPARγ1 variant, distinct from the adipocyte-specific γ2 variant. In summary, podocytes and glomeruli express several PPARγ variants, including Var1 (γ1) and excluding adipocyte-specific Var2 (γ2), which may have implications in podocyte specific signaling and pathophysiology. This suggests that that new selective PPARγ modulators can be potentially developed that will be able to distinguish between the two forms, γ1 and γ2, thus forming a basis of novel targeted therapeutic avenues.

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Isoform-specific functions of PPARγ in gene regulation and metabolism

Cited by 19 publications

References 60 publications

Knockout and Restoration Reveal Differential Functional Roles of PPARγ1 and PPARγ2 in Chicken Adipogenesis

Knockout and Restoration Reveal Differential Functional Roles of PPARγ1 and PPARγ2 in Chicken Adipogenesis

Multidimensional difference analysis in gastric cancer patients between high and low latitude

Alternatively Spliced Landscape of PPARγ mRNA in Podocytes Is Distinct from Adipose Tissue

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