Transcriptional Control of Subcutaneous Adipose Tissue by the Transcription Factor CTCF Modulates Heterogeneity in Fat Distribution in Women

Erdos, Edina; Sandor, Katalin; Young-Erdos, Crystal L.; Halasz, Laszlo; Smith, Steven R.; Osborne, Timothy F.; Divoux, Adeline

doi:10.3390/cells13010086

Cited by 2 publications

References 44 publications

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TBX15 regulates a network of immune response genes in adipose tissue and alters fat mass and depot weight in heterozygous knockout mice

Zolkiewski,

Simon,

Harrison

et al. 2024

Preprint

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Adipose tissue distribution in the body is an indicator of metabolic disease risk, independent of body mass index (BMI), and is indirectly measured by waist-hip-ratio (WHR). T-Box transcription factor-15 (TBX15) has been implicated in regulation of adipose distribution in multiple human and mouse studies, and the TBX15-WARS2 genome-wide association study locus has been associated with BMI-adjusted-WHR signals in multiple investigations. As a potential mediator of this signal, we investigated the role of Tbx15 using heterozygous and homozygous mouse knockout models to determine if loss of this gene alters adipose physiology, and to identify the transcriptional network regulated by Tbx15 in adipose tissue and preadipocyte cells. In a metabolic phenotyping experiment we provided either low fat diet (LFD) or high fat diet (HFD) to male and female heterozygous Tbx15+/- and wildtype Tbx15+/+ mice from weaning and maintained for 24 weeks. Only Tbx15+/- mice maintained on LFD weighed less than wildtype LFD controls, and female LFD Tbx15+/- mice had lower fat mass overall. We found that in LFD Tbx15+/- mice, multiple visceral fat depots weighed less than wildtype controls, and this was maintained when corrected for body mass for both gonadal and mesenteric visceral adipose depots. When comparing adipocyte size in multiple adipose depots, some reduction in number of larger adipocytes was detected in the perirenal adipose tissue of female HFD Tbx15+/- vs Tbx15+/+ mice, mesenteric adipose tissue from female LFD Tbx15+/- vs Tbx15+/+ mice and male HFD Tbx15+/- vs Tbx15+/+ mice. RNA-sequencing of subcutaneous (inguinal) adipose tissues from 12-week old male and female knockout Tbx15-/-, Tbx15+/- and Tbx15+/+ mice raised on a standard chow diet identified 897 upregulated genes and 2328 downregulated genes in female Tbx15-/- mice compared to Tbx15+/+ mice. We then combined this dataset with TBX15 ChIP-sequencing data from mouse preadipocyte 3T3-L1 cells overexpressing TBX15 to identify a credible set of genes directly regulated by TBX15. These 52 genes were enriched for B- and T-cell receptor signalling, JAK-STAT signalling and haematopoietic cell lineage pathways; suggesting a direct regulatory role for TBX15 in these pathways in adipose tissue. Together, these data highlight a role for TBX15 in regulation of differential adipose tissue expansion, particularly under low caloric conditions. Further, we identify a potentially important role for TBX15 in the well described adipocyte-immune cell crosstalk associated with obesity and type 2 diabetes mellitus.

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TBX15 regulates a network of immune response genes in adipose tissue and alters fat mass and depot weight in heterozygous knockout mice

Zolkiewski,

Simon,

Harrison

et al. 2024

Preprint

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Molecular regulation of PPARγ/RXRα signaling by the novel cofactor ZFP407

Charrier,

Ockunzzi,

Main

et al. 2024

PLoS ONE

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Cofactors interacting with PPARγ can regulate adipogenesis and adipocyte metabolism by modulating the transcriptional activity and selectivity of PPARγ signaling. ZFP407 was previously demonstrated to regulate PPARγ target genes such as GLUT4, and its overexpression improved glucose homeostasis in mice. Here, using a series of molecular assays, including protein-interaction studies, mutagenesis, and ChIP-seq, ZFP407 was found to interact with the PPARγ/RXRα protein complex in the nucleus of adipocytes. Consistent with this observation, ZFP407 ChIP-seq peaks significantly overlapped with PPARγ ChIP-seq peaks, with more than half of ZFP407 peaks overlapping with PPARγ peaks. Transcription factor binding motifs enriched in these overlapping sites included CTCF, RARα/RXRγ, TP73, and ELK1, which regulate cellular development and function within adipocytes. Site-directed mutagenesis of frequent PPARγ phosphorylation or SUMOylation sites did not prevent its regulation by ZFP407, while mutagenesis of ZFP407 domains potentially necessary for RXR and PPARγ binding abrogated any impact of ZFP407 on PPARγ activity. These data suggest that ZFP407 controls the activity of PPARγ, but does so independently of post-translational modifications, likely by direct binding, establishing ZFP407 as a newly identified PPARγ cofactor. In addition, ZFP407 ChIP-seq analyses identified regions that did not overlap with PPARγ peaks. These non-overlapping peaks were significantly enriched for the transcription factor binding motifs of TBX19, PAX8, HSF4, and ZKSCAN3, which may contribute to the PPARγ-independent functions of ZFP407 in adipocytes and other cell types.

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Transcriptional Control of Subcutaneous Adipose Tissue by the Transcription Factor CTCF Modulates Heterogeneity in Fat Distribution in Women

Cited by 2 publications

References 44 publications

TBX15 regulates a network of immune response genes in adipose tissue and alters fat mass and depot weight in heterozygous knockout mice

TBX15 regulates a network of immune response genes in adipose tissue and alters fat mass and depot weight in heterozygous knockout mice

Molecular regulation of PPARγ/RXRα signaling by the novel cofactor ZFP407

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