Targeting adipocyte ESRRA promotes osteogenesis and vascular formation in adipocyte-rich bone marrow
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE248799 | GEO | 2024/03/07
REPOSITORIES: GEO
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Project description:The nuclear receptor PPAR gamma is required for adipocyte differentiation, but its role in mature adipocytes is less clear. Here we report that knockdown of PPAR gamma expression in 3T3-L1 adipocytes returned the expression of most adipocyte genes towards preadipocyte levels. Consistently, down regulated but not up regulated genes showed strong enrichment of PPAR gamma binding. Surprisingly, not all adipocyte genes were reversed and the adipocyte morphology was maintained for an extended period after PPAR gamma depletion. To explain this, we focused on transcriptional regulators whose adipogenic regulation was not reversed upon PPAR gamma depletion. We identified GATA2, a transcription factor whose down-regulation early in adipogenesis is required for preadipocyte differentiation, remaining low after PPAR gamma knockdown. Forced expression of GATA2 in mature adipocytes complemented PPAR gamma depletion and impaired adipocyte functionality with a more preadipocyte- like gene expression profile. Ectopic expression of GATA2 in adipose tissue in vivo had similar effect on adipogenic gene expression. These results suggest that PPAR gamma-independent down regulation of GATA2 prevents reversion of mature adipocytes after PPAR gamma depletion. Keywords: cell type comparison, Gata2, PPAR gamma, adipocyte, preadipocytes, differentiation
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Project description:Human bone marrow mesenchymal stromal cells are capable of limited self-renewal and multi-lineage differentiation in vitro. Several studies have demonstrated that microRNAs, post-transcriptional modifiers of protein expression, play crucial roles in the regulation of these complex processes. To gain knowledge regarding the role of microRNAs in human adipocyte regulation, we examined the microRNA expression profile of the immortalized human bone marrow-derived stromal cell line hMSC-Tert20. We identified 12 microRNAs that were differentially expressed during adipogenesis, of which several have previously been shown to play important roles in adipocyte biology. The expression of miR-155, miR-221 and miR-222 decreased during the adipogenic program, suggesting that they act as negative regulators of differentiation. Interestingly, adenovirus-mediated expression of either miR-155 alone or miR-221 plus miR-222 significantly inhibited adipogenesis and repressed induction of the master regulators C/EBP α and PPARgamma Our study provides the first experimental evidence that miR-155, miR-221 and miR-222 function in human adipocyte differentiation.
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