EBF2 Determines and Maintains Brown Adipocyte Identity

Abstract

Summary The master transcription factor, Pparγ regulates the general differentiation program of both brown and white adipocytes. However, it has been unclear whether Pparγ also controls fat lineage-specific characteristics. Here, we show that Early B-Cell Factor-2 (Ebf2) regulates Pparγ binding activity to determine brown versus white adipocyte identity. The Ebf DNA-binding motif was highly enriched within brown adipose-specific Pparγ binding sites that we identified by genome-wide ChIP-Seq. Of the Ebf isoforms, Ebf2 was selectively expressed in brown relative to white adipocytes and was bound at brown adipose-specific Pparγ target genes. When expressed in myoblasts or white pre-adipose cells, Ebf2 recruited Pparγ to its brown-selective binding sites and reprogrammed cells to a brown fat fate. Brown adipose cells and tissue from Ebf2-deficient mice displayed a loss of brown-specific characteristics and thermogenic capacity. Together, these results identify Ebf2 as a key transcriptional regulator of brown fat cell fate and function.

Promoting brown and beige adipocyte biogenesis through the PRDM16 pathway

“…Indeed, PRDM16 directly interacts and modulates the transcriptional activities of CCAAT/enhancer-binding protein-β, PPARγ and early B-cell factor 2 and PPARγ co-activator 1α (PGC1α). 6,8,9,27 Consistent with these observations, genome-wide chromatin immunoprecipitationsequencing analysis of PRDM16 revealed that PRDM16 binding in BAT is highly enriched at the binding sites for C/EBPs, PPARs and EBFs. 28 Importantly, ectopic expression of PRDM16 and CCAAT/enhancer-binding protein-β is sufficient to convert nonadipogenic fibroblasts, such as dermal fibroblasts from mice and humans, into brown adipocytes.…”

Ebf2 is a selective marker of brown and beige adipogenic precursor cells

“…Ebf2-deficient mice develop dysmorphic fatty tissue devoid of brown-fat-specific characteristics in place of BAT (18). Thus, whereas Ebf2 is required to induce the brown-fat cell-selective gene program, it is dispensable for adipogenesis per se.…”

“…Here, we combined lineage and cell surface markers to prospectively isolate brown preadipose cells during embryogenesis. Global mRNA transcriptomic analyses identified a brown-preadipose-specific gene signature, which included early B-cell factor 2 (Ebf2), a critical transcriptional regulator in mature brown adipocytes (18). We found that brown/beige preadipose activity in embryos and adult fat depots was restricted to Ebf2-expressing cells.…”

“…Ectopic expression of Ebf2 in white fat or muscle precursor cells cooperates with a mixture of adipogenic inducers to drive a brown-fat cell-selective differentiation program (18). We wondered whether Ebf2 reprograms precursor cell identity before adipogenic induction.…”

Brown and beige fat: development, function and therapeutic potential

“…Genome-wide analyses have demonstrated that Ppar-γ binds and regulates distinct target genes in brown and white fat cells 116,117 . We recently discovered that Ebf2, a helix-loop-helix transcription factor, regulates Ppar-γ activity to drive the expression of Prdm16 and a brown fat fate 116 (Fig. 2).…”