A Multifunctional Protein, EWS, Is Essential for Early Brown Fat Lineage Determination

Abstract

Summary A recent surge in obesity has given impetus to better understand the mechanisms of adipogenesis, particularly brown adipose tissue (BAT) due to its potential utilization for anti-obesity therapy. Postnatal brown adipocytes arise from early muscle-progenitors but how brown fat lineage is determined is not completely understood. Here, we show that a multifunctional protein EWS (Ewing Sarcoma) is essential for determining brown fat lineage during development. BATs from Ews-null embryos and newborns are developmentally arrested. Ews mutant brown preadipocytes fail to differentiate due to loss of Bmp7 expression, a critical early brown adipogenic factor. We demonstrate that EWS, along with its binding partner YBX1 (Y-box binding protein 1), activates Bmp7 transcription. Depletion of either Ews or Ybx1 leads to loss of Bmp7 expression and brown adipogenesis. Remarkably, Ews-null BATs and brown preadipocytes ectopically express myogenic genes. These results demonstrate that EWS is essential for early brown fat lineage determination.

Brown and Beige Fat: Physiological Roles beyond Heat Generation

“…Consistent with this, brown preadipose cells express many muscle-specific genes and the mitochondrial proteome of brown fat and muscle are highly related to one-another (Forner et al, 2009; Timmons et al, 2007). Interestingly, several factors influence muscle versus brown fat cell fate including PRDM16, C/EBP-β, EHMT1, EWS and ZFP516 (Dempersmier et al, 2015; Kajimura et al, 2009; Ohno et al, 2013; Park et al, 2013; Seale et al, 2008) (Fig. 1).…”

The Ontogeny of Brown Adipose Tissue

“…Deletion of Ewing sarcoma gene Ews results in offspring in which BAT fails to differentiate due to the loss of bone morphogenic protein (Bmp)7 transcription. This defective BAT does, however, express myogenic genes ectopically (82).…”

“…These findings led to the discovery of transcriptional regulator Prdm16 (PRD1-BF1-RIZ1 homologous domain-containing 16), which typifies the BAT lineage as opposed to the myogenic lineage, both arising from a myoblast progenitor and distinctly separate from the white adipogenic pathway (101). Additionally, it has been shown that a multifunctional protein, Ewing sarcoma, is essential for determining BAT lineage (82). Deletion of Ewing sarcoma gene Ews results in offspring in which BAT fails to differentiate due to the loss of bone morphogenic protein (Bmp)7 transcription.…”

The Role of Y-Box Binding Protein 1 in Kidney Injury: Friend or Foe?

“…Moreover, YB-1 is essential for Bmp7 expression during brown adipocyte differentiation in vitro . Furthermore, Ewing Sarcoma (EWS), a multifunctional protein that is essential in determining brown fat lineage during development, forms a complex with YB-1, and this complex directly activates Bmp7 transcription to induce brown adipogenesis [11] (Fig. 2).…”

“…Recently, increasing evidence has shown that YB-1 plays a protective role in acute or chronic kidney injury [6, 10]. Furthermore, YB-1 may be involved in the pathogenesis of obesity-related kidney disease (ORKD) [11]. Unfortunately, no comprehensive review of the role of YB-1 in kidney injury is currently available.…”