Asc-1 regulates white versus beige adipocyte fate in a subcutaneous stromal cell population

Abstract

Adipose tissue expansion, as seen in obesity, is often metabolically detrimental causing insulin resistance and the metabolic syndrome. However, white adipose tissue expansion at early ages is essential to establish a functional metabolism. To understand the differences between adolescent and adult adipose tissue expansion, we studied the cellular composition of the stromal vascular fraction of subcutaneous adipose tissue of two and eight weeks old mice using single cell RNA sequencing. We identified a subset of adolescent preadipocytes expressing the mature white adipocyte marker Asc-1 that showed a low ability to differentiate into beige adipocytes compared to Asc-1 negative cells in vitro. Loss of Asc-1 in subcutaneous preadipocytes resulted in spontaneous differentiation of beige adipocytes in vitro and in vivo. Mechanistically, this was mediated by a function of the amino acid transporter ASC-1 specifically in proliferating preadipocytes involving the intracellular accumulation of the ASC-1 cargo D-serine.

Single cell functional genomics reveals plasticity of subcutaneous white adipose tissue (WAT) during early postnatal development

“…While such contaminating cells are clearly resolved in single cell analyses, this minor contamination might have contributed to some of the gene expression changes observed in bulk RNA-seq analyses. Notwithstanding these limitations, our findings expand on previous work [ 13 , 36 , 41 , 102 , [117] , [118] , [119] ] and provide a resource that will lead to a better understanding of WAT development and metabolic disease origins.…”

ASC‐1 transporter‐dependent amino acid uptake is required for the efficient thermogenic response of human adipocytes to adrenergic stimulation

“…ASC‐1 was described earlier as a cell surface marker of white adipocytes in humans and mice [26,46]. In mice, its presence in a subpopulation of subcutaneous preadipocytes of adolescent adipose tissue and in differentiating preadipocyte cell lines could even inhibit beige differentiation [47]. In a human study, slightly more ASC‐1 mRNA was detected in SC white tissue samples obtained by needle biopsies from the neck than in DN brown samples [36] and this was reflected in the ASC‐1 protein levels we found in SC and DN tissue lysates (Fig.…”

The neutral amino acid transporter SLC7A10 in adipose tissue, obesity and insulin resistance

“…Supporting that SLC7A10 is important for serine transport in adipocytes, another study in mice found that loss of Slc7a10, not in mature adipocytes ( Figure 2B ), but in proliferating preadipocytes increased intracellular D-serine accumulation ( Suwandhi et al, 2021 ), suggesting that Slc7a10 may also be important for export of D-serine (at least when preadipocytes are programmed towards a beige phenotype) ( Figure 2C ). The bidirectional transport of amino acids is possible since SLC7A10 functions as an antiporter, where it transports one small neutral amino acid in one direction coupled to an amino acid in the opposite direction ( Fukasawa et al, 2000 ).…”

“…In the present review we focus on the HAT SLC7A10, which has a particularly high expression in adipocytes and emerged as an important player in metabolic diseases related to obesity, insulin resistance and type 2 diabetes ( Small et al, 2011 ; Jersin et al, 2021 ). Following a brief summary of key roles of adipose tissue in metabolic homeostasis, we discuss the current knowledge of how SLC7A10 modulates adipocyte function ( Arianti et al, 2021 ; Jersin et al, 2021 ; Suwandhi et al, 2021 ) and propose avenues for further research.…”