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

Lisa Suwandhi,Anika Böttcher,Heiko Lickert,Fabian J Theis,Ines Pramme-Steinwachs,David Fischer,Andreas Israel,Ingo Burtscher,Christina Lindner,Alexander Braun,Irem Altun,Viktorian Miok,Philippe Schmitt‐Kopplin ,Thomas Walzthoeni,Tobias Wiedemann,Ruth Karlina,Ahmed Khalil ,Matthias Heinig,Martin Elsner,Silke S Heinzmann,Siegfried Ussar

doi:10.1038/s41467-021-21826-9

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.

Highlights

Adipose tissue expansion, as seen in obesity, is often metabolically detrimental causing insulin resistance and the metabolic syndrome
We identify a subset of cells expressing the mature adipocyte marker alanine serine cysteine transporter-1 (Asc-1), which we show to be enriched in the adolescent stromal vascular fraction (SVF) and to favor white over beige adipocyte differentiation
As adipose tissue expansion in adolescent mice is not associated with insulin resistance or inflammation, we aimed to identify cell populations or genes selectively expressed at this age to elucidate mechanisms promoting healthy tissue expansion in adults

Summary

Introduction

As seen in obesity, is often metabolically detrimental causing insulin resistance and the metabolic syndrome. Loss of Asc-1 in subcutaneous preadipocytes resulted in spontaneous differentiation of beige adipocytes in vitro and in vivo This was mediated by a function of the amino acid transporter ASC-1 in proliferating preadipocytes involving the intracellular accumulation of the ASC-1 cargo D-serine. C57Bl/6 mice, among other strains, show a transient peak in the number of thermogenic beige adipocytes ~14 days postpartum, which decreases thereafter, when mice are housed at room temperature[12] These dramatic changes in cellular composition and size of adipose tissues, especially subcutaneous adipose tissue, have not been studied in detail to elucidate novel mechanisms enabling healthy adipose tissue expansion in adults. We show that single-cell transcriptome profiling by single-cell RNA sequencing (scRNA-seq) of adolescent and adult stromal vascular fraction (SVF) from subcutaneous white adipose tissue of C57Bl/6 mice reveals major differences in adipocyte precursor populations. Our data highlight that understanding the regulatory and cellular differences between adolescent and adult adipose tissues will foster the development of pharmacological approaches maintaining adipose tissue function upon weight gain in adult life

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