Identification of inducible brown adipocyte progenitors residing in skeletal muscle and white fat

Abstract

Brown fat is specialized for energy expenditure and has therefore been proposed to function as a defense against obesity. Despite recent advances in delineating the transcriptional regulation of brown adipocyte differentiation, cellular lineage specification and developmental cues specifying brown-fat cell fate remain poorly understood. In this study, we identify and isolate a subpopulation of adipogenic progenitors (Sca-1 + /CD45 − /Mac1 − ; referred to as Sca-1 + progenitor cells, ScaPCs) residing in murine brown fat, white fat, and skeletal muscle. ScaPCs derived from different tissues possess unique molecular expression signatures and adipogenic capacities. Importantly, although the ScaPCs from interscapular brown adipose tissue (BAT) are constitutively committed brown-fat progenitors, Sca-1 + cells from skeletal muscle and subcutaneous white fat are highly inducible to differentiate into brown-like adipocytes upon stimulation with bone morphogenetic protein 7 (BMP7). Consistent with these findings, human preadipocytes isolated from subcutaneous white fat also exhibit the greatest inducible capacity to become brown adipocytes compared with cells isolated from mesenteric or omental white fat. When muscle-resident ScaPCs are re-engrafted into skeletal muscle of syngeneic mice, BMP7-treated ScaPCs efficiently develop into adipose tissue with brown fat-specific characteristics. Importantly, ScaPCs from obesity-resistant mice exhibit markedly higher thermogenic capacity compared with cells isolated from obesity-prone mice. These data establish the molecular characteristics of tissue-resident adipose progenitors and demonstrate a dynamic interplay between these progenitors and inductive signals that act in concert to specify brown adipocyte development.

Uncoupling protein 1 expression in adipocytes derived from skeletal muscle fibro/adipogenic progenitors is under genetic and hormonal control

“…Previous studies have shown that adipocyte precursors residing in WAT and skeletal muscle from C57Bl/6 and Sv/129 mice differ in their potential to express UCP1 following differentiation 32, 37. In line with these findings, we observed higher levels of UCP1 in skeletal muscle FAPs isolated from Sv/129 mice than in those isolated from C57Bl/6 mice after the brown adipogenic treatment ( Figure 4A).…”

“…Analysing both polyclonal and monoclonal cell cultures, we could not identify any MP subpopulation with adipogenic potential. Our results further support previous work showing that MPs are committed to the myogenic fate30, 31, 49, 51 and that FAPs are the adipocyte precursor population residing in murine30, 31, 32, 52 and human24, 51, 53, 54 adult skeletal muscle. Although we cannot reject the hypothesis that a small subpopulation of satellite cells could form brown adipocytes—as shown by Yin et al 27.…”

“…Firstly, Ucp1 expression in response to BMP7 in FAPs differentiated in the absence of a PPARg agonist has been reported to be highly dependent on the serum batch used 55. This could explain the low Ucp1 expression in protocols that do not include the PPARg agonist rosiglitazone in the differentiation medium 29, 31, 32. Moreover, we show that the thyroid hormone T 3 is critical for UCP1 expression in differentiated FAPs, and this hormone was not always included in the differentiation medium 30, 31.…”

Loss of periostin occurs in aging adipose tissue of mice and its genetic ablation impairs adipose tissue lipid metabolism

“…To test whether aging negatively affects the function of adipose tissue‐resident stem/progenitor cells, we isolated adipogenic progenitors cells (APCs) from BAT and inguinal WAT (iWAT) by flow cytometry for microarray‐based analysis (Schulz et al, 2011). Aside from a number of genes belonging to an imprinted gene network that has been linked to adiposity (Morita et al, 2016), we found the gene encoding for periostin ( Postn ) to be the most strongly downregulated candidate gene (Figure 1a,b).…”

“…AT‐derived progenitor cells were isolated as described (Schulz et al, 2011; Steinbring, Graja, Jank, & Schulz, 2017). A detailed description of the procedures is supplied in the Supporting Information.…”