Impaired adipogenesis and lipid storage capacity in subcutaneous adipose tissue of patients with PMOS
Adeline Divoux, Edina Erdos, Katie L. Whytock, Timothy F. Osborne, Steven R. Smith
Adeline Divoux, Edina Erdos, Katie L. Whytock, Timothy F. Osborne, Steven R. Smith
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Research Article Cell biology Metabolism

Impaired adipogenesis and lipid storage capacity in subcutaneous adipose tissue of patients with PMOS

Abstract

Women with PMOS (formally termed PCOS) have an overall increased prevalence of metabolic syndrome (MetS) and central obesity. To help determine whether there might be changes in s.c. adipose tissue (SAT) associated with these abnormalities, we performed single-nuclei and scRNA-seq on SAT biopsies from 15 premenopausal PMOS women with signs of insulin resistance and 17 healthy BMI-matched controls. In SAT from PMOS versus control we observed a higher ratio of fibrotic versus insulin sensitive adipocytes and a higher ratio of mesenchymal stem cells (MSCs) to preadipocytes. Further in silico analysis suggested that preadipocytes in PMOS are more inflammatory and have a reduced capacity for differentiation. Slit homolog 2 (SLIT2), which is expressed at higher levels in MSC from PMOS, decreased adipogenesis in cell culture assays likely through its interaction with the Roundabout homolog 1 and homolog 2 (ROBO1/2) receptor expressed on the surface of preadipocytes. These new observations are consistent with higher SLIT/ROBO signaling, leading to reduced differentiation in the SAT of PMOS as an underlying mechanism for the aberrant ectopic fat accumulation and the development of MetS in PMOS.

Authors

Adeline Divoux, Edina Erdos, Katie L. Whytock, Timothy F. Osborne, Steven R. Smith

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Figure 3

Association between testosterone level and SAT gene expression and cell population proportion in ABD and GF-AT.

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Association between testosterone level and SAT gene expression and cell ...
(A) Heatmaps representation of the correlations between the gene modules identified by WGCNA analysis and relevant clinical parameters in ABD and GF-AT. (B) Intersection plot showing the number of common genes between the turquoise module (in ABD-AT) and the blue module (in GF-AT). Pathway analysis reveals transcription factor (TRRUST) and pathways enriched in these common genes. EMT, Epithelial Mesenchymal Transition. (C) Correlation matrix of cell proportions and testosterone (total, free and bioavailable) and SHBG level. Only significant correlations (P < 0.05) are represented by a dot; negative correlations are depicted in green and positive correlations are depicted in pink. The size of the dot indicates the R coefficient. (D) Spearman correlation plots between total testosterone and relevant cell clusters in ABD and GF-AT depot, in combined group. PMOS participants are represented in pink; CTRL participants are represented in green. See also Supplemental Figure 2. (E) Correlation matrix of ectopic fat accumulation markers and adipogenesis-related genes in ABD and GF-SAT depot. Only significant correlations (P < 0.05) are represented by a dot; negative correlations are depicted in brown, and positive correlations are depicted in green. The size of the dot indicates the R coefficient.