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 1

General design of the translational study and clinical characteristics of the 15 CTRL and 17 PMOS women.

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General design of the translational study and clinical characteristics o...
(A) General design of clinical and adipose tissue phenotyping studies. ABD-AT, s.c. abdominal adipose tissue; GF-AT, gluteofemoral adipose tissue; snRNA-seq, single-nuclei RNA-seq. (B) Insulin; glucose and free fatty acids (FFA) were quantified in serum samples collected during an OGTT test. n = 15 PMOS and 17 CTRL. *P < 0.05 Wilcoxon test between group at specific time point. AUC for each group have been reported as total area under the curve, plotted and compared using an unpaired 2-tailed t test. (C) IL-8 was measured in the serum samples of 15 PMOS and 17 CTRL women. *P < 0.05 unpaired 2-tailed t test. (D) Adipocyte size was determined by microscopy. Average of 100 adipocytes per sample is represented in ABD and GF depot. CTRL group samples are represented in green, and PMOS group samples are represented in pink. *P < 0.05 paired 2-tailed t test. (E) Correlation matrix of relevant clinical parameters and ABD and GF-AT adipocyte size. n = 15 PMOS and 17 CTRL. 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.