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01-01-2021 | Obesity | Article

Senescence-associated β-galactosidase in subcutaneous adipose tissue associates with altered glycaemic status and truncal fat in severe obesity

Authors: Christine Rouault, Geneviève Marcelin, Solia Adriouch, Cindy Rose, Laurent Genser, Marc Ambrosini, Jean-Christophe Bichet, Yanyan Zhang, Florian Marquet, Judith Aron-Wisnewsky, Christine Poitou, Sébastien André, Geneviève Dérumeaux, Michèle Guerre-Millo, Karine Clément

Published in: Diabetologia | Issue 1/2021

Abstract

Aim/hypothesis

Altered adipose tissue secretory profile contributes to insulin resistance and type 2 diabetes in obesity. Preclinical studies have identified senescent cells as a cellular source of proinflammatory factors in adipose tissue of obese mice. In humans, potential links with obesity comorbidities are poorly defined. Here, we investigated adipose tissue senescent status and relationships with metabolic complications in human obesity.

Methods

The study includes a prospective cohort of 227 individuals with severe obesity. A photometric method was used to quantify senescence-associated β-galactosidase (SA-β-gal) activity in paired subcutaneous and omental adipose tissue biopsies obtained during gastric surgery. Gene and secretory profiling was performed in adipose tissue biopsies and in human primary pre-adipocytes in the presence or absence of senolytic drugs targeting senescent cells. Participants were phenotyped for anthropometric and bioclinical variables, metabolic complications and gastric surgery-induced improvement to address relationships with adipose tissue SA-β-gal.

Results

SA-β-gal activity was sevenfold higher in subcutaneous than in omental adipose tissue and not associated with BMI or chronological age. Several factors, including insulin-like growth factor binding protein 3 (IGFBP3), plasminogen activator inhibitor 1 (PAI1), C–C motif chemokine ligand 2 (CCL2) and IL-6, were upregulated in subcutaneous adipose tissue in relation with SA-β-gal (p for linear trend across tertiles <0.05) and in pre-adipocytes cultured with inflammatory macrophage conditioned media. Senolytic treatment reduced SA-β-gal staining and normalised these alterations. In the whole population, subcutaneous adipose tissue SA-β-gal activity was positively associated with serum leptin, markers of insulin resistance and increased trunk fat mass. Metabolic complications, including type 2 diabetes and dyslipidaemia, were more prevalent in patients with high levels of SA-β-gal, but improved with bariatric surgery whatever the initial adipose tissue senescent status.

Conclusions/interpretation

This study highlights a phenotype of senescence in adipose tissue of severely obese individuals, which characterises prominently subcutaneous fat depots. Subcutaneous adipose tissue senescence is significantly linked to altered glucose metabolism and body fat distribution. Elimination of senescent cells through senolytic treatment could alleviate metabolic complications in severely obese people.

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Title: Senescence-associated β-galactosidase in subcutaneous adipose tissue associates with altered glycaemic status and truncal fat in severe obesity
Authors: Christine Rouault
Geneviève Marcelin
Solia Adriouch
Cindy Rose
Laurent Genser
Marc Ambrosini
Jean-Christophe Bichet
Yanyan Zhang
Florian Marquet
Judith Aron-Wisnewsky
Christine Poitou
Sébastien André
Geneviève Dérumeaux
Michèle Guerre-Millo
Karine Clément
Publication date: 01-01-2021
Publisher: Springer Berlin Heidelberg
Keywords: Obesity
Obesity
Bariatric Surgery
Bariatric Surgery
Insulins
Insulins
Published in: Diabetologia / Issue 1/2021
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-020-05307-0

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