Granzyme B Expression in Visceral Adipose Tissue Associates With Local Inflammation and Glyco-Metabolic Alterations in Obesity

Abstract

Granzyme B (GrB) is a serine protease produced by immune and non-immune cells, able to promote multiple processes, like apoptosis, inflammation, extracellular matrix remodeling and fibrosis. GrB expression in visceral adipose tissue (VAT) was associated with tissue damage, local inflammation and insulin resistance in obesity murine model, but there is no data in humans. Aim of this study was to explore the expression of GrB in VAT from obese subjects in relation to adipose tissue injury, inflammation, metabolic alterations and GrB circulating levels. For this purpose, 85 obese individuals undergoing bariatric surgery and 35 healthy subjects (as control) were recruited at Sapienza University, Rome, Italy. Study participants underwent clinical work-up and routine biochemistry. mRNA expression of GrB in VAT and of a panel of VAT inflammatory markers was analyzed by real-time PCR. Serum GrB levels were measured by Elisa Affymetrix EBIO. We observed that 80% of obese patients expressed GrB mRNA in VAT, and GrB VAT expression was associated with the presence of local inflammation and glucose homeostasis alterations. Moreover, GrB serum levels, which were higher in obese subjects compared to non-obese healthy individuals, were associated with GrB expression in VAT and glyco-metabolic impairment. Our data show, for the first time in humans, that obese subjects with "sick" fat and altered glucose tolerance exhibit GrB expression in VAT, and suggest that GrB might contribute to obesity-related VAT inflammatory remodeling and glucose homeostasis dysregulation. Moreover, increased circulating GrB levels might represent a possible peripheral marker of VAT dysfunction in metabolic diseases.

Keywords: Granzyme B; glyco-metabolic alterations; inflammation; obesity; visceral adipose tissue.

Figure 1

Comparison between Granzyme B (GrB) expression in visceral adipose tissue (VAT) from normo-glycemic obese subjects (n= 62) and IFG/T2D obese subjects (n=23). GrB mRNA expression levels are shown as arbitrary units (A.U.). Data are shown as mean ± standard deviation. *p < 0.05.

Figure 2

The potential contribution of Granzyme B (GrB) to the inflammation and dysfunction of adipose tissue in obese subjects. GrB, produced by different adipose tissue infiltrating inflammatory cells, may contribute to the promotion of the apoptotic, inflammatory and extracellular matrix (ECM) remodeling processes occurring in adipose tissue in obesity, leading to adipose tissue fibrosis and dysfunction, and driving up to glyco-metabolic impairment.