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.
Highlights
Obesity represents a global health problem and its prevalence is rapidly rising [1]
We investigated whether a relationship existed between Granzyme B (GrB) expression in visceral adipose tissue (VAT) of obese patients and their clinical and biochemical parameters, such as body mass index (BMI), waist circumference, SBP, DBP, FBG, FBI, total cholesterol, HDL, triglycerides, LDL, AST, ALT, HbA1c, homeostasis model assessments of insulin resistance (HOMA-IR) and HOMA-b
We found that VAT GrB expression was associated with the presence of glycometabolic alterations, in particular with higher FBG (r= 0.29, p=0.008), HbA1c (r= 0.23, p=0.01) and blood pressure (SBP, r= 0.26 p= 0.019; DBP, r=0.22, p=0.04) levels, as well as with the diagnosis of impaired fasting glucose (IFG; r=0.43, p=0.01) and type 2 diabetes (T2D) (r= 0.31, p=0.04) (Table 3)
Summary
Obesity represents a global health problem and its prevalence is rapidly rising [1]. The excessive accumulation of body fat and the consequent adipose tissue (AT) dysfunction is considered a crucial risk factor for the development of metabolic diseases [2], as type 2 diabetes (T2D) [3, 4].Visceral AT (VAT) plays a major role in regulating systemic energy homeostasis, and in condition of obesity it expands and rearranges its structure. AT produces cytokine and chemokines, promoting tissue infiltration by immune cells, as cytotoxic lymphocytes (cytotoxic T lymphocytes –CTLs- and natural killer –NK- cells) and proinflammatory macrophages [9, 10]. In this inflammatory context, adipocytes undergo apoptosis and extracellular matrix (ECM) endures degradation; the instability of protein composition and the dynamics of ECM proteins lead to VAT remodeling and functional impairment [11, 12]. This “sick” VAT loses its storage capacity releasing free fatty acids in the bloodstream and secretes several bioactive molecules that support local and systemic inflammation, leading to insulin resistance [13,14,15,16]
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