Increased Interleukin-32 Levels in Obesity Promote Adipose Tissue Inflammation and Extracellular Matrix Remodeling: Effect of Weight Loss

Abstract

Interleukin (IL)-32 is a recently described cytokine involved in the regulation of inflammation. We aimed to explore whether IL-32 could function as an inflammatory and angiogenic factor in human obesity and obesity-associated type 2 diabetes. Samples obtained from 90 subjects were used in the study. Obese patients exhibited higher expression levels of IL-32 in visceral adipose tissue (AT) as well as in subcutaneous AT and peripheral blood mononuclear cells. IL32 was mainly expressed by stromovascular fraction cells, and its expression was significantly enhanced by inflammatory stimuli and hypoxia, whereas no changes were found after the incubation with anti-inflammatory cytokines. The addition of exogenous IL-32 induced the expression of inflammation and extracellular matrix-related genes in human adipocyte cultures, and IL32-silenced adipocytes showed a downregulation of inflammatory genes. Furthermore, adipocyte-conditioned media obtained from obese patients increased IL32 gene expression in human monocyte cultures, whereas the adipocyte-conditioned media from lean volunteers had no effect on IL32 mRNA levels. These findings provide evidence, for the first time, about the inflammatory and remodeling properties of IL-32 in AT, implicating this cytokine in obesity-associated comorbidities.

Adipokine dysregulation and adipose tissue inflammation in human obesity

“…IL‐32 exerts important roles in the pathogenesis of infectious, autoimmune and inflammatory diseases . Increased IL‐32 expression has been found in VAT from patients with obesity promoting inflammation and ECM remodelling and contributing to the development of obesity‐associated comorbidities . Reportedly, the increased circulating levels of IL‐32 in human obesity and obesity‐associated T2D decrease after weight loss .…”

“…136 Reportedly, the increased circulating levels of IL-32 in human obesity and obesity-associated T2D decrease after weight loss. 136 Previous studies have demonstrated that inflammatory cytokines such as IL-1β, interferon (IFN)-γ or TNF-α induce the expression of IL-32 and, in turn, IL-32 also stimulates IL-8, IL-6, IL-1β and TNF-α production, constituting a classical proinflammatory mediator with relevant functions in angiogenesis, ECM remodelling and apoptosis (Figure 3). In this sense, a potential involvement of IL-32 in the development of obesity-associated colon cancer as a proinflammatory and ECM remodelling cytokine has been proposed.…”

Macrophage functions in lean and obese adipose tissue

“…Obesity is associated with increased IL-32 levels, and these are reduced following bariatric surgery 251 . This cytokine may represents a therapeutic target and warrants further study.…”

Dermatopontin, A Novel Adipokine Promoting Adipose Tissue Extracellular Matrix Remodelling and Inflammation in Obesity

“…RNA (2 µg) were reverse transcribed to cDNA according to standard procedures [26]. The mRNA levels for adiponectin (ADIPOQ), collagen (COL)-1A1, COL6A3, decorin (DCN), elastin (ELN), IL1B, IL6, IL8, IL18, kruppel-like factor 4 (KLF4), matrix metalloproteinase (MMP)-2, MMP9, TGFB1, tumour necrosis factor-α (TNF) and tenomodulin (TNMD) were quantified by Real-Time PCR (7300 Real Time PCR System, Applied Biosystems, Foster City, CA, USA) as previously described [26]. Primers and probes (Merck, Darmstadt, Germany) were designed using the software Primer Express 2.0 (Applied Biosystems, Foster City, CA, USA) ( Supplementary Table S1).…”

“…Primers and probes (Merck, Darmstadt, Germany) were designed using the software Primer Express 2.0 (Applied Biosystems, Foster City, CA, USA) ( Supplementary Table S1). The cDNA was amplified as previously described [26]. The endogenous control gene 18S rRNA (Applied Biosystems) was the endogenous control for Real-Time PCR experiments and a relative quantification was obtained using the ∆∆Ct formula.…”