Subcutaneous Adipose Tissue Cell-derived Cytokines Are Early Markers of Impaired Glucose Tolerance in Severe Obesity

Abstract

Background Excessive adiposity provides an inflammatory environment. However, in people with severe obesity, how systemic and local adipose tissue (AT)-derived cytokines contribute to worsening glucose tolerance is not clear. Methods 92 severely obese (SO) individuals undergoing bariatric surgery were enrolled and subjected to detailed clinical phenotyping. Following an Oral Glucose Tolerance Test, participants were included in three groups, based on the presence of normal glucose tolerance (NGT), impaired glucose tolerance (IGT) or Type 2 Diabetes (T2D). Serum and subcutaneous AT (SAT) biopsies were obtained and Mesenchymal Stem Cells (MSCs) were isolated, characterized and differentiated in adipocytes in vitro. TNFA and PPARG mRNA levels were determined by qRT-PCR. Circulating, adipocyte- and MSC-released cytokines, chemokines and growth factors were assessed by multiplex ELISA. Results Serum levels of IL-9, IL-13 and MIP-1β were increased in SO individuals with T2D, as compared with those with either IGT or NGT. At variance, SAT samples obtained from SO individuals with IGT displayed levels of TNFA which were 3-fold higher compared to those with NGT, but not different from those with T2D. Elevated levels of TNFα were also found in differentiated adipocytes, isolated from the SAT specimens of individuals with IGT and T2D, compared to those with NGT. Consistent with the pro-inflammatory milieu, IL-1β and IP-10 secretion was significantly higher in adipocytes from individuals with IGT and T2D. Moreover, increased levels of TNFα, both mRNA and secreted protein, were detected in MSCs obtained from IGT and T2D, compared to NGT SO individuals. Exposure of T2D and IGT–derived MSCs to quercetin reduced TNFα levels and was paralleled by a significant decrease of the secretion of inflammatory cytokines. Conclusion In severe obesity, enhanced SAT-derived inflammatory phenotype is an early step in the progression toward T2D and may be, at least in part, attenuated by quercetin.

Lifestyle and Dietary Habits Affect Plasma Levels of Specific Cytokines in Healthy Subjects

“…The BMI has the heaviest impact on the correlation between LGCI-related risk factors and cytokines. Indeed, many studies have characterized the cytokine profile in subjects with obesity and/or severe obesity detecting differences compared with normal weight individuals (10,27,28). In this study, we have found that, despite the removal from the analysis of subjects with obesity, BMI was still significantly associated with CRP levels.…”

“…Obesity drives the pathological expansion of the adipose tissue, which harbors enlarged hypertrophic adipocytes, impaired vasculogenesis, and enhanced fibrosis and hypoxia. Dysfunctional adipose tissue secretes pro-inflammatory cytokines that promote local and systemic inflammation, contributing to the onset of obesity-related diseases (8)(9)(10). The loosening of the cytokine balance between the pro-inflammatory and anti-inflammatory control is a characteristic feature also of aging.…”

Circulating Inflammation Markers Partly Explain the Link Between the Dietary Inflammatory Index and Depressive Symptoms

“…Still, here we aimed to identify specific associations of DII with psychological domains strictly related to depressive symptoms, which prompted us to perform sensitivity analyses adjusting for resilience. Similarly, adiposity may play a mediator role since it can be clearly influenced by fat-rich (proinflammatory) diets and adipose tissues contribute to the secretion of inflammatory cytokines, 37 hence we included RFM adjustment in sensitivity models to detect potential fat-independent associations. A detailed description of these variables is reported in Supplementary Methods.…”