Metabolically-Unhealthy Obesity Is Associated With Increased Adipose Tissue Inflammatory Gene Expression and 24-Hour Plasma Concentrations of PAI-1, but Not Other Inflammatory Cytokines

Abstract

Insulin resistant glucose metabolism is the most common metabolic complication associated with obesity; however, a subset of people with obesity have normal insulin sensitivity and are considered to be metabolically healthy. In rodent models of obesity, adipose tissue (AT) inflammation contributes to whole-body insulin resistance mediated, at least in part, by production of proinflammatory cytokines that are secreted into the systemic circulation. We therefore hypothesized that AT markers of inflammation and plasma concentrations of inflammatory cytokines would be greater in people with metabolically-unhealthy obesity (MUO) and insulin-resistant glucose metabolism than in insulin-sensitive people with metabolically-healthy obesity (MHO). We measured AT expression of genes that encode for proinflammatory proteins by using RNA sequencing and plasma cytokine concentrations assessed serially over 24 hours by using multiplex assays in: i) 28 people with MHO (defined as normal glucose tolerance and normal insulin-stimulated glucose disposal assessed using the hyperinsulinemic-euglycemic clamp procedure [48 ± 2 µmol/kg fat-free mass/min]); and ii) 28 people with MUO (defined as prediabetes and impaired insulin-stimulated glucose disposal [28 ± 1 µmol/kg fat-free mass/min]). AT markers of inflammation (expression of SERPINE1, CCL3, CCL5, CD68, CD74, MRC1, and CXCL16) were greater in the MUO than in the MHO group (all P < 0.05). However, the 24-hour plasma concentration areas-under-the curve (AUC) for TNFα, MCP-1, IL-6, RANTES, IL-1β, IL-17, and IFN-γ were not different between MHO and MUO groups. In contrast, 24-hour plasma plasminogen activator inhibitor 1 (PAI-1) AUC was greater in the MUO (1,759 ± 169 ng/mL x h) group than in the MHO (716 ± 85 ng/mL x h) group (P < 0.001) and plasma PAI-1 was inversely correlated with whole-body insulin sensitivity (r= -0.57; P < 0.001). We conclude that, with the exception of PAI-1, AT inflammation does not contribute to whole-body insulin resistance by increasing systemic circulating inflammatory cytokine levels. However, increased AT production of PAI-1 is associated with whole-body insulin resistance in people with MUO.