PAI-1 Exacerbates White Adipose Tissue Dysfunction and Metabolic Dysregulation in High Fat Diet-Induced Obesity

Abstract

Background: Plasminogen activator inhibitor (PAI)-1 levels and activity are known to increase during metabolic syndrome and obesity. In addition, previous studies have implicated PAI-1 in adipose tissue (AT) expansion while also contributing to insulin resistance. As inflammation is also known to occur in AT during obesity, we hypothesized that in a high-fat diet (HFD)-induced obese mouse model PAI-1 contributes to macrophage-mediated inflammation and metabolic dysfunction.Methods: Four- to five-weeks-old male C57B6/6J mice were fed a HFD (45%) for 14 weeks, while age-matched control mice were fed a standard laboratory chow diet (10% fat). Additional studies were performed in PAI-1 knockout mice and wild type mice treated with an inhibitor (PAI-039) of PAI-1. Macrophage polarization were measured by real time PCR.Results: HFD mice showed increased expression of PAI-1 in visceral white AT (WAT) that also displayed increased macrophage numbers. PAI-1 deficient mice exhibited increased numbers of anti-inflammatory macrophages in WAT and were resistant to HFD-induced obesity. Similarly, pharmacological inhibition of PAI-1 using PAI-039 significantly decreased macrophage infiltration in WAT and improved metabolic status in HFD-induced wild-type mice. Importantly, the numbers of M1 macrophages appeared to be increased by the HFD and decreased by either genetic PAI-1 depletion or PAI-039 treatment.Conclusions: Collectively, our findings provide support for PAI-1 contributing to the development of inflammation in adipose tissue and explain the mechanism of inflammation modulated by PAI-1 in the disordered metabolism in HFD-induced obesity.

Transplantation of adipose tissue lacking PAI-1 improves glucose tolerance and attenuates cardiac metabolic abnormalities in high-fat diet-induced obesity

“…PAI-1 is mainly produced within white adipose tissue, with adipocytes being the major source of production for circulating PAI-1 in obese individuals. Previous studies have revealed that PAI-1 deficiency protects against obesity and metabolic dysfunction [2,7]. Indeed, our recent study demonstrated that genetic deletion and pharmacological inhibition of PAI-1 improve glucose tolerance and insulin sensitivity [2], which was supported by reduced inflammation and macrophage infiltration into WAT.…”

“…Previous studies have revealed that PAI-1 deficiency protects against obesity and metabolic dysfunction [2,7]. Indeed, our recent study demonstrated that genetic deletion and pharmacological inhibition of PAI-1 improve glucose tolerance and insulin sensitivity [2], which was supported by reduced inflammation and macrophage infiltration into WAT. Further supporting a relationship between PAI-1 and metabolism, an increased release of cytokines has been linked to PAI-1 expression in human adipose tissue explants and obese mice.…”

“…Abnormalities in adipose tissue (AT) lead to insulin resistance and contribute to the development of obesity and T2DM [1]. Various consequences of AT dysfunction occur and include the accumulation of adipokines such as leptin, adipocyte-specific secretory factor/resistin, and plasminogen activator inhibitor-1 (PAI-1) [2,3]. These adipokines regulate multiple and crucial aspects of whole-body physiology and energy metabolism.…”

Adipose Tissue Inflammation and Metabolic Disorders

“…Other differences between the two types of adipose tissues are the depot localization, profile of secreted molecules, cell population, vascularization and also innervation [2][3][4]. While both of these adipose tissue groups contribute a significant role in maintaining systemic homeostasis, WAT is the primary site of metabolic dysregulation in many metabolic diseases [5,6].…”

Serum biomarkers in patients with stable and exacerbated COPD‐bronchiectasis overlap syndrome

“…PAI‐1 is the main inhibitor for fibrinolysis. PAI‐1 plays an important role in the pathogenesis of arterial and venous thrombosis at high concentrations, and has been associated with obesity, insulin resistance, diabetes and premature aging 12‐14 . All of these conditions are common in patients with COPD 15,16 .…”