Image_1_PAI-1 Exacerbates White Adipose Tissue Dysfunction and Metabolic Dysregulation in High Fat Diet-Induced Obesity.TIF (123 kB)
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Image_1_PAI-1 Exacerbates White Adipose Tissue Dysfunction and Metabolic Dysregulation in High Fat Diet-Induced Obesity.TIF

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posted on 26.09.2018, 12:53 authored by Lin Wang, Liyuan Chen, Zheran Liu, Yaofang Liu, Mao Luo, Ni Chen, Xin Deng, Yulin Luo, Jing He, Liping Zhang, Michael A. Hill, Rong Li, Jianbo Wu

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.

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