Angiopoietin Like Protein 2 (ANGPTL2) Promotes Adipose Tissue Macrophage and T lymphocyte Accumulation and Leads to Insulin Resistance.

Yusuke Sasaki,Masanori Aikawa,Jose-Luiz Figueiredo,Katsumi Yabusaki,Wataru Yano,Tomohiro Sugano,Tyler Faits,Hengmin Zhang,Keisuke Inoue,Mary C Whelan,Andrew K Mlynarchik,Ken Mizuno,Masayuki Ohta,Dhruv Desai,Masaki Yamabi

doi:10.1371/journal.pone.0131176

Yusuke Sasaki, Masanori Aikawa + Show 13 more

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https://doi.org/10.1371/journal.pone.0131176

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Abstract

ObjectivesAngiopoietin-like protein 2 (ANGPTL2), a recently identified pro-inflammatory cytokine, is mainly secreted from the adipose tissue. This study aimed to explore the role of ANGPTL2 in adipose tissue inflammation and macrophage activation in a mouse model of diabetes.Methodology/Principal FindingsAdenovirus mediated lacZ (Ad-LacZ) or human ANGPTL2 (Ad-ANGPTL2) was delivered via tail vein in diabetic db/db mice. Ad-ANGPTL2 treatment for 2 weeks impaired both glucose tolerance and insulin sensitivity as compared to Ad-LacZ treatment. Ad-ANGPTL2 treatment significantly induced pro-inflammatory gene expression in white adipose tissue. We also isolated stromal vascular fraction from epididymal fat pad and analyzed adipose tissue macrophage and T lymphocyte populations by flow cytometry. Ad-ANGPTL2 treated mice had more adipose tissue macrophages (F4/80+CD11b+) and a larger M1 macrophage subpopulation (F4/80+CD11b+CD11c+). Moreover, Ad-ANGPTL2 treatment increased a CD8-positive T cell population in adipose tissue, which preceded increased macrophage accumulation. Consistent with our in vivo results, recombinant human ANGPTL2 protein treatment increased mRNA levels of pro-inflammatory gene products and production of TNF-α protein in the human macrophage-like cell line THP-1. Furthermore, Ad-ANGPTL2 treatment induced lipid accumulation and increased fatty acid synthesis, lipid metabolism related gene expression in mouse liver.ConclusionANGPTL2 treatment promotes macrophage accumulation and activation. These results suggest potential mechanisms for insulin resistance.

Highlights

Obesity, a global burden, closely associates with several health problems such as type 2 diabetes, insulin resistance, atherosclerosis, dyslipidemia, cardiovascular disease, hypertension, and cancer [1, 2]
Angptl2 overexpression enhanced Foxo1, G6Pc and Pepck expression in both lean and obese mice (Fig 1F). These results indicate that Angptl2 overexpression worsen both glucose tolerance and insulin sensitivity
The present study demonstrates that adenovirus-mediated human Angiopoietin-like protein 2 (ANGPTL2) expression in lean and diabetic db/db mice induced adipose tissue inflammation and reduced glucose tolerance and insulin sensitivity

Summary

Introduction

A global burden, closely associates with several health problems such as type 2 diabetes, insulin resistance, atherosclerosis, dyslipidemia, cardiovascular disease, hypertension, and cancer [1, 2]. The recent knowledge, has recognized the adipose tissue as one of the key organs that regulate systemic metabolism [3,4,5,6]. Activated macrophages may induce chronic low-grade inflammation in the adipose tissue, leading to systemic inflammation and insulin resistance [4,5,6,7,8,9,10]

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