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

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.

ANGPTL2 is associated with an increased risk of cardiovascular events and death in diabetic patients

“…Rather than the absolute quantity of adipose tissue, the degree of low-grade inflammation, in which adipose tissue is substantially implicated in type 2 diabetes, seems to play a determining role in insulin resistance [34] and, subsequently, for CV complications in these patients [35]. Indeed, inflammation plays a pivotal role in the promotion of vascular damage in type 2 diabetes [36], and the implication of ANGPTL2 as a proinflammatory cytokine favouring macrophage accumulation and activation in this process therefore seems plausible [15].…”

“…Indeed, inflammation plays a pivotal role in the promotion of vascular damage in type 2 diabetes [36], and the implication of ANGPTL2 as a proinflammatory cytokine favouring macrophage accumulation and activation in this process therefore seems plausible [15]. However, data derived from preclinical research regarding the beneficial [37] or deleterious [15,34] role of ANGPTL2 in insulin resistance remain somewhat contradictory.…”

Serum Angiopoietin–Like Protein 2 Is a Novel Risk Factor for Cardiovascular Disease in the Community

“…Experimental studies have shown that ANGPTL2 works as a proinflammatory mediator. [2][3][4][5] Adipocyte-derived ANGPTL2 is reported to be a key mediator linking obesity to adipose tissue inflammation. An animal study showed that ANGPTL2 in adipose tissue induces chronic adipose tissue inflammation and systemic insulin resistance, 2,3 resulting in an increased CVD risk.…”

“…1,2 It has been reported that ANGPTL2 is a proinflammatory mediator, and it accelerates the development of insulin resistance, endothelial dysfunction, and atherosclerosis in mice. [2][3][4][5] Histological studies of mice and humans have shown that ANGPTL2 is abundantly expressed in visceral adipose tissue, endothelial cells, and macrophages infiltrating atheromatous plaques. [2][3][4][5] In healthy volunteers, an elevated concentration of serum ANGPTL2 was closely associated with obesity, insulin resistance, and increased levels of serum high-sensitivity C-reactive protein (hs-CRP), an inflammatory marker.…”

“…[2][3][4][5] Histological studies of mice and humans have shown that ANGPTL2 is abundantly expressed in visceral adipose tissue, endothelial cells, and macrophages infiltrating atheromatous plaques. [2][3][4][5] In healthy volunteers, an elevated concentration of serum ANGPTL2 was closely associated with obesity, insulin resistance, and increased levels of serum high-sensitivity C-reactive protein (hs-CRP), an inflammatory marker. 3 Because these conditions are well known to be risk factors for the development of cardiovascular disease (CVD), [6][7][8][9][10][11][12] we hypothesized that increased concentrations of serum ANGPTL2 might be involved in the development of CVD through the accumulation of metabolic disorders and inflammation.…”