Abstract
Objectives:
Angiopoietin-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 findings:
Adenovirus 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.
Conclusion:
ANGPTL2 treatment promotes macrophage accumulation and activation. These results suggest potential mechanisms for insulin resistance.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adenoviridae / genetics
-
Adipose Tissue, White / drug effects
-
Adipose Tissue, White / metabolism*
-
Adipose Tissue, White / pathology
-
Angiopoietin-Like Protein 2
-
Angiopoietin-like Proteins
-
Angiopoietins / genetics
-
Angiopoietins / metabolism*
-
Angiopoietins / pharmacology
-
Animals
-
Antigens, Differentiation / genetics
-
Antigens, Differentiation / metabolism
-
CD11b Antigen / genetics
-
CD11b Antigen / metabolism
-
CD11c Antigen / genetics
-
CD11c Antigen / metabolism
-
Cell Movement / drug effects
-
Diabetes Mellitus, Experimental / genetics
-
Diabetes Mellitus, Experimental / metabolism*
-
Diabetes Mellitus, Experimental / pathology
-
Genetic Vectors
-
Glucose Tolerance Test
-
Humans
-
Insulin Resistance
-
Lipid Metabolism / drug effects
-
Liver / drug effects
-
Liver / metabolism
-
Liver / pathology
-
Macrophages / drug effects
-
Macrophages / metabolism*
-
Macrophages / pathology
-
Male
-
Mice
-
Mice, Inbred C57BL
-
Obesity / genetics
-
Obesity / metabolism*
-
Obesity / pathology
-
Signal Transduction
-
T-Lymphocytes / drug effects
-
T-Lymphocytes / metabolism*
-
T-Lymphocytes / pathology
-
Tumor Necrosis Factor-alpha / biosynthesis
-
Tumor Necrosis Factor-alpha / genetics
Substances
-
ANGPTL2 protein, human
-
Angiopoietin-Like Protein 2
-
Angiopoietin-like Proteins
-
Angiopoietins
-
Angptl2 protein, mouse
-
Antigens, Differentiation
-
CD11b Antigen
-
CD11c Antigen
-
Tumor Necrosis Factor-alpha
-
monocyte-macrophage differentiation antigen
Grants and funding
Kowa Company, Ltd., Japan. The funder provided support in the forms of salaries for authors YS, MO, TS, MY, WY, KY, KI and KM, and a research grant to MA. But the funder did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.