title: Angiopoietin Like Protein 2 (ANGPTL2) Promotes Adipose Tissue Macrophage and T lymphocyte Accumulation and Leads to Insulin Resistance.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  ANGPTL2 treatment promotes macrophage accumulation and activation. These results suggest potential mechanisms for insulin resistance.
authors.affiliation: Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Tokyo New Drug Research Laboratories, Kowa Company, Ltd., Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sasaki
authors.affiliation: Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Tokyo New Drug Research Laboratories, Kowa Company, Ltd., Tokyo, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ohta
authors.affiliation: Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Dhruv
authors.initials: D
authors.lastname: Desai
authors.affiliation: Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Jose-Luiz
authors.initials: JL
authors.lastname: Figueiredo
authors.affiliation: Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Mary C
authors.initials: MC
authors.lastname: Whelan
authors.affiliation: Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Tokyo New Drug Research Laboratories, Kowa Company, Ltd., Tokyo, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Sugano
authors.affiliation: Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Tokyo New Drug Research Laboratories, Kowa Company, Ltd., Tokyo, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Yamabi
authors.affiliation: Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Tokyo New Drug Research Laboratories, Kowa Company, Ltd., Tokyo, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Yano
authors.affiliation: Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Tyler
authors.initials: T
authors.lastname: Faits
authors.affiliation: Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Tokyo New Drug Research Laboratories, Kowa Company, Ltd., Tokyo, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Yabusaki
authors.affiliation: Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Hengmin
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Mlynarchik
authors.affiliation: Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Tokyo New Drug Research Laboratories, Kowa Company, Ltd., Tokyo, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Tokyo New Drug Research Laboratories, Kowa Company, Ltd., Tokyo, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Mizuno
authors.affiliation: Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Masanori
authors.initials: M
authors.lastname: Aikawa
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism; D039521:CD11c Antigen / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005822:Genetic Vectors; D005951:Glucose Tolerance Test; D006801:Humans; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
chemical_list: C485792:ANGPTL2 protein, human; D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; C485793:Angptl2 protein, mouse; D000943:Antigens, Differentiation; D039481:CD11b Antigen; D039521:CD11c Antigen; D014409:Tumor Necrosis Factor-alpha; C036763:monocyte-macrophage differentiation antigen