Angiopoietin-like protein 2 promotes chronic adipose tissue inflammation and obesity-related systemic insulin resistance.
Recent studies of obesity have provided new insights into the mechanisms underlying insulin resistance and metabolic dysregulation. Numerous efforts have been made to identify key regulators of obesity-linked adipose tissue inflammation and insulin resistance. We found that angiopoietin-like protein 2 (Angptl2) was secreted by adipose tissue and that its circulating level was closely related to adiposity, systemic insulin resistance, and inflammation in both mice and humans. Angptl2 activated an inflammatory cascade in endothelial cells via integrin signaling and induced chemotaxis of monocytes/macrophages. Constitutive Angptl2 activation in vivo induced inflammation of the vasculature characterized by abundant attachment of leukocytes to the vessel walls and increased permeability. Angptl2 deletion ameliorated adipose tissue inflammation and systemic insulin resistance in diet-induced obese mice. Conversely, Angptl2 overexpression in adipose tissue caused local inflammation and systemic insulin resistance in nonobese mice. Thus, Angptl2 is a key adipocyte-derived inflammatory mediator that links obesity to systemic insulin resistance.
Tabata
Mitsuhisa
M
Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
Kadomatsu
Tsuyoshi
T
Fukuhara
Shigetomo
S
Miyata
Keishi
K
Ito
Yasuhiro
Y
Endo
Motoyoshi
M
Urano
Takashi
T
Zhu
Hui Juan
HJ
Tsukano
Hiroto
H
Tazume
Hirokazu
H
Kaikita
Koichi
K
Miyashita
Kazuya
K
Iwawaki
Takao
T
Shimabukuro
Michio
M
Sakaguchi
Kazuhiko
K
Ito
Takaaki
T
Nakagata
Naomi
N
Yamada
Tetsuya
T
Katagiri
Hideki
H
Kasuga
Masato
M
Ando
Yukio
Y
Ogawa
Hisao
H
Mochizuki
Naoki
N
Itoh
Hiroshi
H
Suda
Toshio
T
Oike
Yuichi
Y
D041721:3T3-L1 Cells; D052436:Adipose Tissue, White / Q000378:metabolism*; D050154:Adiposity / Q000502:physiology; D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D016023:Integrins / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism*
C485792:ANGPTL2 protein, human; D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; C485793:Angptl2 protein, mouse; D016023:Integrins