PGRN is a key adipokine mediating high fat diet-induced insulin resistance and obesity through IL-6 in adipose tissue.
Adipose tissue secretes adipokines that mediate insulin resistance, a characteristic feature of obesity and type 2 diabetes. By differential proteome analysis of cellular models of insulin resistance, we identified progranulin (PGRN) as an adipokine induced by TNF-α and dexamethasone. PGRN in blood and adipose tissues was markedly increased in obese mouse models and was normalized with treatment of pioglitazone, an insulin-sensitizing agent. Ablation of PGRN (Grn(-/-)) prevented mice from high fat diet (HFD)-induced insulin resistance, adipocyte hypertrophy, and obesity. Grn deficiency blocked elevation of IL-6, an inflammatory cytokine, induced by HFD in blood and adipose tissues. Insulin resistance induced by chronic administration of PGRN was suppressed by neutralizing IL-6 in vivo. Thus, PGRN is a key adipokine that mediates HFD-induced insulin resistance and obesity through production of IL-6 in adipose tissue, and may be a promising therapeutic target for obesity.
Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan.
Toshiya
T
Matsubara
Ayako
A
Mita
Kohtaro
K
Minami
Tetsuya
T
Hosooka
Sohei
S
Kitazawa
Kenichi
K
Takahashi
Yoshikazu
Y
Tamori
Norihide
N
Yokoi
Makoto
M
Watanabe
Ei-Ichi
E
Matsuo
Osamu
O
Nishimura
Susumu
S
Seino
D041721:3T3-L1 Cells; D054392:Adipokines / Q000378:metabolism*; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology; D059305:Diet, High-Fat; D000077155:Granulins; D007333:Insulin Resistance; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000097:blood / Q000378:metabolism* / Q000517:prevention & control; D000077205:Pioglitazone; D000077153:Progranulins; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D054392:Adipokines; D000077155:Granulins; C120204:Grn protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D000077153:Progranulins; D011994:Recombinant Proteins; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D000077205:Pioglitazone