PGRN is a Key Adipokine Mediating High Fat Diet-Induced Insulin Resistance and Obesity through IL-6 in Adipose Tissue

• Published in: Cell metabolism 2012-01, Vol.15 (1), p.38-50
• Main Authors: Matsubara, Toshiya, Mita, Ayako, Minami, Kohtaro, Hosooka, Tetsuya, Kitazawa, Sohei, Takahashi, Kenichi, Tamori, Yoshikazu, Yokoi, Norihide, Watanabe, Makoto, Matsuo, Ei-ichi, Nishimura, Osamu, Seino, Susumu
• Format: Article
• Language: English
• Subjects: 3T3-L1 Cells; Adipokines - metabolism; Adipose Tissue - drug effects; Adipose Tissue - metabolism; Animals; Dexamethasone - pharmacology; Diet, High-Fat; Insulin Resistance; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Intercellular Signaling Peptides and Proteins - pharmacology; Interleukin-6 - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity - blood; Obesity - metabolism; Obesity - prevention & control; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Recombinant Proteins - pharmacology; Thiazolidinediones - pharmacology; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2011.12.002

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. ► PGRN is a key adipokine identified by differential proteome analysis ► PGRN is associated with insulin resistance both in vitro and in vivo ► PGRN mediates systemic insulin resistance by induction of IL-6 in adipose tissues ► Ablation of PGRN prevents HFD-induced insulin resistance and obesity