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. ► 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