Subtherapeutic dose of pioglitazone reduces expression of inflammatory adipokines in db/db mice.

Agonists of the thiazolidinedione class of peroxisome proliferator-activated receptor-gamma exhibit both insulin-sensitizing and anti-inflammatory effects. We hypothesized that pioglitazone might be able to exert its anti-inflammatory properties at a lower dose than that required for its insulin-sensitizing effect. In order to investigate this hypothesis, we evaluated the effects of pioglitazone on inflammatory as well as metabolic biomarkers in serum and white adipose tissue (WAT) at 2 different doses. Female db/db mice were treated orally with therapeutic (30 mg/kg) and subtherapeutic (3 mg/kg) doses of pioglitazone for 14 days followed by an oral glucose tolerance test. Other parameters measured were inflammatory markers such as tumor necrosis factor (TNF)-alpha, interleukin-6 (IL-6) and metabolic biomarkers in serum (insulin, glucose and adiponectin). Moreover, adiponectin, fatty acid-binding protein (aP2) and lipoprotein lipase (LPL) mRNA expression in WAT were determined by real-time PCR. A subtherapeutic dose of pioglitazone significantly suppresses the expression of TNF-alpha and IL-6 mRNA in WAT, but does not alter the serum glucose, insulin and WAT expression of adiponectin, adipocyte aP2 and LPL. A therapeutic dose of pioglitazone improves insulin sensitivity, enhances LPL, aP2 and adiponectin expression, and also suppresses TNF-alpha and IL-6 expression. In conclusion, the current study indicates that the anti-inflammatory effect of pioglitazone is produced at a subtherapeutic dose, which is considerably lower than the dose needed to produce any desired metabolic effects. Anti-inflammatory effects of pioglitazone may precede its insulin-sensitizing effects in db/db mice.