Diabetes: New conductors for the peroxisome proliferator-activated receptor γ (PPARγ) orchestra.

The PPARγ nuclear receptor orchestrates fatty acid storage and glucose metabolism by coordinating the expression of genes involved in lipid uptake, adipogenesis and inflammation. It is a target for the insulin-sensitising thiazolidinediones (TZDs) which have been used to treat diabetes since the late nineties. Adverse secondary effects of TZDs have underpinned continued investigations into the molecular details governing PPARγ regulation and new therapeutic approaches which represent the focus of this article. Recent findings position Cdk5 as a lead conductor of PPARγ. Cdk5 regulates PPARγ directly, via phosphorylation, and may also inhibit it indirectly, via phosphorylation and activation of phospholipase D2 (PLD2) which generates the endogenous inhibitor cyclic phosphatidic acid (CPA). Whilst the multifunctional nature of Cdk5 precludes it from therapeutic targeting all is not lost as selective PPARγ modulators (SPPARMs) have shown promising preclinical and clinical results heralding a new generation of drugs to conduct a more refined PPARγ program.