The clinical significance of PPARα and γ agonism

Abstract

The thiazolidinediones are synthetic ligands for nuclear peroxisome proliferator activated receptors (PPARs). PPARγ is a transcription factor, which in adipose tissue promotes adipocyte differentiation and also induces apoptosis of terminally differentiated insulin-resistant adipocytes. This promotes the appearance of smaller insulin-sensitive cells. PPARγ ctivation also stimulates the genes controlling triglyceride lipolysis, fatty acid uptake and storage in adipose tissue. It induces a diversion of fatty acids away from muscle and influences the expression of adipocytokines leading to improved insulin signalling in muscle and liver. It may also regulate genes involved in insulin signalling. These all result in an increase in insulin sensitivity. PPARγ s also expressed in atherosclerotic lesion foam cells and its activation may exert anti-inflammatory actions and stimulate expression of genes involved in the reverse cholesterol transport pathway. Thiazolidinediones also improve lipoprotein metabolism and this activity is most pronounced for agents that activate PPARα such as may be the case for pioglitazone.