Effects of PPARalpha on cardiac glucose metabolism: a transcriptional equivalent of the glucose-fatty acid cycle?

Cardiovascular disease is exceptionally prevalent in patients with diabetes mellitus and is the most common cause of death. With the emerging pandemic of obesity and resulting metabolic abnormalities, the occurrence of cardiovascular disease is almost nearly certain to increase at a remarkable rate in the near future. Currently, several ligands for the peroxisome proliferator-activated receptor (PPAR) family of nuclear receptors are prescribed as lipid-lowering and insulin-sensitizing drugs. The PPARs are ligand-activated transcription factors that influence the expression of the entire program of fatty acid utilization enzymes. It is believed that these compounds remedy glucose homeostasis and cardiovascular disease by lowering circulating lipid levels, improving the profile of secreted adipokines, as well as via their anti-inflammatory properties. Conversely, overexpression of the PPARalpha isoform in the muscle or heart of mice drives diminished glucose transporter gene expression and glucose uptake into those insulin target tissues. Although the effects of overexpressing PPARalpha in a specific tissue obviously differ from activating PPARalpha in a systemic manner, studies such as this may influence the development of the next generation of PPAR ligands.