Peroxisome proliferator-activated receptor δ: a multifaceted metabolic player.

ABSTRACT

PURPOSE OF REVIEW Therapeutic strategies to alleviate the growing epidemic of insulin-resistant syndromes (obesity and type 2 diabetes) as well as the conferred cardiovascular disease risk remain sparse. The peroxisome proliferator-activated receptor δ (PPARδ) has emerged as a versatile regulator of lipid homeostasis and inflammatory signaling, making it an attractive therapeutic target for the treatment and prevention of type 2 diabetes and atherosclerosis. RECENT FINDINGS: PPARδ activation regulates lipid homeostasis and inflammatory signaling in a variety of cell types, conferring protection from metabolic disease and atherosclerosis. Specifically, PPARδ activation in the liver stimulates glucose utilization and inhibits gluconeogenesis, which improves insulin resistance and hyperglycemia. In macrophages, PPARδ-specific activation with synthetic agonists inhibits VLDL-induced triglyceride accumulation and inflammation. In mice, PPARδ agonists halt the progression of atherosclerosis and stabilize existing lesions by promoting an anti-inflammatory milieu within the diseased macrovasculature. In humans, PPARδ activation improves insulin sensitivity and reduces atherogenic dyslipidemia via a mechanism complementary to statin monotherapy. SUMMARY: Recent advances in the understanding of PPARδ reveal that activation of this receptor represents a multifaceted therapeutic strategy for the prevention and treatment of insulin-resistant syndromes and atherosclerosis.