PPAR delta: a dagger in the heart of the metabolic syndrome

Abstract

Obesity is a growing threat to global health by virtue of its association with insulin resistance, glucose intolerance, hypertension, and dyslipidemia, collectively known as the metabolic syndrome or syndrome X. The nuclear receptors PPARalpha and PPARgamma are therapeutic targets for hypertriglyceridemia and insulin resistance, respectively, and drugs that modulate these receptors are currently in clinical use. More recent work on the less-described PPAR isotype PPARdelta has uncovered a dual benefit for both hypertriglyceridemia and insulin resistance, highlighting the broad potential of PPARdelta in the treatment of metabolic disease. PPARdelta enhances fatty acid catabolism and energy uncoupling in adipose tissue and muscle, and it suppresses macrophage-derived inflammation. Its combined activities in these and other tissues make it a multifaceted therapeutic target for the metabolic syndrome with the potential to control weight gain, enhance physical endurance, improve insulin sensitivity, and ameliorate atherosclerosis.

Figure 1

PPARδ: an inflammatory switch. In the absence of ligand, PPARδ-RXR heterodimers bind to consensus PPAR DNA response elements (PPREs) and repress target gene expression by recruiting corepressors and associated repressive proteins including B cell lymphoma-6 (BCL-6) (top). Upon addition of PPARδ ligand (bottom left), PPARδ-RXR heterodimers undergo a conformational shift. This dismisses the corepressor complex, including BCL-6, in exchange for a complex of coactivator proteins and results in enhanced PPARδ target gene expression. BCL-6, an inflammatory suppressor protein, is thereby liberated to repress inflammatory gene expression. Genetic deletion of PPARδ also releases BCL-6 and repressor complexes from PPARδ target gene promoters, rendering BCL-6 available to suppress inflammation (bottom right). It is unknown whether the expression of direct PPARδ target genes (bottom left and right) has antiinflammatory effects. Target gene expression may occur either by ligand-induced transcriptional activation (large green arrow) or more modestly by transcriptional derepression (small green arrow).

Figure 2

Therapeutic targets of PPARδ in the metabolic syndrome. Receptor activation improves multiple aspects of the metabolic syndrome through tissue- and cell-specific effects. In skeletal muscle, PPARδ regulates fatty acid transport and oxidation, thermogenesis, and the formation of slow-twitch muscle fibers, resulting in enhanced endurance performance. It likewise activates fatty acid transport and oxidation as well as thermogenesis in adipose tissue, retarding weight gain. PPARδ regulates the availability of BCL-6, an inflammatory suppressor protein released upon ligation of PPARδ, thereby functioning as an “antiinflammatory switch” to control macrophage-elicited inflammation and atherogenesis. In the liver, PPARδ activation suppresses glucose production by upregulating the pentose phosphate shunt. PPARδ activation also improves atherogenic dyslipidemia by raising serum HDL cholesterol levels via unclear mechanisms. Additionally, PPARδ activation in the heart enhances contractile function and may improve cardiomyopathy.