Rationally designed PPARδ-specific agonists and their therapeutic potential for metabolic syndrome.

The peroxisome proliferator-activated receptor (PPAR) family of nuclear receptors regulates a wide variety of lipid-related genes, including those responsible for adipose differentiation, cholesterol metabolism, and lipidmetabolism and transport. There are three different PPAR nuclear receptors, with different localizations and specializations. PPARα is primarily expressed in the liver, heart, kidney, and muscle, and is involved in lipid metabolism, whereas PPARγ is expressed in adipose tissues and is a target for treating type II diabetes because of its role in insulin sensitization (1, 2). The third receptor, PPARδ, is ubiquitously expressed, and activation in animal models improves lipid homeostasis and insulin sensitivity (3). These regulatory roles make the PPAR nuclear receptors attractive targets for treating dyslipidemia and type II diabetes. Fibrates and thiazolidinediones (TZDs) are used to treat these conditions by selectively activating PPARα and PPARγ, respectively. However, there are health issues caused by long-term use of these drugs, and thus a safe compound that specifically targets PPARδ could potentially aid in treatment of both hyperlipidemia and type II diabetes (2, 4). In PNAS, Wu et al. develop a highly selective set of compounds that target PPARδ and discover a mechanism of ligand specificity, which may be unique to the PPAR nuclear receptor family and could aid in further development of highly specific PPAR ligands (5). The PPAR family of nuclear receptors is implicated in metabolic syndrome, which affects 35% of the United States population and is a major risk factor for developing cardiac disease and type II diabetes (6). Metabolic syndrome is defined by a cluster of risk factors, such as obesity, elevated serum triglycerides, dyslipidemia, hypertension, and elevated glucose levels in the fasting state. TZDs activate PPARγ and reduce glucose levels, improve insulin sensitivity, and can improve lipid homeostasis. However, TZD use can increase adipogenesis and lead to increased obesity in patients, and can also increase risk for cardiac disease and stroke (4). Because PPARδ regulates lipid transport and uptake, research has been conducted on the efficacy of compounds that act as agonists or partial agonists for both PPARδ and PPARγ, or as panagonists for all three PPARs, but no such compounds have successfully gone through trials (7). The only promising PPARδ agonist thus far is GW501516, which has 1,000-fold specificity for PPARδ over the αand γ-receptors; its extremely high affinity makes it a strong activator, and binding of the compound induces recruitment of a transcriptional coactivator, PGC-1α (8). In preclinical trials, treatment with this agonist increased lipid metabolism and increased HDL levels, while preventing weight gain on a high-fat diet in mice, and protected animals against developing type II diabetes (8). Despite these promising indications that it could treat metabolic syndrome, treated mice and rats developed cancer and further development ceased (9). It is unclear whether activation of PPARδ or an off-target effect was responsible for carcinogenesis, and a more highly specific ligand is needed to enable researchers to definitively show whether PPARδ activation is a viable therapeutic target, or if activation is too dangerous.