Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of nuclear hormone receptor superfamily comprising of the following three subtypes: PPARα, PPARγ, and PPARδ. PPARs (PPARα, -γ and -δ) belong to a nuclear receptor transcription factor superfamily that regulates metabolic transcription. Importantly, PPARs play essential roles in the regulation of cellular differentiation, development, and metabolism (carbohydrate, lipid, protein), and tumorigenesis of higher organisms. All PPARs heterodimerize with the retinoid X receptor (RXR) and bind to specific regions on the DNA of target genes. Activation of PPAR-α reduces triglyceride level and is involved in regulation of energy homeostasis. Activation of PPAR-γ enhances glucose metabolism, whereas activation of PPAR-δ enhances fatty acids metabolism.

PPARδ can transcriptionally regulate target genes. PPARδ exerts essential regulatory functions in the heart, which requires constant energy supply. Therefore, PPARδ plays a key role in energy metabolism, controlling not only fatty acid (FA) and glucose oxidation, but also redox homeostasis, mitochondrial biogenesis, inflammation, and cardiomyocyte proliferation. PPARδ signaling is impaired in the heart under various pathological conditions, such as pathological cardiac hypertrophy, myocardial ischemia/reperfusion, doxorubicin cardiotoxicity and diabetic cardiomyopathy. PPARδ deficiency in the heart leads to cardiac dysfunction, myocardial lipid accumulation, cardiac hypertrophy/remodeling and heart failure.

GW 501516 (GW 1516; GSK-516) is a potent and selective PPARδ agonists.

Activation of the receptor will increase fat-burning capacity and muscle production, as it changes the body’s fuel preference from glucose to lipids. GW 501516 shows 1000-fold selectivity over the other human subtypes, PPARα and-γ. In vitro, GW 501516 exerts anti-inflammatory effects in mouse cultured proximal tubular (mProx) cells. Besides, GW 501516 inhibits palmitate- and TNFα-induced increases in MCP-1 mRNA expression in a dose-dependent manner. In vivo, GW 501516 causes impaired bone formation, leading to decreased BMD and deterioration of bone properties in OVX rats. Meanwhile, GW 501516 attenuates interstitial inflammation and proximal tubular cell damage in a protein-overload mouse nephropathy model. What’s more, GW 501516 treatment enhances running endurance and the proportion of succinate dehydrogenase (SDH)-positive muscle fibres in both trained and untrained mice.


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[2] Kintz P, et, al. Drug Test Anal. 2020 Jul;12(7):980-986.