GW501516, sometimes called GW1516 or cardarine, is a selective agonist and modulator of PPAR-delta (peroxisome proliferator activated-receptor δ) that is considered an exercise mimetic. Invented or discovered in a partnership between GlaxoSmithKline and Ligand Pharmaceuticals in the 1990s, GW501516 activates AMPK (adenosine-monophosphate-activated protein kinase) and stimulates glucose uptake by skeletal muscle. Potential health promoting effects of GW501516 appear to occur due to increase fatty acid oxidation capacity in skeletal muscle. Though clinically investigated for beneficial properties in metabolic dysfunction and cardiovascular disease, GW50516 was abandoned for development in 2007. Later published studies revealed that higher doses improved fitness or exercise performance dramatically in laboratory animals, and GW50516 was added to WADA’s banned list of “doping compounds” in 2009 as well as the subject of additional safety warnings for athletes.
In human males considered to be obese, GW50516 treatment (PPAR-delta selective agonism) as compared to a PPARalpha agonist demonstrated improvement of several metrics of health and fitness:
The PPARdelta agonist (10 mg o.d. GW501516), a comparator PPARalpha agonist (20 mug o.d. GW590735), and placebo were given in a double-blind, randomized, three-parallel group, 2-week study to six healthy moderately overweight subjects in each group. Metabolic evaluation was made before and after treatment including liver fat quantification, fasting blood samples, a 6-h meal tolerance test with stable isotope fatty acids, skeletal muscle biopsy for gene expression, and urinary isoprostanes for global oxidative stress…..Treatment with GW501516 showed statistically significant reductions in fasting plasma triglycerides (-30%), apolipoprotein B (-26%), LDL cholesterol (-23%), and insulin (-11%), whereas HDL cholesterol was unchanged. A 20% reduction in liver fat content (P < 0.05) and 30% reduction in urinary isoprostanes (P = 0.01) were also observed. Except for a lowering of triglycerides (-30%, P < 0.05), none of these changes were observed in response to GW590735 [a PPARalpha agonist]. The relative proportion of exhaled CO(2) directly originating from the fat content of the meal was increased (P < 0.05) in response to GW501516, and skeletal muscle expression of carnitine palmitoyl-transferase 1b (CPT1b) was also significantly increased.
Researchers speculate that many or all of these effects were due to enhanced fatty acid oxidation (FAO) in skeletal muscle.
Similar to AICAR (AICA-riboside, also called acadesine) GW50516 and related compounds appear promising for treating adiposity, metabolic syndrome, and effects of sedentary lifestyle; both have been touted as “exercise in a pill”. In conjunction with AICAR, the primary action of which is as an AMPK agonist, GW50516 has demonstrated significant increases in exercise endurance in animal studies through a synergistic mechanism when administered together.
Ali et al discuss the role of PPAR-δ in normal physiological function:
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily of ligand-activated transcriptional regulators. PPARdelta has an established role in metabolism, wound healing, and angiogenesis…. [thus far] little is known about its function in endothelial homeostasis. 
Further, PPAR- δagonists represent a hopeful area of study for treating or even preventing vascular issues by promoting endothelial stress resistance:
We have identified an important relationship between PPARdelta, PGC1alpha, and haem oxygenase-1, demonstrating that haem oxygenase-1 induction plays an important role in cytoprotective actions of PPARdelta ligands in vascular endothelium. In light of the protective effects of haem oxygenase-1 against atherogenesis, we suggest that PPARdelta represents a potentially important therapeutic target in the vasculature.
Foreman et al state that "proliferation of the C20 mouse mammary gland cancer cell line is inhibited by ligand activation of PPARbeta/delta due in part to increased apoptosis" suggesting that as an additive therapy, PPARdelta agonists such as GW501516 may be useful for treating certain types of cancer or for promoting continued remission.
Wang et al show that PPARdelta agonists are useful targets for investigation regarding obesity prevention:
[T]argeted activation of PPARdelta in adipose tissue specifically induces expression of genes required for fatty acid oxidation and energy dissipation, which in turn leads to improved lipid profiles and reduced adiposity. ...In vitro, activation of PPARdelta in adipocytes and skeletal muscle cells promotes fatty acid oxidation and utilization. Our findings suggest that PPARdelta serves as a widespread regulator of fat burning and identify PPARdelta as a potential target in treatment of obesity and its associated disorders.
Narkar et al discuss prospective usefulness of GW50516 or similar compounds in treating conditions related to obesity and sedentary lifestyle:
The benefits of endurance exercise on general health make it desirable to identify orally active agents that would mimic or potentiate the effects of exercise to treat metabolic diseases. Although certain natural compounds, such as reseveratrol, have endurance-enhancing activities, their exact metabolic targets remain elusive. We therefore tested the effect of pathway-specific drugs on endurance capacities of mice in a treadmill running test. We found that PPARbeta/delta agonist and exercise training synergistically increase oxidative myofibers and running endurance in adult mice. Because training activates AMPK and PGC1alpha, we then tested whether the orally active AMPK agonist AICAR might be sufficient to overcome the exercise requirement. Unexpectedly, even in sedentary mice, 4 weeks of AICAR treatment alone induced metabolic genes and enhanced running endurance by 44%.
This AMPK-PPARdelta pathway “can be targeted by orally active drugs to enhance training adaptation or even to increase endurance without exercise”.
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