Peroxisome proliferator-activated receptor β/δ (PPAR-β/δ) agonists are a class of compounds that specifically target PPAR-β/δ receptors, activating them. These receptors regulate the expression of multiple genes involved in metabolism, inflammation and cellular function, so artificially manipulating their activation may be useful for therapeutic purposes. GW0742 is one such PPAR-β/δ agonist that has high specificity for this receptor and has been a subject of extensive preclinical research.

 

What Does Activation of PPAR-β/δ Receptors Do?

PPAR-β/δ receptors are normally activated by endogenous lipid ligands, including oxidized and nitrated fatty acid derivatives, cyclopentenone prostaglandins, and polyunsaturated fatty acids. These molecules are produced in response to inflammation or a change in metabolism, so PPAR-β/δ receptor activation typically occurs when these molecules are present.

Once activated, these receptors form a heterodimer with retinoid X receptors (RXR), which modulate gene expression responsible for regulating lipid metabolism, inflammation and oxidative stress. They work to:

• Limit inflammatory activity by inactivating NF-κB and promoting the expression of antioxidant enzymes, reducing reactive oxygen species (ROS) and preventing an exaggerated inflammatory response². This is important as, although inflammation is a natural and necessary response to pathogens or injury, excessive or prolonged inflammation can cause damage to tissues.
• Modulate energy metabolism by responding to dietary lipids and the metabolic products of lipids. Lipid and glucose metabolism is enhanced by improving mitochondrial function, as well as fatty acid oxidation and desaturation pathways. This reduces stress and inflammation of the endoplasmic reticulum, an organelle vital for the correct folding of proteins, and regulates energy balance and metabolic homeostasis.
• Modulate cellular stress responses by preventing apoptosis during inflammation and injury and by enhancing pexophagy, the recycling of old or excess peroxisomes, which helps maintain homeostasis within the cell and reduces oxidative damage³.

 

The importance of this receptor’s role is emphasised by what we have observed in knockout models of PPAR-β/δ. Models that do not express this receptor are prone to cardiovascular issues and suffer from premature death⁴. Without this receptor, broad, negative effects on metabolism and inflammation are seen, which can promote the development of disease⁵.

Normal functioning of this receptor ensures appropriate regulation of inflammation, metabolism and response to stress, helping the body to maintain homeostasis and immune and metabolic functions.

PPAR-β/δ receptors can be activated not only by lipid ligands, but by synthetic ligands as well, meaning that these beneficial effects can be pharmacologically induced. Some PPAR-β/δ agonists, such as seladelpar and elafibranor have already been approved for use as drugs to treat primary biliary cholangitis (PBC) in patients who are intolerant to ursodeoxycholic acid^6,7.

The experimental drug GW0742 is a PPAR-β/δ receptor agonist that has been shown to elicit the same downstream effects as natural PPAR-β/δ activation. It has demonstrated a broad range of benefits that could be useful in the treatment of several diseases.

 

What does GW0742 do?

Since GW0742 activates PPAR-β/δ receptors, mimicking the effect of natural ligands, it can artificially stimulate the beneficial responses associated with the activation of these receptors. Although it has not been tested on humans, researchers have been able to study the activity of this molecule using in vitro tests and with the help of animal models.

 

Metabolic Activity

GW0742 enhances fatty acid oxidation and improves energy homeostasis in various tissues. This shift in metabolism can be beneficial in the treatment of several diseases that are driven or exacerbated by metabolic dysfunction.

In models of obesity, hepatic metabolism is shifted to favour β-oxidation, reducing endoplasmic reticulum stress, inflammation and insulin resistance when treated with GW0742⁸. It also helps to mitigate the metabolic dysregulation brought about by a high-sugar diet^9,10.

In endothelial cells, it reduces glycolysis and fatty acid oxidation in monolayers but enhances fatty acid oxidation during tubulogenesis, supporting vascular repair¹¹. This emphasises how context-dependent the signalling of this receptor can be, reducing certain aspects of metabolism in cells that are already less metabolically active, but enhancing fatty acid oxidation to support the energy demands of cells that are actively promoting angiogenesis.

This compound affects metabolism in models of other diseases as well, its benefits often being owed to a combination of the aforementioned activities, all of which are closely linked. This trend will become more obvious as we look at further examples of research in other therapeutic areas.

 

Renal disorders

Problems with the kidneys are often overlooked due to symptoms being subtle until the later stages of the disease. The damage that is caused to the kidneys is often a result of mechanisms involving metabolic, immune and environmental factors.

In models of diabetic nephropathy, GW0742 has demonstrated renoprotective activity. This is linked to its ability to modulate the immune response, which reduces inflammation and fibrosis¹².

 

Cardiovascular Health

Inflammation, oxidative stress and endothelial dysfunction all contribute to the development of atherosclerosis and hypertension, which, if left untreated, can progress to coronary heart disease, stroke or heart failure. GW0742 has been shown to improve cardiovascular function and mitigate cardiovascular disease.

Although vascular remodelling can be a beneficial process that allows blood vessels adapt to the changing demands of the body, such as during exercise and wound healing, it can become pathological and cause problems such as the thickening, stiffening and narrowing of arteries, which can eventually lead to serious issues such as heart attacks or stroke. GW0742 prevents vascular remodelling in models of hypertension and reduces inflammation, helping to prevent the development of atherosclerosis. It can also act on PPAR-β/δ receptors in the brain, promoting a reduction in sympathetic nerve activity and lowering blood pressure^13,14.

Its ability to reduce inflammation is also seen in models of autoimmune disease, where systemic inflammation damages multiple organs.

 

Autoimmunity

An unchecked immune response causes exaggerated or widespread inflammation. GW0742 can reprogram immunometabolism by promoting oxidative metabolism over a glycolysis-dependent proinflammatory state. This allows energy to be used more efficiently and reduces the production of inflammatory cytokines, modulating the immune system¹⁵.

It has been tested in models for multiple sclerosis and found to reduce clinical symptoms and the formation of new cortical lesions when given during disease progression. This was linked to decreased astroglial and microglial inflammatory activation and lower levels of certain inflammatory cytokines in the brain. It also increased the expression of some myelin-related genes¹⁶.

Chronic hypertension is closely linked to systemic lupus erythematosus (SLE) and is known to contribute to kidney damage. As mentioned earlier, GW0742 can reduce hypertension and thus reduce renal hypertrophy in lupus models, protecting the kidneys from damage. Its renoprotective activity is not limited to its antihypertensive properties. It reduces endothelial dysfunction and vascular oxidative stress by enhancing endothelial nitric oxide synthase activity, decreasing ROS, lowering pro-inflammatory cytokines and enabling the expression of genes related to DNA repair, reducing DNA damage^17,18.

 

Neurodegeneration and Brain Health

In models of neurodegeneration, it improves energy metabolism, reduces inflammation and inhibits apoptosis. A study on Alzheimer’s disease found that GW0742 enhanced fatty acid oxidation in astrocytes, increased hippocampal neurogenesis and reversed memory deficits. The researchers reported that it did not reduce amyloid beta plaques, which would suggest that this benefit is owed to the metabolic support it provides¹⁹. Another study found that it could shift microglia to a phagocytic phenotype that protects neurons from inflammation-induced death. In this particular study, it did reduce amyloid beta load²⁰.

In models of global cerebral ischemia-reperfusion injury, a type of injury that might occur as a result of ischemic stroke or post-cardiac arrest brain injury, it improved cognitive and memory impairments by reducing oxidative stress and inflammatory cytokines²¹. In another model, where an intracerebral haemorrhage was induced, neuroprotective effects were again observed and were thought to be due to anti-inflammatory activity and the activation of anti-apoptotic pathways²².

 

Pulmonary System

GW0742 has been found to exert multiple benefits on the pulmonary system by reducing inflammation, promoting tissue repair and improving vascular function. In models of lipopolysaccharide-induced pulmonary inflammation and bleomycin-induced injury, GW0742 decreased neutrophil infiltration and lowered proinflammatory cytokines, reducing inflammation^2,23.

In a model of emphysema, it repaired damaged alveoli, increased surfactant protein expression and improved lung function²⁴.

 

Cancer

The genetic mutations that arise in cancer cells and lead to their abnormal and harmful behaviours are thought to arise as a result of a variety of intrinsic factors, such as DNA replication errors, as well as extrinsic factors, such as exposure to mutagenic chemicals or radiation. Cancer is linked to metabolic and immune system dysregulation, as well as chronic inflammation, and by correcting these systems, we can sometimes see an improvement in disease.

GW0742 reduces the viability and metabolic activity of cancer cells. In one study, it was found to accomplish this by antagonising thyroid hormone receptors, reducing the viability of granulosa tumour cells and upregulating TRβ expression, a hormone receptor involved in regulating metabolism, liver function and thyroid hormones²⁵.

It also inhibits the growth of MCF7 and UACC903 cell lines, which are breast cancer and melanoma cell lines, respectively²⁶.

Despite the fact that PPAR-β/δ activation is involved in cellular processes that are linked to the development and progression of cancer, research on PPAR-β/δ agonists, such as GW0742 have generally demonstrated inhibitory activity towards cancer cells.

 

Limitations and Safety Considerations

All of the studies conducted on GW0742 to date have been pre-clinical tests. It has not been tested on humans, so although it has yielded promising results in studies so far, we still cannot be sure that it will exert these benefits in humans.

Despite the findings of most of the studies on this compound, which suggest anti-inflammatory activity, higher doses may actually enhance inflammatory cytokines¹³. We also know that it can affect metabolism in different ways depending on context. Since this chemical can produce different downstream effects depending on dose and context, there may be yet undiscovered factors that affect its activity in unpredictable ways. As such, the appropriate therapeutic dose and situational use must be carefully considered.

It has not been noted to have caused any adverse effects in any of the animal models it has been tested on. Studies on models which overexpress PPAR-β/δ receptors have found that it increases the number of oxidative muscle fibres and running endurance of mice, enhances tumour angiogenesis and suppresses the activation of PPAR-α and PPAR-γ^27,28.

 

Conclusion

GW0742 is a PPAR-β/δ receptor agonist that exerts similar benefits to natural PPAR-β/δ agonism, such as improved metabolism, anti-inflammatory activity and cytoprotection. The dysregulation of metabolism and inflammation are components of several diseases such as cardiovascular, autoimmune and neurodegenerative diseases as well as obesity and cancer, making GW0742 a compound of significant interest for use in therapies aimed at treating these diseases.

Although it has been extensively investigated, the research is limited to preclinical studies. The only indication that it could exert any negative effects has come from in vitro studies involving particularly high doses of the ligand or overexpression of the PPAR-β/δ receptor. Given the broad range of therapeutic areas explored and positive data collected so far, GW0742 could potentially become a useful medicine for treating disease, so it will be interesting to see the results of clinical studies on this compound in the future.

 

Researchers can buy GW0742 here.

 

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