endurobol (GW501516) / Ligand, GSK - LARVOL DELTA

Investigating the Role of PPAR Delta in Alloreactive T Cells (ASH 2024) - "Culturing agonist-treated cells with 3H-palmitate demonstrated an increase in 3H2O production that was inhibitable by etomoxir, confirming a GW501516-driven increase in FAO in allogenically-stimulated cells. Thus, alloreactive CD8 donor T cells appear to adapt to loss of PPARδ through the upregulation of glutamine metabolism and an increased reliance on metabolid fuels provide through the panthothenate pathway. Future work will interrogate the vitamin B5/CoA axis in PPARδ KO alloreactive CD8 T and examine potential upstream influence by AMPK and mTOR, the two primary energy regulators of T cells, with the long-term goal of pinpointing therapeutic targets in reducing GVHD."

Bone Marrow Transplantation • Graft versus Host Disease • Immunology • AMPK • CD4 • CD8 • CPT1A • PLIN2

GLP-1 receptor agonist protects glucose-stimulated insulin secretion in pancreatic β-cells against lipotoxicity via PPARδ/UCP2 pathway. (PubMed, Cell Mol Life Sci) - "C57BL/6J mice fed a high-fat diet (HFD) for 12 weeks were treated with exenatide (Exe), GW501516 (GW, a PPARδ agonist), saline, or dimethyl sulfoxide (DM) for 8 weeks, followed by phenotypic assessments. Moreover, Ex-4 failed to reverse mitochondrial function or GSIS in pancreatic β-cells with UCP2 overexpression despite an increase in PPARδ expression. Thus, GLP-1RA Exe/Ex-4 preserved GSIS against lipotoxicity in pancreatic β-cells by modulating mitochondrial function through the PPARδ/UCP2 axis."

Journal

Fatty acid metabolism suppresses neonatal cardiomyocyte proliferation by increasing PDK4 and HMGCS2 expression through PPARδ. (PubMed, PLoS One) - "GW501516, a peroxisome proliferator-activated receptor δ (PPARδ) activator, also upregulated fatty acid metabolism genes and disturbed NRCM proliferation, whereas GSK3787, a PPARδ inhibitor, recovered FA-induced the cell cycle arrest. Furthermore, overexpression of PDK4 or HMGCS2 using a lentiviral vector suppressed cell cycle activity in NRCMs, and silencing either gene regained cell cycle even in FA-rich condition. In conclusion, fatty acid metabolism increased PDK4 and HMGCS2 via PPARδ activation and suppressed NRCM proliferation."

Journal • HMGCS2 • PDK4

Novel Solid Forms of Cardarine/GW501516 and Their Characterization by X-Ray Diffraction, Thermal, Computational, FTIR, and UV Analysis. (PubMed, Pharmaceutics) - "Further investigations have been conducted by powder X-ray diffraction, DTA/TGA thermal analysis, and FTIR spectroscopy. The stability and solubility were analyzed as well."

Journal • Cardiovascular • Dyslipidemia • Metabolic Disorders

GW501516 facilitated tumor immune escape by inhibiting phagocytosis. (PubMed, Eur J Pharmacol) - "In vivo implanted tumor models demonstrated that GW501516 facilitated tumor immune escape, whereas PPARδ loss reversed this effect. Collectively, these findings suggest that GW501516 activates PPARδ to promote colon tumor immune escape via CD47 upregulation."

Journal • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor • CD47 • SIRPA

PPARβ/δ upregulates the insulin receptor β subunit in skeletal muscle by reducing lysosomal activity and EphB4 levels. (PubMed, Cell Commun Signal) - "Overall, these findings reveal that PPARβ/δ activation increases InsRβ levels by alleviating ER stress and lysosomal degradation."

Journal • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus • EPHB4 • IR

Fatty acids disturb cardiomyocyte proliferation by increasing PDK4 and HMGCS2 via PPARδ activation (AHA 2024) - "GW501516, a peroxisome proliferator-activated receptor δ (PPARδ) agonist, also increased fatty acid metabolism factors with the reduction of Ki67 positive cardiomyocytes, whereas fenofibrate, a PPARα agonist, or pioglitazone, a PPARγ agonist, caused little or no change in these phenotypes. Fatty acids disturbed NRCM proliferation by upregulating PDK4 and HMGCS2 through the activation of PPARδ independently from β-oxidation."

Heart Failure • Metabolic Disorders • HMGCS2 • PDK4 • PPARA

Peroxisome proliferator-activated receptor δ suppresses the cytotoxicity of CD8+ T cells by inhibiting RelA DNA binding activity. (PubMed, Cancer Res Commun) - "Treatment of ApcMin/+ mice with the PPAR-δ agonist GW501516 reduced the activation of normal and tumor-associated intestinal CD8+ T cells and increased intestinal adenoma burden...Mechanistically, we found that PPAR-δ binds to RelA, interfering with RelA-p50 heterodimer formation in the nucleus, thereby inhibiting its DNA binding in CTLs. Thus, PPAR-δ is a critical regulator of CTL effector function."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CD8 • GZMB • IFNG • PPARA

PPARβ/δ attenuates hepatic fibrosis by reducing SMAD3 phosphorylation and p300 levels via AMPK in hepatic stellate cells. (PubMed, Biomed Pharmacother) - "Likewise, GW501516 attenuated the phosphorylation of the main downstream intracellular protein target of TGF-β1, suppressor of mothers against decapentaplegic (SMAD)3, as well as the levels of the SMAD3 co-activator p300 via the activation of AMP-activated protein kinase (AMPK) and the subsequent inhibition of extracellular signal-regulated kinase-1/2 (ERK1/2) in LX-2 cells. Overall, these findings uncover a new mechanism by which the activation of AMPK by a PPARβ/δ agonist reduces TGF-β1-mediated activation of HSCs and fibrosis via the reduction of both SMAD3 phosphorylation and p300 levels."

Journal • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • AMPK • COL1A1 • SMAD3 • SMAD4 • TGFB1

Exenatide Activates PPARd to Promote Mitochondrial Function for Insulin Secretion in Islet ß-Cells (ADA 2024) - "However, related molecular mechanisms remain to be further explored. C57BL/6J mice were treated with exenatide, GW501516 (GW, a PPARδ agonist) or saline for 8 weeks after a 12-week high-fat diet (HFD) challenge. Exenatide protects GSIS function in islet β cells by enhancing mitochondrial function through promoting PPARδ expression."

Metabolic Disorders

ACTIVATION OF PPARΔ IN BONE MARROW ENDOTHELIAL PROGENITOR CELLS REPAIRS THEIR HEMATOPOIESIS-SUPPORTING ABILITY AFTER MYELOSUPPRESSIVE INJURY (EHA 2024) - "GW501516, an agonist of PPARδ, repaired the damagedBM EPCs triggered by 5-fluorouracil (5FU) in vitro. The current work provides the first evidence that insufficient level of PPARδ contributes to BM EPC dysfunction,whereas activation of PPARδ in BM EPCs repairs their hematopoiesis-supporting ability after myelosuppressivetherapy, which may provide a potential therapeutic target not only for patients with leukemia, but also forthose with other cancers."

Acute Myelogenous Leukemia • Anemia • Aplastic Anemia • Bone Marrow Transplantation • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Thrombocytopenia • Thrombocytopenic Purpura • Transplantation

Five Novel Polymorphs of Cardarine/GW501516 and Their Characterization by X-ray Diffraction, Computational Methods, Thermal Analysis and a Pharmaceutical Perspective. (PubMed, Pharmaceutics) - "The polymorphs were further investigated by thermal DSC analysis and X-ray diffraction on powders. From a pharmaceutical perspective, the stability and solubility of the polymorphs were analyzed as well."

Journal • Cardiovascular • Metabolic Disorders

Estradiol contributes to sex differences in resilience to septic-induced metabolic dysregulation and dysfunction in the heart via GPER-1-mediated PPARδ/NLRP3 signaling. (PubMed, Metabolism) - "Our findings collectively illuminate the sex-specific cardiac mechanisms influencing septic mortality, offering insights into physiological and pathological dimensions. From a pharmacological standpoint, this study introduces specific GPER-1 activation as a promising therapeutic intervention for males under septic conditions. These discoveries advance our understanding of the sex differences in septic-induced cardiac dysfunction and also present a novel avenue for targeted interventions with potential translational impact."

Journal • Infectious Disease • Metabolic Disorders • Septic Shock • GPER1 • NLRP3

Activation of PPARδ in bone marrow endothelial progenitor cells improves their hematopoiesis-supporting ability after myelosuppressive injury. (PubMed, Cancer Lett) - "Moreover, GW501516, an agonist of PPARδ, repaired the damaged BM EPCs triggered by 5-fluorouracil (5FU) in vitro and in vivo. Mechanistically, we found that increased expression of NADPH oxidases (NOXs), the main ROS-generating enzymes, may lead to elevated ROS level in BM EPCs, and insufficient PPARδ may trigger BM EPC damage via ROS/p53 pathway. Collectively, we found that defective PPARδ contributes to BM EPC dysfunction, whereas activation of PPARδ in BM EPCs improves their hematopoiesis-supporting ability after myelosuppressive therapy, which may provide a potential therapeutic target not only for patients with leukemia but also for those with other cancers."

Journal • Bone Marrow Transplantation • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation

GW501516-Mediated Targeting of Tetraspanin 15 Regulates ADAM10-Dependent N-Cadherin Cleavage in Invasive Bladder Cancer Cells. (PubMed, Cells) - "By targeting Tspan15 to block ADAM10 activity on N-cadherin, GW501516 could prevent NTF pro-tumoral effects and be a promising molecule to treat bladder cancer. More interestingly, it could optimize the effects of the N-cadherin antagonists those such as ADH-1 that target the N-cadherin ectodomain."

Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • ADAM10 • CDH2 • CEBPZ

The role of PPARδ in murine T cell activation (IMMUNOLOGY 2024) - "To understand PPARδ's impact on FAO in T cells, we stimulated naïve T cells with F1 splenocytes (in a mixed leukocyte reaction (MLR)) in the presence of the PPARδ agonist GW501516...Together, these data imply that PPARδ both drives FAO and mediates anti-inflammatory actions in T cells responding to an allogeneic stimulus. The intersectional role of PPARδ in metabolism and inflammation requires nuanced consideration, particularly regarding its therapeutic potential in modulating T-cell mediated immune responses."

Preclinical • Graft versus Host Disease • Immunology • Oncology • Transplantation • CD4 • CD8 • TNFA

PPARβ/δ-ANGPTL4 axis mediates the promotion of mono-2-ethylhexyl phthalic acid on MYCN-amplified neuroblastoma development. (PubMed, Sci Total Environ) - "Because MEHP can bind to the PPARβ/δ protein and initiate the expression of the downstream gene angiopoietin-like 4 (ANGPTL4), the PPARβ/δ-specific agonist GW501516 and antagonist GSK3787, the recombinant human ANGPTL4 protein, and the knockdown of gene expression confirmed the regulation of the PPARβ/δ-ANGPTL4 axis on the malignant phenotype of neuroblastoma...We have demonstrated for the first time that MEHP can target binding to PPARβ/δ and affect the progression of neuroblastoma by activating the PPARβ/δ-ANGPTL4 axis. This mechanism confirms the health risks of plasticizers as tumor promoters and provides new data support for targeted prevention and treatment of neuroblastoma."

Journal • CNS Tumor • Metabolic Disorders • Neuroblastoma • Oncology • Solid Tumor • MYCN

Inhibitory Effect of PPARδ Agonist GW501516 on Proliferation of Hypoxia-induced Pulmonary Arterial Smooth Muscle Cells by Regulating the mTOR Pathway. (PubMed, Curr Med Sci) - "GW501516 inhibited the proliferation of PASMCs induced by hypoxia through blocking the mTOR/Skp2/p27 signaling pathway."

Journal • SKP2

Hydrogen sulfide ameliorates senescence in vascular endothelial cells through ameliorating inflammation and activating PPARδ/SGLT2/STAT3 signaling pathway. (PubMed, Acta Biochim Biophys Sin (Shanghai)) - "GYY4137, GW501516 and EMPA preserve endothelial-dependent relaxation (EDR) in D-gal-treated aortae, while GSK0660 destroys aortic relaxation even with GYY4137 supplementation. In summary, senescent ECs manifest aggravated the expressions of the inflammatory molecules SGLT2 and p-STAT3 and decreased the productions of PPARδ, eNOS and CSE. H S ameliorates endothelial dysfunction through the anti-inflammatory effect of the PPARδ/SGLT2/p-STAT3 signaling pathway in senescent ECs and may be a potential therapeutic target for anti-ageing treatment."

Journal • Aesthetic Medicine • Inflammation • NOS3

Medium-chain fatty acids modify macrophage expression of metabolic and inflammatory genes in a PPAR β/δ-dependent manner. (PubMed, Sci Rep) - "J774A.1 murine macrophages were exposed to octanoate or decanoate as MCFA, a long-chain fatty acid control (palmitate), or the PPAR β/δ agonist GW501516, with or without lipopolysaccharide (LPS) stimulation, and with or without an siRNA-induced knockdown of PPAR β/δ...MCFA influenced the transcriptional responses of macrophages favoring cholesterol efflux and a less inflammatory response compared to palmitate. These effects were partially mediated by PPAR β/δ."

Journal • Cardiovascular • Infectious Disease • Inflammation • Metabolic Disorders • ABCA1 • IL6 • MMP9 • NOS2 • PLIN2 • PLTP

Study of the Effect of PPARß/δ Activation on Diabetic Cardiomyopathy (ADA 2023) - "In addition, we showthat PPARβ/δ suppression exacerbated hyperglycemia-induced DC and that PPARβ/δ activationthrough administration of agonists like GW501516 prevented the induction of some of themolecular mechanisms involved in the development of DC in these cells. Overall, these findingsdemonstrate the implication of PPARβ/δ in DC and suggest that its activation might be aneffective therapeutic tool for preventing or treating DC."

Diabetes • Metabolic Disorders

Unraveling the individual contributions of the PPAR isotypes to the pan-PPAR agonist Lanifibranor-induced improvements of the vascular alterations and liver histology in a rat model of early NAFLD (EASL-ILC 2023) - "We studied the underlying mechanism by exploring the mono-PPAR agonists Fenofibrate (PPAR-alpha agonist), GW501516 (PPAR-delta agonist) and Rosiglitazone (PPAR-gamma agonist) using a rat model of early NAFLD. The mono-PPAR agonists reduce the increased portal pressure and related functional vascular intrahepatic alterations associated with early NAFLD. However, with Lanifibranor all improvements in vascular function were more pronounced than with each specific agonist. Together with the impact on histology, these data suggest that there is an additive effect of combined PPAR agonism compared to mono-agonism leading to an improvement of the vascular alterations in early NAFLD."

Preclinical • Fibrosis • Hepatology • Immunology • Inflammation • Liver Failure • Non-alcoholic Fatty Liver Disease

PPARβ/δ Agonism with GW501516 Increases Myotube PGC-1α Content and Reduces BCAA Media Content Independent of Changes in BCAA Catabolic Enzyme Expression. (PubMed, PPAR Res) - "These data confirm the ability of GW to increase muscle PGC-1α content and decrease BCAA media content without affecting BCAA catabolic enzymes/transporter. These findings suggest heightened BCAA uptake (and possibly metabolism) may occur without substantial changes in the protein levels of related cell machinery."

Journal • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

INSUFFICIENT PPARΔ IN BONE MARROW ENDOTHELIAL PROGENITOR CELLS LEADS TO THEIR IMPAIRED HEMATOPOIESIS-SUPPORTING ABILITY (EHA 2023) - "Our results suggest that PPARδ promotes the hematopoiesis-supporting ability of human BM EPCs. DefectivePPARδ in BM EPCs may be involved in the pathogenesis of PGF, whereas the hampered hematopoiesis-supporting ability of BM EPCs of PGF patients could be attenuated by the agonist of PPARδ (GW501516) in vitro . Our findings may provide a promising therapeutic approach for patients with PGF post-allo-HSCT."

Bone Marrow Transplantation • Hematological Disorders • Transplantation • PPARA • PPARG

PPARδ Agonist GW501516 Suppresses the TGF-β-Induced Profibrotic Response of Human Bronchial Fibroblasts from Asthmatic Patients. (PubMed, Int J Mol Sci) - "In conclusion, our data demonstrate that a PPARδ agonist stimulates antifibrotic effects in an in vitro model of bronchial subepithelial fibrosis. This suggests its potential role in the development of a possible novel therapeutic approach for the treatment of subepithelial fibrosis during asthma."

Journal • Asthma • Dyslipidemia • Fibrosis • Genetic Disorders • Immunology • Obesity • Pulmonary Disease • Respiratory Diseases • SMAD2 • TGFB1