THE TRANSPLANT ATHLETE

„PPARδ and lipid metabolism

The importance of PPARδ in lipid catabolism has been described in various essential tissues, such as skeletal muscle, which induces fatty acids beta-oxidation [2], in adipose tissue, which prevents obesity [29], protecting the heart from cardiomyopathy [30], and liver [31] pointing at PPARδ as a potential drug target in the treatment of metabolic diseases. Hypolipidemic drugs, unsaturated fatty acids, and their derivatives can directly activate PPAR receptors, particularly PPARα and PPARδ [17,32,33].

…Furthermore, cardarine can ameliorate hyperglycemia, insulin resistance, and lipotoxicity in beta cells [40].

…The antidiabetic effect of PPARδ is partly due to the activation of 5′ adenosine monophosphate-activated protein kinase (AMPK) that increases insulin activity, improving glucose control [44]. AMPK, a sensing glucose signal, is activated by reduced energy intake and glucose starvation [45]. In addition, diet restriction, physical exercise, and the drug metformin can start the AMPK [46].

…Cardarine increased fatty acids oxidation preventing the down-regulation of AMPK caused by a high-fat diet in the liver and amplifying the PGC-1alpha-lipin 1-PPAR-α pathway [51]. AMPK exerts a prominent role in fatty acid oxidation [52], and the PPARδ-PGC-1 pathway contributes to the hypo-triglyceridemic effect of the drug. Genetic and pharmacological studies showed that AMPK is required for maintaining glucose homeostasis [53].

…The activation of AMPK by pharmacological agents presents a unique challenge, given the complexity of the biological control of ATP synthesis and consumption and its deregulation in cancer [54]. PPARs regulate the triglycerides acids (TCA) cycle flux [55], promoting endurance exercise [18] and energy production [56].

GW501516/Cardarine in Oxidative Stress and Inflammation

Cardarine prevents TNF-α-induced Nuclear factor B (NF-κB) activation in human HaCaT cells (an immortalized human keratinocyte line) [60]. NF-κB is a ubiquitously expressed transcription factor controlling the expression of numerous genes involved in inflammation. In vitro, in the AC16 cell line derived from human cardiomyocytes, PPARδ activation can reduce the inflammatory response to the exposition of the saturated fatty acid palmitate [61]… Cardarine reduces the inflammatory state in white adipose tissue (WAT) and hepatic stellate cells (HSCs), reducing lipogenesis and insulin resistance. Damages in the liver are alleviated by increasing the beta-oxidation process and decreasing the expression of the genes involved in lipogenesis and gluconeogenesis [62].

Neuroprotective effect of GW501516/Cardarine

PPARα agonists found a clinical application in neurodegenerative disorders, which includes Parkinson’s disease (PD) [66], Alzheimer’s disease (AD) [67], Huntington’s disease (HD), Amyotrophic Lateral Sclerosis (ALS) [68], and multiple sclerosis (MS) [69]. The neuroprotective effect of PPAR agonists in vitro and in vivo models of PD regulates the expression of a set of genes involved in cell survival [66].

PPARα activation may improve mitochondrial function and oxidative stress and reduce neuroinflammation in the brain, suggesting the potential application of PPAR agonists in treating neurodegenerative disorders [70]. Many studies reported the beneficial effects of PPARα agonists on cognitive behavior in preclinical AD models [71].

Effects of GW501516/Cardarine on the Heart and cardio-vascular functions

GW501516/Cardarine exerts various and interesting effects on cardiac function because it is a primary physiological regulator of cardiac energy metabolism in cardiomyocytes reducing insulin resistance [44] and contrasting the pathological alterations present in heart failure and diabetic cardiomyopathy [79]. Although GW501516/Cardarine can reduce cardiovascular diseases, some controversies exist [80]. PPARδ activation reduces the expression of the NF-kB gene in mice and human cardiac cells and the AMPK mechanism, a lipid-induced inflammatory pathway in human cardiac cells. The transcriptional control of NF-kB entails the progression of heart failure and cardiac hypertrophy [61]. Furthermore, PPARδ attenuates endoplasmic reticulum stress and increases autophagic markers in human cardiac cells induced by palmitate [81].

GW501516/Cardarine and physical performance

Physical exercise induces changes in several transcriptional gene regulators in skeletal muscle, significantly contributing to metabolic changes [100]. Notably, exercise activates glycogen catabolism [101], increases insulin sensitivity [102], fatty acids utilization [103], and exerts an anti-inflammatory effect [104]. Furthermore, physical exercise regulates the AMPK gene activity and AMPKα2 gene methylation in human blood and eminently in the skeletal muscle [105]. AMPK is another endurance gene regulator of energy expenditure [106], and its activation maintains cellular energy stores, switching on catabolic pathways that produce ATP, primarily by enhancing oxidative metabolism and mitochondrial biogenesis [107]. In human macrophage analysis, co-activation of AMPK and PPARδ increased the expression of FAO genes [108]. Cardarine prevents the down-regulation of AMPK induced by high fat diet amplifying the PGC.1 pathway [51]. „

 Vittorio Emanuele Bianchi, Vittorio Locatelli. GW501516 (Cardarine): Pharmacological and Clinical Effects. Genet Mol Med. 2023; 5(1): 1-12.

My opinion:

Cararine had massive impact of loosing belly fat, especially in the first two weeks of supplementation, someone could say: it was just water discharge which is typical for the first period of loosing fat, yes thats true however I didn’t have it much. Also i could observe some impacy of strenght and endurance during my workouts. It does work!