Cardarine (GW501516) Effects on Improving Metabolic Syndrome

The present study hypothesized that treatment with GW501516 (a selective PPAR-δ agonist) lowers lipids by increasing fatty acid oxidation without adverse effects on oxidative stress. Caucasian men (age 18-50 years, n=18) were randomly assigned to treatment with GW501516, GW590735, or placebo for two weeks while residing in a clinical research facility. A meal tolerance test, skeletal muscle biopsy, and blood/breath sampling were conducted. The study reported that treatment with GW501516 ameliorated multiple metabolic abnormalities associated with metabolic syndrome including oxidative stress, obesity, dyslipidemia, and insulin resistance, all while increasing fatty acid oxidation. Notably, no adverse effects were reported. However, the restricted living conditions and/or diets that the participants were subjected to likely do not resemble their normal lifestyle. Therefore, the beneficial effects of GW501516 on metabolic health observed in the study should further be investigated in a real-life setting. During participant recruitment, the use of dietary supplements were minimally considered, thereby increasing the risk for confounding effects on the metabolic parameters assessed in the study. Also, recruiting a larger and more diverse population would allow for a more detailed analysis that may benefit a broader range of people (i.e., examining the effects of GW501516 in certain ethnic groups or with/without exercise programs). Additional research on GW501516 and other PPAR-δ agonists is encouraged since it appears that this class of drugs can ameliorate multiple metabolic syndrome features. Future studies should consider additional metrics relevant to metabolic syndrome such as C-reactive protein, cortisol, and homocysteine.

11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

Glucocorticoid action on target tissues is determined by the density of “nuclear” receptors and intracellular metabolism by the two isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD) which catalyze interconversion of active cortisol and corticosterone with inert cortisone and 11-dehydrocorticosterone. 11β-HSD type 1, a predominant reductase in most intact cells, catalyzes the regeneration of active glucocorticoids, thus amplifying cellular action. 11β-HSD1 is widely expressed in liver, adipose tissue, muscle, pancreatic islets, adult brain, inflammatory cells, and gonads. 11β-HSD1 is selectively elevated in adipose tissue in obesity where it contributes to metabolic complications. Similarly, 11β-HSD1 is elevated in the ageing brain where it exacerbates glucocorticoid-associated cognitive decline. Deficiency or selective inhibition of 11β-HSD1 improves multiple metabolic syndrome parameters in rodent models and human clinical trials and similarly improves cognitive function with ageing. The efficacy of inhibitors in human therapy remains unclear. 11β-HSD2 is a high-affinity dehydrogenase that inactivates glucocorticoids. In the distal nephron, 11β-HSD2 ensures that only aldosterone is an agonist at mineralocorticoid receptors (MR). 11β-HSD2 inhibition or genetic deficiency causes apparent mineralocorticoid excess and hypertension due to inappropriate glucocorticoid activation of renal MR. The placenta and fetus also highly express 11β-HSD2 which, by inactivating glucocorticoids, prevents premature maturation of fetal tissues and consequent developmental “programming.” The role of 11β-HSD2 as a marker of programming is being explored. The 11β-HSDs thus illuminate the emerging biology of intracrine control, afford important insights into human pathogenesis, and offer new tissue-restricted therapeutic avenues.