New GW studies done - spoiler, you do not need to exercise to gain benefits!


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The May issue of Cell Metabolism has a study that looked much deeper into GW and how it works, etc. Their results are a bit surprising. I will quote the study and then give an overview of what it says. The source is here:

In addition to stimulating fatty acid metabolism in sedentary mice, PPAR; activation potently suppresses glucose catabolism and does so without affecting either muscle fiber type or mitochondrial content. By preserving systemic glucose levels, PPAR; acts to delay the onset of hypoglycemia and extends running time by approx. 100 min in treated mice.

This basically says PPAR activation causes the body to use up its glucose stores much slower, thereby allowing for greater endurance. It does this by causing the body to use fat as its energy source.

Exercise training enhances endurance, in part, by delaying the depletion of carbohydrate stores (mainly glycogen in liver and muscle). The adaptive benefits of exercise training are commonly attributed to the glycolytic-to-oxidative fiber-type transformation and increased mitochondrial energetic capacity (Holloszy and Booth, 1976xBiochemical adaptations to endurance exercise in muscle. Holloszy, J.O. and Booth, F.W. Annu. Rev. Physiol. 1976; 38: 273–291

Crossref | PubMedSee all ReferencesHolloszy and Booth, 1976), programs in which the AMPK-PGC1; signaling pathway is now known to play a major role. At the same time, exercise also enhances muscle fatty acid (FA) oxidation

If you exercise, your body will make new muscle fibers that are designed to not use as much glycogen, use the glycogen more efficiently, and cause the body to use fat as its primary energy source. I think we all already understood this even if we did not know the nitty gritty as to why.

small molecule ligands that specifically activate PPAR;, including GW501516 (GW), have revealed multiple beneficial metabolic effects, including
(1) increased energy expenditure
(2) elevated FA oxidation(
(3) reduced obesity and insulin resistance(
(4) exercise-induced muscle remodeling, and, collectively
(5) enhanced running endurance by 80% or more

I think that is clear enough. Anything that activates PPAR, such as exercise and GW, have amazingly powerful benefits for you.

Despite the requirement for muscle PPAR; in exercise-induced metabolic adaptations and endurance enhancement, the glycolytic-to-oxidative fiber-type switch and mitochondrial biogenesis are still achieved in PDmKO mice. Furthermore, sedentary PDmKO mice are indistinguishable from WT mice in terms of mitochondrial content and oxidative phosphorylation (OXPHOS) capacity as well as muscle fiber-type com********** In addition, whole-body energy expenditure (measured as oxygen consumption rate [VO2];, energy substrate utilization are all independent of muscle PPAR; expression. This indicates a role for PPAR; in adaptive, but not innate, muscle activity and stands in contrast to previous reports.

Ok, this is starting to get exciting. The two types of mice are PDmKO mice and WT mice. WT mice are normal mice used in laboratories. PDmKO mice have been genetically altered to be unable to increase endurance via exercise. The study shows that BOTH groups of mice had reduced glycogen use and increased fat use while using GW!!! This means it acts independently of your genetic makeup.

Previous studies showed that treatment of mice with the PPAR; agonist GW dramatically increased running endurance, but only when combined with daily exercise. Based on the above, we re-examined the impact of GW on muscle energy substrate usage and endurance in fully sedentary mice. Unexpectedly, treatment of WT mice with GW (40 mg/kg in food) for a longer time (8 weeks compared to 4 weeks) reduced RER to a level similar to exercise training, indicative of increased FA metabolism. Consistent with an energy substrate shift, the longer 8 week GW treatment of sedentary mice was sufficient to confer approx. 1.5 hr longer running time than untreated controls. This endurance benefit is lost in PDmKO mice and thus dependent on muscle PPAR; activation and muscle fiber-type composition—changes commonly associated with endurance enhancement—were not affected by GW treatment. Thus, while establishing that ligand activation of PPAR; can enhance endurance in sedentary mice, these findings implicate a novel mechanism of action.

Endurance increase was found even in the mice that DID NOT EXERCISE! That is quite different from the previous study...but the previous study only went on for 4 weeks while this one went on for 8 weeks. Apparently, continued use provides increased benefits over time. The mice who genetically cannot increase endurance did not see endurance increases. Still, quite awesome that you can be a couch potato and STILL get benefits from GW on your endurance!

Interestingly, while the blood glucose in the control mice started dropping after 90–120 min of running, GW-treated mice were able to maintain normal glycemic levels for extended periods and delay the onset of blood glucose reduction even after 180 min of running. It is important to note that the glucose-sparing effects of GW treatment parallel those seen with exercise training, suggesting a common underlying mechanism. Blood lactate was also monitored during our run-to-exhaustion tests, which showed minimal fluctuation in both control and GW-treated mice, indicating that the endurance regimen did not exceed the aerobic threshold of the tested mice. In combination, our data describe a PPAR-controlled muscle reprogramming that boosts exercise endurance by inversely regulating fat and glucose metabolism, thereby preserving circulating glucose to support other tissues such as the brain.

GW mirrors the effects of endurance training in the body, even to the point where it does not reduce the glucose levels being sent to the brain and other organs while actively reducing the amount sent to the muscles. This is awesome!

Global transcriptional analyses in the glycolytic white quadriceps muscle (WQ) identified 975 genes with altered expression upon GW treatment, with 492 up- and 483 downregulated. In addition to the key mitochondrial genes Pdk4 and Cpt1b described above, gene ontology (GO) analysis of upregulated genes revealed significant enrichment in the PPAR signaling pathway as well as lipid and FA catabolism. Interestingly, lipogenic genes including PPAR; (master adipogenic regulator) and FA synthase (Fasn) were also induced, which would theoretically lead to a futile cycle of lipid catabolism and anabolism. Additionally, genes involved in antioxidant defense and glutathione synthesis (including Cat, Sod3, and Gpx1) were highly upregulated. Counterintuitively, pathways in carbohydrate metabolism, including the hexose metabolic process, pentose-phosphate shunt, and insulin signaling, were also significantly enriched is consistent with the induction of an anabolic program, suggesting a possible role in muscle repair.

Conversely, pathways of insulin signaling, glycolysis, and carbohydrate catabolism were significantly enriched in the downregulated gene set. Notably, these transcriptional changes, combined with the suppression of the recently identified mitochondrial pyruvate carrier Mpc1, coordinately reduce muscle glucose catabolism. These studies reveal that PPAR; reprograms muscle metabolism for endurance by reciprocal regulation of gene programs promoting FA oxidation and suppressing glucose metabolism.

GW causes genes to "flip" their state, allowing for up and down regulation of specific body functions. Of interest is that antioxidants and glutathione synthesis was enhanced, as well as muscle repair pathways, which muscle glucose metabolism was suppressed. Also, insulin signally was significantly enriched.

Activation of muscle PPAR; either genetically or pharmacologically is sufficient to dramatically improve endurance capacity. However, fiber-type changes and mitochondrial biogenesis found in the PPAR***948; transgenic models were not seen in “ligand-only” activation. Instead, we find that PPAR***948; ligand prioritizes energy substrate usage to increase FA catabolism while lowering glycolysis with the net effect of preserving systemic glucose.

Notably, pharmacologic activation of PPAR; replicates the exercise-induced changes in substrate utilization to preserve systemic glucose and thereby delay the onset of hypoglycemia, or “hitting the wall.” While exercise-induced muscle remodeling is well documented, the health benefits have been largely attributed to mitochondrial biogenesis and fiber-type transformation. In contrast, pharmacophores that activate PPAR; promote endurance through preserving glucose, essentially “pushing back the wall,” without affecting mitochondrial biogenesis or fiber-type transformation. This ability to chemically activate energetic circuits regulated by PPAR; has the potential to confer health benefits in a variety of human diseases.

Endurance training literally changes your muscle fiber type so they use less glycogen and more fat as their energy source. GW does not change your muscle fiber type, but it replicates all the changes CAUSED by the new muscle fiber type, thereby giving you the same benefit as if you had performed endurance training.

What this means, in a nutshell, is that you can take GW and be a couch potato and, after 8 weeks, your body will act as if you had been doing 8 weeks of endurance training. The downside is that it goes away when you stop. The extra fat you lose does not return (provided you have a proper diet), but since you do not form the new muscle fibers you will lose the benefits when you stop taking GW whereas you keep them if you stop exercising (slowly losing it over time). My recommendation is to take GW to increase your endurance AND do endurance training. You will have a synergistic effect of the two, helping you to create MORE of the new muscle fiber type in a shorter period of time.

In other news, it appears GW actually is being looked at as a way to kill cancer, not cause it.

GW501516 is a selective and high-affinity synthetic agonist of peroxisome proliferator-activated receptor; (PPAR;). This molecule promoted the inhibition of proliferation and apoptosis in a few cancer cell lines, but its anticancer action has never been investigated in bladder tumor cells. Thus, this study was undertaken to determine whether GW501516 had antiproliferative and/or apoptotic effects on RT4 and T24 urothelial cancer cells and to explore the molecular mechanisms involved. Our results indicated that, in RT4 cells (derived from a low-grade papillary tumor), GW501516 did not induce cell death. On the other hand, in T24 cells (derived from an undifferentiated high-grade carcinoma), this PPAR948; agonist induced cytotoxic effects including cell morphological changes, a decrease of cell viability, a G2/M cell cycle arrest, and the cell death as evidenced by the increase of the sub-G1 cell population. Furthermore, GW501516 triggered T24 cell apoptosis in a caspase-dependent manner including both extrinsic and intrinsic apoptotic pathways through Bid cleavage. In addition, the drug led to an increase of the Bax/Bcl-2 ratio, a mitochondrial dysfunction associated with the dissipation of ***916;***936;m, and the release of cytochrome c from the mitochondria to the cytosol. GW501516 induced also ROS generation which was not responsible for T24 cell death since NAC did not rescue cells upon PPAR; agonist exposure. For the first time, our data highlight the capacity of GW501516 to induce apoptosis in invasive bladder cancer cells. This molecule could be relevant as a therapeutic drug for high-grade urothelial cancers.

GW is able to kill many kinds of cancer cells WITHOUT harming the non-cancerous cells around it. A papillary tumor is a non-cancerous tumor (benign), for those who do not know (I had to look it up). Only one study has shown GW to cause cancer while none of the others have shown GW to cause cancer in any of their test subjects.

Also, you guys need to add Greek letter ability to this board - it will then stop converting the Greek letters into asterisks and numbers. :) I had to do a lot of editing to remove them.