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SARMs Selective androgen receptor modulators or SARMs are intended to have the same kind of effects as androgenic drugs like anabolic steroids but be much more selective in their action




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Old 03-05-2018, 10:49 PM
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GW501516 “Exercise in a Bottle”

GW1516, also written GW 50516, is a drug and research chemical developed by pharmaceutical client GlaxoSmithKline, which acts as a PPARδ (peroxisome proliferator activated receptor delta) modulator and selective agonist.[1][2] GW1516 activates AMP-K (5′ adenosine monophosphate-activated protein kinase) and stimulates skeletal muscle glucose uptake.[3]

GW1516 has been demonstrated to effectively reverse metabolic abnormalities in obese men with metabolic syndrome (a pre-diabetic condition), likely due to the fact that it stimulus fatty acid oxidation.[4]

GW1516 holds promise for treating obesity and adiposity and has been touted, much like AICAR, as “exercise in a pill,” etc.[6] In conjunction with AICAR, an AMPK agonist which acts synergistically with GW1516, significant increases in exercise endurance have been demonstrated in animal studies.[5]

Ali et al write on the role of PPARk in the body’s normal functioning:
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily of ligand-activated transcriptional regulators. PPARdelta has an established role in metabolism, wound healing, and angiogenesis. However, little is known about its function in endothelial homeostasis. [7]

Ali et also infer from their data that PPARk agonists may be a hopeful area of study for treating vascular issues or perhaps preventing vascular issues by promoting stress resistance:

We have identified an important relationship between PPARdelta, PGC1alpha, and haem oxygenase-1, demonstrating that haem oxygenase-1 induction plays an important role in cytoprotective actions of PPARdelta ligands in vascular endothelium. In light of the protective effects of haem oxygenase-1 against atherogenesis, we suggest that PPARdelta represents a potentially important therapeutic target in the vasculature.[7]

Foreman et al conclude that “proliferation of the C20 mouse mammary gland cancer cell line is inhibited by ligand activation of PPARbeta/delta due in part to increased apoptosis” meaning that as an additive therapy, PPARdelta agonists such as GW1516 may be useful for treating certain types of cancer or for promoting continued remission.[8]

Dimoupolos et al write:
Peroxisome proliferator-activated receptor-delta (PPARdelta) activation enhances skeletal muscle fatty acid oxidation and improves whole body glucose homeostasis and insulin sensitivity. Recently, GW501516, a selective PPARdelta agonist, was reported to increase glucose uptake in human skeletal myotubes by an AMPK-dependent mechanism that may contribute to the improved glucose tolerance. Here, we demonstrate that whilst GW501516 increases expression of PGC-1alpha and CPT-1 and stimulates fatty-acid oxidation in L6 myotubes, it fails to enhance insulin sensitivity, AMPK activity or glucose uptake and storage. Our findings exclude sarcolemmal glucose transport as a potential target for the therapeutic action of PPARdelta agonists in skeletal muscle.[9]

Wang et al show that PPARdelta agonists are useful targets for investigation regarding obesity prevention:

[T]argeted activation of PPARdelta in adipose tissue specifically induces expression of genes required for fatty acid oxidation and energy dissipation, which in turn leads to improved lipid profiles and reduced adiposity. …In vitro, activation of PPARdelta in adipocytes and skeletal muscle cells promotes fatty acid oxidation and utilization. Our findings suggest that PPARdelta serves as a widespread regulator of fat burning and identify PPARdelta as a potential target in treatment of obesity and its associated disorders.[10]

Narkar et al, authors of the pioneering study on AICAR, highlight some of the reasons GW1516 and other “exercise mimetics” are desirable for treating conditions prevalent in the current medical milieu:

The benefits of endurance exercise on general health make it desirable to identify orally active agents that would mimic or potentiate the effects of exercise to treat metabolic diseases. Although certain natural compounds, such as reseveratrol, have endurance-enhancing activities, their exact metabolic targets remain elusive. We therefore tested the effect of pathway-specific drugs on endurance capacities of mice in a treadmill running test. We found that PPARbeta/delta agonist and exercise training synergistically increase oxidative myofibers and running endurance in adult mice. Because training activates AMPK and PGC1alpha, we then tested whether the orally active AMPK agonist AICAR might be sufficient to overcome the exercise requirement. Unexpectedly, even in sedentary mice, 4 weeks of AICAR treatment alone induced metabolic genes and enhanced running endurance by 44%. These results demonstrate that AMPK-PPARdelta pathway can be targeted by orally active drugs to enhance training adaptation or even to increase endurance without exercise.[11]

[1] Sznaidman ML, Haffner CD, Maloney PR, Fivush A, Chao E, Goreham D, Sierra ML, LeGrumelec C, Xu HE, Montana VG, Lambert MH, Willson TM, Oliver WR Jr, Sternbach DD (May 2003). “Novel selective small molecule agonists for peroxisome proliferator-activated receptor delta (PPARdelta)–synthesis and biological activity”. Bioorg. Med. Chem. Lett. 13 (9): 1517–21.
[2]Dimopoulos N, Watson M, Green C, Hundal HS (October 2007). “The PPAR delta agonist, GW501516, promotes fatty acid oxidation but has no direct effect on glucose utilization or insulin sensitivity in rat L6 skeletal muscle cells”. FEBS Lett. 581 (24): 4743–8.
[3]Krämer DK, Al-Khalili L, Guigas B, Leng Y, Garcia-Roves PM, Krook A (July 2007). “Role of AMP kinase and PPAR delta in the regulation of lipid and glucose metabolism in human skeletal muscle”. J. Biol. Chem. 282 (27): 19313–20.
[4]Risérus U, Sprecher D, Johnson T, Olson E, Hirschberg S, Liu A, Fang Z, Hegde P, Richards D, Sarov-Blat L, Strum JC, Basu S, Cheeseman J, Fielding BA, Humphreys SM, Danoff T, Moore NR, Murgatroyd P, O’Rahilly S, Sutton P, Willson T, Hassall D, Frayn KN, Karpe F (February 2008). “Activation of peroxisome proliferator-activated receptor (PPAR)delta promotes reversal of multiple metabolic abnormalities, reduces oxidative stress, and increases fatty acid oxidation in moderately obese men”. Diabetes 57 (2): 332–9.
[5]Narkar VA, Downes M, Yu RT, Embler E, Wang Y-X, Banayo E, Mihaylova MM, Nelson MC, Zou Y, Juguilon H, Kang H, Shaw RJ,2 Evans RM (August 2008). “AMPK and PPAR Agonists Are Exercise Mimetics”. Cell 134: 1–11.
[6] “Exercise In A Pill: Researchers Identify Drugs That Enhance Exercise Endurance”. Science News. ScienceDaily. 2008-08-01. (Science Daily)
[7]Ali F, Ali NS, Bauer A, Boyle JJ, Hamdulay SS, Haskard DO, Randi AM, Mason JC. PPARdelta and PGC1alpha act cooperatively to induce haem oxygenase-1 and enhance vascular endothelial cell resistance to stress. Cardiovasc Res. 2010 Mar 1;85(4):701-10.
[8]Foreman JE, Sharma AK, Amin S, Gonzalez FJ, Peters JM. Ligand activation of peroxisome proliferator-activated receptor-beta/delta
(PPARbeta/delta) inhibits cell growth in a mouse mammary gland cancer cell line. Cancer Lett. 2010 Feb 28;288(2):219-25.
[9] Dimopoulos N, Watson M, Green C, Hundal HS. The PPAR delta agonist, GW501516, promotes fatty acid oxidation but has no direct effect on glucose utilization or insulin sensitivity in rat L6 skeletal muscle cells. FEBS Lett. 2007 Oct 2;581(24):4743-8.
[10]Wang YX, Lee CH, Tiep S, Yu RT, Ham J, Kang H, Evans RM. Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity. Cell. 2003 Apr 18;113(2):159-70.
[11] Narkar VA, Downes M, Yu RT, Embler E, Wang YX, Banayo E, Mihaylova MM, Nelson MC, Zou Y, Juguilon H, Kang H, Shaw RJ, Evans RM. AMPK and PPARdelta agonists are exercise mimetics. Cell. 2008 Aug 8;134(3):405-15.
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Old 03-06-2018, 01:31 PM
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