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  #1  
Unread 06-11-2013, 11:02 AM
acecombact1 acecombact1 is offline
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Default PPAR-delta agonists and skeletal muscle insulin resistance

Lyle,

I read your article about nutrient partitioning during dieting and found it interesting that you mentioned that increased insulin resistance in the skeletal muscle is a good thing since it shift muscle utilization from glucose to fatty acids!

Recently i have been interested in PPAR-delta agonist, GW 501516, to increase my endurance and conditioning. I came across a study that claims oral administration of a PPAR-delta agonist to rodents worsens, maximal insulin-stimulated glucose transport in skeletal muscle of different fibers.

The study states that "Unexpectedly, treatment with the PPAR-delta agonist significantly reduced insulin-stimulated glucose transport in both soleus and epitrochlearis muscles, regardless of dietary fat content. The reduction in insulin-stimulated glucose transport induced by the agonist was associated with large increases in total muscle fatty acid translocase (FAT)/CD36protein content, but not diacylglycerol or ceramide contents. Agonist treatment did not alter the protein content of PPAR-delta, GLUT4, or insulin-signaling proteins (IRS-1, p85 PI3-K, Akt). Agonist treatment led to a small, but significant increase, in the oxidative capacity of glycolytic but not oxidative muscle"

Based on that would you think that GW 501516 would be any help to dieting, or preserving lean muscle mass on caloric deficit?
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  #2  
Unread 06-11-2013, 11:08 AM
niloluiz niloluiz is offline
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Given that the aforementioned study was performed on rats, it's difficult to extrapolate those results for any human application.
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  #3  
Unread 06-11-2013, 11:16 AM
acecombact1 acecombact1 is offline
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Quote:
Originally Posted by niloluiz View Post
Given that the aforementioned study was performed on rats, it's difficult to extrapolate those results for any human application.
I agree, most studies done on humans using this compound show improvement in LDL/HDl ratios, and improvement in muscle utilization efficiency and whatnot.

However i found this?: The peroxisome proliferator-activated receptor (PPAR) β/δ agonist GW501516 inhibits IL-6-induced signal transducer and activator of transcription 3 (STAT3) activation and insulin resistance in human liver cells.

http://www.ncbi.nlm.nih.gov/pubmed/22179221

I know the study is done in vitro, however it shows that GW501516 inhibits IL-6-induced signal! Leptin and IL-6 belong to the same family. I know its a far shot theory, and Lyle is gonna shut me down

But i see this class of drugs to have some hope in manipulating leptin levels
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  #4  
Unread 06-11-2013, 11:22 AM
acecombact1 acecombact1 is offline
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Another related study

Role of lipid peroxidation and PPAR-δ in amplifying glucose-stimulated insulin secretion.
Cohen G, Pharmacology, School of Pharmacy, Faculty of Medicine, Institute for Drug Research, Hebrew University, Jerusalem, Israel.

Abstract
OBJECTIVE:
Previous studies show that polyunsaturated fatty acids (PUFAs) increase the insulin secretory capacity of pancreatic β-cells. We aimed at identifying PUFA-derived mediators and their cellular targets that are involved in the amplification of insulin release from β-cells preexposed to high glucose levels.

CONCLUSIONS:
Elevated glucose levels augment the release of AA and LA from phospholipids and their peroxidation to 4-HNE in β-cells. This molecule is an endogenous ligand for PPAR-δ, which amplifies insulin secretion in β-cells.
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  #5  
Unread 06-11-2013, 01:49 PM
Primalkid Primalkid is offline
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Reminds me of all the petri-dish and rodent study benefits of ursolic acid that don't play out in humans.
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  #6  
Unread 06-11-2013, 02:23 PM
niloluiz niloluiz is offline
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Quote:
Originally Posted by acecombact1 View Post
I agree, most studies done on humans using this compound show improvement in LDL/HDl ratios, and improvement in muscle utilization efficiency and whatnot.
(...)
But i see this class of drugs to have some hope in manipulating leptin levels
Well if there is human studies than we can extrapolate from there. Still the question is, how much impact this causes and what kind of real-world results would be possible with it? If the objective is improved fat loss or even stabilization of leptin during dieting.... how profound would be the effect?

I didn't read the papers to see if there's enough data to at least guesstimate an answer for those questions.
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  #7  
Unread 06-11-2013, 02:51 PM
Heavy_Lifter85 Heavy_Lifter85 is offline
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Isn't this the compound that causes massive amounts of tumors in rodents? There may be some really sick cyclists a few years from now.
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  #8  
Unread 06-12-2013, 03:30 PM
acecombact1 acecombact1 is offline
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There are some human studies, but not related directly to Leptin regulation or anything:


3.2. Evidence supporting a role for activated PPAR***948; in mediating fuel switching in human skeletal muscle: data from in vitro and clinical studies
Recent studies have revealed clear roles for PPAR***948; in the regulation of lipid and glucose metabolism in human skeletal muscle [7, 38]. PPAR***948; stimulates the expression of genes involved in (a) increasing of lipid oxidation (fatty acid binding protein 3 (FABP3) and CPT1) and (b) reducing carbohydrate oxidation (pyruvate dehydrogenase kinase 4 (PDK4)) in human skeletal muscle [38], as it does in rodents [5, 810]. These in vitro human skeletal muscle data with GW1516 support the long-known observation that an increase in fatty acid oxidation reduces the glucose utilization of isolated muscle reflecting the mutual inhibition in the metabolism of substrates involved in the glucose-fatty acid cycle [35, 36, 39]. Recent data from a clinical study indicate that this situation holds true in human subjects. A statistically significant reduction in fasting insulin levels was observed in a study performed on moderately obese men given a dose of 10 mg o.d. of GW1516 was given for 2 weeks [7]. These subjects also showed decrease fasting plasma nonesterified fatty acid (NEFA) concentrations and increased expression of CPT1b in muscle. Interestingly, GW1516 treatment slightly reduced the expression of PPAR***948;, showing that overexpression of the receptor itself is not necessary for the induction of PPAR***948;-mediated effects, the resident levels of the receptor protein being sufficient. In contrast, similar treatment with a PPAR***945; agonist (GW590735) did not result in any change in plasma insulin levels, nor did it cause a significant increase in CPT1b mRNA [7].
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  #9  
Unread 06-12-2013, 03:31 PM
acecombact1 acecombact1 is offline
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Quote:
Originally Posted by Heavy_Lifter85 View Post
Isn't this the compound that causes massive amounts of tumors in rodents? There may be some really sick cyclists a few years from now.

Yes, the dosages were given to the rodents were 300X the dosage recommended for humans in clinical trials
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  #10  
Unread 06-12-2013, 03:32 PM
acecombact1 acecombact1 is offline
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This is also interesting:

http://www.pbs.org/wgbh/nova/body/evans-narkar-qa.html
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