For general fat loss, is administration of PPAR-gamma antagonist favorable over long term for people who are relatively healthy (bb's like us)?

For those who'd like some background: to simplify matters a bit, PPAR gamma promotes pre-adipocyte differentiation. The idea is that, with PPAR-gamma antagonist, one can prevent fat cell turn-over. With exercise AND PPAR gamma antagonist administration over long term, one might be able to become leaner.

I don't think there are any PPAR gamma antagonists that have made it to clinical trials in humans yet.

PPAR-gamma antagonist will work very well in my opinion.

DHEA, and the sulphate, and I think a metabolite, have been shown to antagonize PPAR-gamma under various conditions.

It is looking like 10,12 CLA works via PPAR-g antagonism as well -- need to find one that is 70-80% 10,12 -- thought I heard someone had a higher grade material -- but, I have not lookied into yet.

I would use it in gel #3

DHEA ingestion has been shown to be antagonistic to PPAR-gamma. This property hasn't been studied rigourously in an human clinical trials that I am aware of. However, I strongly believe that the synergistic combinations of DHEA, and CLA -(especially predominantly high-amounts of the 10,12 isomers), combined with a few other nutrients will work quite well in vivo as a PPAR-gamma inhibitor with multiple beneficial applications...

I couldn't tell you where but I recall reading somewhere that a combination PPAR-gamma antagonist/PPAR-delta/beta agonist was in the works.

Would be a super drug for fat loss and all the rest.

Lyle

The thing that has always bugged me about DHEA though is that (in rats) it acts directly on the pancreas to increase insulin secretion in response to glucose, leading to increased glucose uptake in muscle, with the consequent reduction in mitochondrial beta oxidation of lipids. This is what we were talking about in the other thread recently on the potential folly of trying to increase glucose uptake at the same time one is trying to burn fat. Presumably the other antiadipogenic effects of DHEA offset this decrease in beta oxidation.

Being a big fan of T3, one could offset the abovementioned adipogenic effect of DHEA by using T3 to reduce insulin secretion.

A single drug like lyle mentioned, or even a cocktail of different PPAR agonists and antagonists would be great.

AMPK activation is able to do exactly this, and has PPAR-y/p300 anatgonistic effects as well, among other actions. I believe now AMPK is one of the primary reasons intense exercise is such a great nutrient partitioner, after having gone through the literature.

The negative effects of AMPK on protein synthesis makes AICAR a less than perfect supplement, unfortunately. Granted, that effect probably could be offset, as mTOR is not the end-all be-all regulator of protein synthesis.

These may be of interest:

http://www.ncbi.nlm.nih.gov/entrez/query.f...8&dopt=Abstract

http://www.ncbi.nlm.nih.gov/entrez/query.f...9&dopt=Abstract

We actually had a lengthy discussion about AICAR and AMPK a while back:

http://forum.avantlabs.com/index.php?act=S...t=3983&hl=aicar

I'm not convinced it's a free lunch though, for the reasons we discussed in the thread (reduced futile cycling for instance) and because there has to be a fate for the glucose that undergoes glycolysis but that does apparently not enter the citric acid cycle because acetylCoA from fatty acids is entering it instead when AICAR activates AMPK.

The glucose could be acting as a substrate for increased denovo lipogenesis, or the increased lactate from glycolysis without mitochondrial oxidation of the glucose could be acting as a fuel somewhere else (as in some other muscle tissue unexamined in the study). Unfortunately the second study did not shed much light on the fate of that glucose, other than it was not being stored in muscle as increased glycogen under the action of AICAR.

There is no possibility of increased glycogen synthesis?

There is always the possibility that both fatty acids AND glucose were being used for fuel. The next to last paragraph in the discussion alludes to that. It's not as if this is an all or nothing type of system where ONLY fat OR glucose can be used for ATP production. Under most non-extreme circumstances (i.e. RQ not 0.7 or 1.0), most cells in the body use a mix.




In muscle? Doubtful, not a lipogenic tissue.



A good possibilty, occurs under other conditions. Also, liver can use lactate for gluconeogenesis.



It does point out that goofy shit happens when you induce rather non-physiological conditions on a cell. High insulin and high AMPK shouldn't occur under normal physiological conditions for the most part (tho the next to last paragraph mentions an increase in AMPK/fat oxidation under exercising conditions before insulin has fallen).

Lyle

Nandi12- I did come across that thread, although I apparently missed your posts, as I skipped to the middle- my apologies.

You bring up a godd point regarding the fate of the glucose- I always assumed that it was going towards glycogen, but given AMPK's antagonistic effect on glycogen synthase, that seems to be unlikely, immedietly. IIRC, in the "lazy mice" study by Mu et al., the AMPK-a2 transgenic mice were actually unable to respond to hypoxia-induced glucose uptake enhancement- if this is so, then it suggests that glycogen synthesis ultimately occurs, although, to my knowledge, no study has measured glycogen synthesis in relation to AMPK over a period of several hours.

I am interested in hearing your thoughts on this, as I can't understand why studies that have measured body comp have not seen changes between AICAR vs. placebo, yet given AMPK's powerful anti-lipogenic effects (which leads me to belive de novo lipogenesis is not the fate of the glucose), this does not make sense- unless, as you suggest, the reduction in futile cycling is great enough to offset AMPK's effects.

I was being rather sloppy; I should have been more careful in my wording. I was sort of using lactate and glucose interchangably. The lactate (which was quite elevated under AICAR) is free to diffuse to the liver where it can be converted back to glucose and used as a substrate for lipogenesis there or in adipose tissue. Once phosphorylated after entering the muscle cell, the glucose itself cannot diffuse back out of the cell to be used in adipocytes as a fat substrate.



I believe the second article noted no increase in glycogen after AICAR treatment

If you check out the paper by Fajas et al. (2003) in Journal of Lipid Research, I think you'll find some references to NSAIDS and antagonism of PPARgamma.

I contacted the authors of this paper and they feel that the concentrations of NSAIDs (non-steroidal anti-inflammatory drugs) needed to inhibit clonal expansion of pre-adipocytes can be achieved in humans via oral means.

I've been looking into this for a while, but continue to be perplexed. Some research suggests aspirin and other NSAIDS antagonize PPARgamma, and some research suggest the opposite. Of course, you also have to consider what other PPARgamma-stimulating substances NSAIDS might compete with in vivo, and how they might behave in their presence as opposed to in a test tube.

In short, I don't see anybody getting ripped off of aspirin.

I think there's your answer then. If oxidative metabolism was 'tied up' by FFA oxidation, the glucose went through anaerobic glycolysis to lactate.



Only relevant in rats as you well know.

Lyle

Yes, that's true. We've had several discussions on this board about how in humans de novo lipogenesis is "the road less travelled" to paraphrase the title of one paper on the subject. But that seems to be exactly because preferential oxidation of glucose in the citric acid cycle blocks the oxidation of fatty acids. I wonder though if AMPK activation via AICAR could throw a monkey wrench in that whole system, with glucose now being shunted away from mitochondrial oxidation into de novo lipogenesis. Pure speculation, obviously.

looks that way. From mouse models anyway. If you knock out PPAR-gamma or RXR receptors things get very nice indeed. (particularly for RXR knockout mice). However in mice bread with both knockouts you get lipodsitrophy which is to be expected. Seeing how thrifty larger organisms are in terms of fat storage I am even more inclined to thinkg a PPAR-gamma antagonist would work well. Hence my interest in DHEA.

There are some research studies that seem to indicate that differentiation of pre-adipocytes are important for fat redistribution. As we get older, this mechanism fails, and old people have weird pockets of fat -- this is attributed to mal-functions related to PPAR-gamma.

I suppose it is worthwhile looking into DHEA a bit more.

......