The PPAR dilemma

good read.

Here is a thread from the Avant site that might interest readers of this thread:

I cited some additional evidence that suggests indiscriminate NSAID use is not too wise. I can't imagine anyone actually advocating the use of PPARgamma agonists except in serious type II diabetes, as instynct does in this thread.

This is a decent review of bezafibrate:

Re: The PPAR dilemma

Posted by: Big Cat

What's even more surprising is that there is a very cheap, extremely effective ligand that both blocks PPARgamma (Valmaseda et al, 1999) and other markers of differentiation (Schwarz et al, 1997), activates PPARdelta directly (Shaw et al, 2003) and further activates metabolic expenditure by increasing UCP1 by 31% (Kumar et al, 1999) : Vitamin A ... [/B]

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Unfortuantely, the amount of Vitamin A I suspect is necessary is likely toxic.
Think Accutane level.

A PPAR-gamma antagoinst/PPAR-delta agonist would rule for fat loss. Fish oils appears to work somewhat in that capacity, BTW.

PPAR-alpha agonism will have at most a small effect, slight increase in fat oxidation in the liver, might add up over time. Can also cause cardiac cell death.

Lyle

Vitamin A doses are generally less toxic than you think. I did discuss this at length with my dad and two other doctors. They all seem of the opinion that its far healthier to give extremely large doses for a short period of time, than it is to give high normal doses for extended periods of time. Vitamin A treatments are usually extremely high, 45.000 units, for a short time of 2 or 3 months, rather than a mere 10.000 units for a whole year.

On top of that Vitamin A is mostly stored in adipose tissue under the influence of insulin. Meaning under diet conditions you do not store as much vitamin A as normal, so toxic levels are less likely to build up. I've been experimenting with this for nearly 6 months now and I'm very satisfied with the results. I've narrowed it down to 25.000 to 30.000 units for a period of 12 weeks, followed by at least 8 months without.

I hear you on the PPARalpha and cardiac problems. PPARa overexpression seemed to mimic the effects of diabetes on the heart.

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On top of that Vitamin A is mostly stored in adipose tissue under the influence of insulin. Meaning under diet conditions you do not store as much vitamin A as normal, so toxic levels are less likely to build up. I've been experimenting with this for nearly 6 months now and I'm very satisfied with the results.

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What results have you seen?

Lyle

Posted by: Nandi12

This is a decent review of bezafibrate:

It seems to confirm for a large part that the beneficial effects are indeed mostly PPARbeta mediated.

It also raises another important issue I have talked about a few times. Now I'm not the big believer in leptin, not because I don't think its interesting or because I can't see its use, but mostly because of lack of clear points of significant manipulation. But since many people here do seem to be on the leptin bandwagon, that makes it even harder for me to understand why PPARgamma antagonism hasn't had a much more prominent place in counter-acting fat gain much sooner. PPARgamma reduces leptin. By blocking PPARgamma, you not only inhibit lipogenisis, you also increase leptin secretion.

PPARgamma antagonism/PPARbeta agonism simply is the best target for fat loss available to us.

Posted by: Big Cat

[B]It seems to confirm for a large part that the beneficial effects are indeed mostly PPARbeta mediated.

It also raises another important issue I have talked about a few times. Now I'm not the big believer in leptin, not because I don't think its interesting or because I can't see its use, but mostly because of lack of clear points of significant manipulation. But since many people here do seem to be on the leptin bandwagon, that makes it even harder for me to understand why PPARgamma antagonism hasn't had a much more prominent place in counter-acting fat gain much sooner. PPARgamma reduces leptin. By blocking PPARgamma, you not only inhibit lipogenisis, you also increase leptin secretion.

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2 things
a. Unless leptin has already been lwoered by diet/etc, raising it is ineffective. Raising leptin in fat people with diabetes won't do anything in terms of preventing fat gain. Remember that leptin is NOT an anti-obesity hormone, it's an anti-starvation hormone. Raising leptin while dieting (or preventing the drop) is a fundamentally different thing than raising it prior to dieting.

b. current diabetes/drug treatment is mainly concerned with generating rapid clinical improvements in what they think matters which is blood gluose levels. And PPAR gamma agonism certianly does that in the short-term.

In fat/diabetics PPAR-antagnoism would cause more problems than it would solve. It would raise leptin, doing little and limit blood glucose into fat cells even more.

It'd only be in a dieting/lean individual sitaution that such would be useful.

Lyle

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Remember that leptin is NOT an anti-obesity hormone, it's an anti-starvation hormone.

This is the key concept that seems to be lost on those who advocate leptin stimulation for weight loss. Normally I don't do all that well in the stock market but I lucked out with a quick trade on Amgen several years ago when they were hyping leptin as the key to treating obesity. You can actually make money off of PubMed.

Posted by: lylemcd

2 things
a. Unless leptin has already been lwoered by diet/etc, raising it is ineffective. Raising leptin in fat people with diabetes won't do anything in terms of preventing fat gain. Remember that leptin is NOT an anti-obesity hormone, it's an anti-starvation hormone. Raising leptin while dieting (or preventing the drop) is a fundamentally different thing than raising it prior to dieting.

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On a brighter note, lit also suggests that PPARdelta agonism and PPARgamma antagonism may help improve insulin and leptin sensitivity ... So even from that standpoint it may still be a superior target.

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b. current diabetes/drug treatment is mainly concerned with generating rapid clinical improvements in what they think matters which is blood gluose levels. And PPAR gamma agonism certianly does that in the short-term.

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Only because of expansion of a cell lineage with fresh receptors. If we go over current treatment and the times the medical profession has been wrong in the past, we'd have a long discussion. So I don't really see the relevance of this remark. I personally don't consider "lets create some more room to store the glucose" a valid approach. I have been using a variety of methods, on top of a solid diet to limit the culprit, namely glucose uptake into the body with much greater success.

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In fat/diabetics PPAR-antagnoism would cause more problems than it would solve. It would raise leptin, doing little and limit blood glucose into fat cells even more.

I'm not saying its a one stop solution. So far I have been able to combine it with four-pronged approach at lowering blood sugar. First is glucomannan fiber, which slows digestion. The second is a combination of sacharrase blockers with two distinct benefits. Minimal targeting of other disachharidases, and an anti-microbial function so as to limit the main side effect of glucomannan and sacharrase blockers in general, namely diarrhea. Thirdly a compound that inhibits glucose uptake across the gut without exerting any effect on internal glucose metabolism, and lastly a compound that acts like insulin in activating GLUT4, but lowers actual insulin and doesn't possess insulin's adipigenic properties. Together you limit glucose intake, serum glucose levels, serum insulin levels and slowly improve leptin sensitivity. Add in various products that target obesity specifically, such as a PPARgamma blocker and a PPARdelta agonist, a non-steroidal 11bHSD blocker to avoid diet induced central obesity and a good diet, and you find yourself with a valid approach to treat both type II diabetes and the ensuing obesity problems.

Posted by: Nandi12

This is the key concept that seems to be lost on those who advocate leptin stimulation for weight loss. Normally I don't do all that well in the stock market but I lucked out with a quick trade on Amgen several years ago when they were hyping leptin as the key to treating obesity. You can actually make money off of PubMed.

You'll have to teach me that someday

Aside from any benefit PPARdelta agonists can play in treating insulin/leptin sensitivity, it would also be wise to remember that many people who suffer Type II also often suffer hyperlipidemia and obesity, and that PPARd agonists and PPARg antagonists can play a role in treatment there as well. Provided of course you don't immediately assume PPARg agonism to be the first and only step in treating high serum glucose.

Now that I've had a chance to read that link to avant you provided, I think you've posted it before. Because I remember telling you in reply to your question about other PPARbeta/delta stimulants, that carbacyclin was also a dual alpha/beta agonist.

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[i]Originally posted by Big Cat [/i

Only because of expansion of a cell lineage with fresh receptors. If we go over current treatment and the times the medical profession has been wrong in the past, we'd have a long discussion. So I don't really see the relevance of this remark. I personally don't consider "lets create some more room to store the glucose" a valid approach. I have been using a variety of methods, on top of a solid diet to limit the culprit, namely glucose uptake into the body with much greater success.

You're missing my point entirely.

You asked why they use PPAR-g agonists when it has these negative effects. I told you why THEY do it.

I don't think it's a valid approach either. It's rather stupid in the long term. Exercise + a reduction in carbs + a reduction in fat mass wold work better. But see below.

What you or I think is irrelevant to what the clinicians want to see and what the drug trials are looking at. They want rapid short term improvements in clinical parameters related to diabetes. That long-term it causese more problems than it solves (via fat mass expansion) is fairly irrelevant to that.

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I'm not saying its a one stop solution. So far I have been able to combine it with four-pronged approach at lowering blood sugar. First is glucomannan fiber, which slows digestion. The second is a combination of sacharrase blockers with two distinct benefits. Minimal targeting of other disachharidases, and an anti-microbial function so as to limit the main side effect of glucomannan and sacharrase blockers in general, namely diarrhea. Thirdly a compound that inhibits glucose uptake across the gut without exerting any effect on internal glucose metabolism, and lastly a compound that acts like insulin in activating GLUT4, but lowers actual insulin and doesn't possess insulin's adipigenic properties. Together you limit glucose intake, serum glucose levels, serum insulin levels and slowly improve leptin sensitivity. Add in various products that target obesity specifically, such as a PPARgamma blocker and a PPARdelta agonist, a non-steroidal 11bHSD blocker to avoid diet induced central obesity and a good diet, and you find yourself with a valid approach to treat both type II diabetes and the ensuing obesity problems. [/B]

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Only exercise and diet is more effective - The Simpsons

But people are fucking lazy and diabetics are known for being absolutely horrid about taking care of their condition. I'm sur ehte above works wonderfully, if a diabetic treatment guy says "take this one pill and that's it" the average lazy fuck will do it.

Lyle

Posted by: Nandi12

This is the key concept that seems to be lost on those who advocate leptin stimulation for weight loss. Normally I don't do all that well in the stock market but I lucked out with a quick trade on Amgen several years ago when they were hyping leptin as the key to treating obesity. You can actually make money off of PubMed.

AT the time, nobody knew any better, Amgen couldn't have known.
Still, I see people referring to leptin or considering it incorrectly, as an anti-obesity hormone. It's not.

What would be (and has been shown to be effective in at least two small human trials) is repalcing leptin to pre-diet levels AFTER weight reduction.

But this is not the kind of drug that obeisyt folks want, they don't want a drug where you have to diet anyhow. They want adrug that *causes* weight loss.

Leptin isn't it.

Lyle

Posted by: lylemcd

Only exercise and diet is more effective - The Simpsons

But people are fucking lazy and diabetics are known for being absolutely horrid about taking care of their condition. I'm sur ehte above works wonderfully, if a diabetic treatment guy says "take this one pill and that's it" the average lazy fuck will do it.

I think for many of these people they need a kick in the butt to show them they can do it, and like it. Such treatments are necessary, even if it is just a first step. Getting healthy, but even more importantly staying healthy, can only happen with a varied diet and a lot of exercise. No arguing. But try getting a 400 lbs person to run enough laps to burn a pound of fat off, and in the face of the first exercise he's done in years, not gain another by the post-exercise meal.

The epidemic has gone so far that we need some sort of first line treatment that pays off, even if just minimally, without adequate exercise and that aids in maintaining the diet.