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Targeting Alpha 2 for maximum fat loss

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Phosphate Bond
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I figured it would be interesting to get peoples opinions on this.

It appears to me that the alpha 2 is at the crux of the problem involving the adipocyte. Typically it is upregulated in adipocytes resistant to lipolysis and having it downregulated is advantageous for being able to generate a cAMP respone (cAMP initiates lipolysis)

One ligand for the alpha 2 is ATP (intracellular) which results in both opening the k+ channel and pumping intracellular calcium extracellularly. Now this good for three reasons- 1) lowering intracellular calcium reduces actions of phosphodiesterase and obese people are known to have high levels of calcium in their adipocytes 2.) opening the potassium channel resets the gradient for the Beta 2 (beta 2 is diametrically opposed to alpha 2 at potassium channels) 3.) ATP iteslf is a substrate for adenylate cyclase to act (ATP--> cAMP)

There are several ways to increase intracellular ATP. Training that improves blood flow and thus the delivery of oxygen via hemoglobin . Thyroid hormone improves the rate of ATP synthesis. Perhaps certain nutrients like r-alpha lipoic acid help re-direct energy metabolism through the quicker and more efficient complex 1 rather than complex II. EPA is known to promote ATP formation several ways and seems to act via alpha 2 mechanisms.

So the question in my mind is where do you go from here? I've used products like fish oil and R-ala in the past and feel they have a place in supplementation but there use must carefully being integrated into the plan. Actually excessive fish oil supplementation produces an interesting effect: It basically increases ATP too much along a beta 2 blockade produced by arachidonic acid depletion. What happens is the potassium channel opens, however since there is beta 2 blockade the cell has no other pathway to control this movement of potassium other than calcium influx to lower the ATP. This will continue over and over again until a state of hypometabolism is reached which probably corresponds with phosphatidylserine replacing phosphatidylinositol (second messanger of alpha 1) Actually that is the difference between EPA and DHA, both increase beta receptor sensitivity but in different ways. EPA helps increase ATP and DHA does this by calcium influx (which you need for visual acuity) which opposes cAMP.

Lately I've been trying a blend of arachidonic acid and EPA Which I think may get me the best of both worlds. . The EPA increases ATP and reduces calcium levels while the AA controls the outward movement of potassium but has no effect on extracellular calcium movement inward (at least from the exterior of the cell...it may cause calcium release from the sarcosplasmic reticulum as ATP drops, It may also impair the ability of the cell to pump out calcium already there, but that's why you make sure alpha 2 is fully activated before doing this.). In skeletal muscle the intracellular movement of potassium is an anabolic effect from AA and is probably tied to PPAR beta effects occuring there also (which helps burn the fat released at the same time)

Or maybe I should just stick to manipulating energy metabolism independent of omega 3s with stuff like R-ala/thiamine analogs? Or maybe a combination of both?

One thing I am fairly confident saying is that calcium influx in a low ATP environemnt (alpha 2 upregulated) would be a disaster. All it would do is increase intracellular calcium with little hope of being able to pump it out. Like I said before obese people have this problem as evidenced by the the high 1,25 OH vitamin D in their fat cells accompanied by the intracellular calcium which blunts ATP accumumulation and cAMP. Unfortunately DHA by itself could do this if used in the wrong situation. The take home message here is you need to fix intracellular calcium problem before attempting to increase cAMP.

In a nutshell:

EPA: alpha 2 agonist
AA: beta 2 agonist (let me say that it at least appears to be necessary and/or possibly enhances beta 2 response)

Both alpha 2 and beta 2 fully activated leads to maximal cAMP potential via alpha 1s unobstructed ability to raise cAMP through Beta 1. "Crosstalk" between alpha 1 and beta 1 is clearly documented in the literature and I can explain this to anyone interested. This alpha 1 to beta 1 cAMP response should also be fairly resistant to downregulation in a manner similar to Beta 3 (which I'm not really sure exists per se, "Beta 3" may just be a metabolic state where cooperation between alpha 1 and beta 1 is maximized)


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liorrh
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OT: yes you can change fiver type and the best example is injury/immobilization. everything becomes type II. its all about input-> input determines function function determines form.


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Kimbo
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Posted by: @liorrh
OT: yes you can change fiver type and the best example is injury/immobilization. everything becomes type II. its all about input-> input determines function function determines form.

Yeah, I think type IIC fibers actually appear after at least a few days of inactivity - which is ironic, since they are extremely fast twitch fibers. Upon hitting the gym again they convert to IIB.

If someone says something about you, and it really bothers you, it's probably because it's true.


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Phosphate Bond
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Posted by: @The Godfatha
Trouble I was under the distinct impression that a high intensity cardio session after resistance exercise would only further increase cortisol levels (that are elevated from the weight lifting anyway) rather than decrease it?

Phosphate I thought you believed that AA and DHA is the best combination (due to EPA depletion of AA) and you said you took that combo on BB.com. Have you changed your mind now or do you feel specifically for fat loss that AA + EPA would be better? I may have just misunderstood the thread completely.

No it definitely looks like EPA can increase AA via its effects on reducing intracellular calcium (this enhances AA storage in the membrane and enhances a beneficial accumulation)

I had this great abstract that pointed out how cooperation between AA and EPA was the key to biological understanding. DHA has a role too although its much smaller. If anything DHA would keep the resting sodium and bicarbonate threshold in the kidney manageable in some cases (also enhances availabilty of molecular O2 needed for COX-2 and other neurotransmitters enzymes like tyrosine hydroxylase ) so you could focus and concentrate more inositol through glycolysis in muscle before cortisol interupted this . What I'm saying is the gradient towards high glycolysis in muscle (and in the brain, activating key neurotransmitter synthesizing enzymes) would be greater as long as you could control basal glucose metabolism everywhere else (you want to be burning fat in resting conditions not glucose) This would be more important for an endomorph than an ectomorph but the principle still applies. I suspect cortisol works by decreasing glycolysis and thus phosphoinositol concentrations in muscle and fat would be affected (it seems to increase phosphatidylcholine in some cases)

There are acid/base relationships you need to understand in order to make sense of what I just said (for anyone knowledgeable on this I was talking about correcting metabolic alkalosis with respiratory acidosis which seems to found in obesity), but if happen to undestand a few key relationships it fits together nicely. Where people drop the ball is by going too agressive with their fish oil and depleting AA you need for good insulin sensitivity and the ideal sharp insulin response that is highly anabolic in skeletal muscle. I've overdosed on fish oil myself and flax on top of this only makes it worse because you simultaneously cripple endogenous AA formation.


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The Godfatha
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Posted by: @Phosphate Bond
No it definitely looks like EPA can increase AA via its effects on reducing intracellular calcium (this enhances AA storage in the membrane and enhances a beneficial accumulation)

I had this great abstract that pointed out how cooperation between AA and EPA was the key to biological understanding. DHA has a role too although its much smaller. If anything DHA would keep the resting sodium and bicarbonate threshold in the kidney manageable (also enhances availabilty of molecular O2 needed for COX-2 and other neurotransmitters enzymes like tyrosine hydroxylase ) so you could focus and concentrate more inositol through glycolysis in muscle before cortisol interupted this . What I'm saying is the gradient towards high glycolysis in muscle would be greater as long as you could control basal glucose metabolism everywhere else. This would be more important for an endomorph than an ectomorph but the principle still applies. Yeah I think cortisol works by decreasing glycolysis and thus phosphoinositol concentrations in muscle and fat.

There are acid/base relationships you need to understand in order to make sense of what I just said, but if happen to undestand a few key relationships it fits together nicely. Where people drop the ball is by going too agressive with their fish oil and depleting AA you need for good insulin sensitivity and the ideal sharp insulin response that is highly anabolic in skeletal muscle. I've overdosed on fish oil myself and flax on top of this only makes it worse because you simultaneously cripple endogenous AA formation.

In your opinion (and I know many people will probably disagree with you) is 6g of fish oil (6x standard 180/120 caps) excessive? Obviously it is difficult to give a definate answer beacuse it depends on the AA levels in the diet as well but assuming a standard BBer diet i.e. few egg yolks, mostly lean chicken and turkey, tuna etc


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Phosphate Bond
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Posted by: @The Godfatha
In your opinion (and I know many people will probably disagree with you) is 6g of fish oil (6x standard 180/120 caps) excessive? Obviously it is difficult to give a definate answer beacuse it depends on the AA levels in the diet as well but assuming a standard BBer diet i.e. few egg yolks, mostly lean chicken and turkey, tuna etc

Tough to say. However consider this...

Fish oil has the interesting advantage of letting a person walk around with a lowered plasma volume and not go into lactic acidosis. This is because it improves the efficiency of the electron transport chain (deep water fish like this because their is less O2 underwater to pass electrons to). Although sodium and bicarbonate reabsorption is lowered at rest , PH will balance through the lungs because you'll compensate by blowing off more CO2 (an acid ) under basal conditions.

However if you really did deplete AA you'll have problems during exercise when metabolism accelerates and you start making H+ from cellular metabolism. This is because you will have lost the ability to match sodium and bicarbonate reabsorption to acid production (giving water). Not to mention the CO2 being produced which further worsens the ph problem here (remember you were balancing through the lungs previously)

Definitely being able to store AA and use it when you need it helps you produce energy. Although the starting set-point of sodium retention does matter. In fact, I'm pretty sure all that metabolic syndrome stuff is tied in with excessive anaerobic basal metabolsim (from excessively high sodium set-point compounded by CO2 retention) which stimulates triglyceride production and lipoprotein lipase activity in adipocytes.


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Spook
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Posted by: @liorrh
OT: yes you can change fiver type and the best example is injury/immobilization. everything becomes type II. its all about input-> input determines function function determines form.

You need to be careful with your language. If you actually mean fiber type switch you are wrong if you mean myosin change you are correct. Look at studies on myoblast formation and EDL to solus (or vice versa) transplantation to see why fibers don't actually change type. Particularly telling are the ones that transplant EDL satellite cells in to the solus or vice versa. Namely the satellite pools are quite different and allthough the mysoin form does change according to transplant things like fuel selection and other oddities do not.

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liorrh
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Posted by: @Spook
You need to be careful with your language. If you actually mean fiber type switch you are wrong if you mean myosin change you are correct. Look at studies on myoblast formation and EDL to solus (or vice versa) transplantation to see why fibers don't actually change type. Particularly telling are the ones that transplant EDL satellite cells in to the solus or vice versa. Namely the satellite pools are quite different and allthough the mysoin form does change according to transplant things like fuel selection and other oddities do not.

I did a lot of research regarding data on muscle of immobilized or injured patients and I remember they all became "type II" by that I mean is they all became anaerobic in the simplistic sense - lost most of their aerobic cellular machinery that was upregualted and kept so with normal movement, like mitochondria, enzymes, buffering capablities, most of their volume etc. so I'm not sure why would they be metabilically the same. I know the study with the cross linking of the nerves, I was under the impression it also supported what I said but that is based on hearsay, I never read it
you are talking about something that I didn't hear about - the trasnplanting of satelite cells. interesting, I'll need to check that out.


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trouble
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I thought I might kick this thread back up again and put it on track.

PB: tell me, what have you come arcoss regarding adenosine regulation of AA in adipocytes?


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Phosphate Bond
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Posted by: @trouble
I thought I might kick this thread back up again and put it on track.

PB: tell me, what have you come arcoss regarding adenosine regulation of AA in adipocytes?

Do you mean arachidonic acid stored as a triglyceride inside the adipocyte (which is a definite problem exacerbated by all that sodium set-point and lipoprotein lipase regulation stuff I was talking about in that other thread) or as a phospholipid on the cell surface of the fat cell?


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trouble
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Either one.


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Phosphate Bond
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Posted by: @trouble
Either one.

Do you have any abstracts in mind? This is really complicated because adenosine impacts the kidney and the lungs. That response will in turn modify what the cell "sees" on top of any direct adenosine response.

If you look at this somewhat backwards using caffeine (an adenosine blocker) its pretty interesting. It seems to act like an alpha 1 blocker, but upregulates it at the same time ("ionized" calcium does this too. The ioniztion being ph dependent is a key point to understand). What really interests me is what happens to intracellular ATP concentrations which I suspect get impacted later on.

Speaking of Calcium, magnesium can act like an adenosine agonist in some situations. I think it depends on what direction/perspective you are coming from when trying to figure out how this all works.

A quick and dirty way to think of this is whenever ATP (adenosine and magnesium to a lesser extent) is too high calcium influx will occur bring to halt any cAMP going. This will occur unless calcium coming off plasma proteins is strong enough to oppose this outward movement (total "ionized" calcium opposes intracellular ATP effect on K+ channels). Adenosine blockers are supposed to prevent this from happening also.

Now here is the kicker. You occassionally should downregulate the alpha 1 especially in the kidney and not always having cAMP going endlessly in the face of alpha 1 upregulation. In muscle it may differnt though because I can see how an upregulated alpha 1 (phosphoinositol) would help here. Thats were the differential effects of weight training impact the big picture so much.

Only problem to upregulating the alpha 1 (phosphoinositol) in muscle is typically you'd need to downregulate it elsewhere (especially kindney and lungs)


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trouble
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Yes sir, you understood the gist of my query on the action of adenosine, and also my recommendation for more attention by board members to magnesium citrate supplementation.

The pH problems you mention can be partially offset with NAC, cannot it not?

Adenosine, as you note, plays many roles. I vaguely recall that it've seen it mentioned that it antagonizes cellular AA induced apoptosis.


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Phosphate Bond
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Posted by: @trouble
Yes sir, you understood the gist of my query on the action of adenosine, and also my recommendation for more attention by board members to magnesium citrate supplementation.

The pH problems you mention can be partially offset with NAC, cannot it not?

Adenosine, as you note, plays many roles. I vaguely recall that it've seen it mentioned that it antagonizes cellular AA induced apoptosis.

Cysteine would probably lend itself to releasing some sodium and bicarbonate in the kidney is my guess ("Mucomist"/NAC is supposed to work in the lungs as well) .

Whey protein does this also and its a cysteine donor. DHA increases cysteine formation and it seems to lower the sodium threshold too.

My guess is that NAC is like DHA and that it would work better if any ATP problems are addressed first. Some people don't react well to NAC. Maybe some of these alpha 2 problems are correlated to homocysteine (come to think of it they probably are because the same cytosolic NADH/NAD+ ratio that can lower energy metabolism determines serine availability necessary for cysteine formation. Most importantly though it needs to be intracellular cysteine and that is why methionine needs to be available ) ?. I do know the enyme converting homocysteine to cysteine is blocked if there is a methionine deficiency.

At this point this thread is begging for a re-cap to integrate all this stuff together. I'll try to summarize it after I get back. At the core of it I think it lowering the sodium bicarbonate threshold at rest (if you were trying to become leaner) , but still being able to stimulate it when you need to in order to match in step H+ produced from cellular metabolsim when you exercise (being able to do that requires ATP to store AA which ironically happens best opposite to its function at least in resting conditions it seems).


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Phosphate Bond
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Posted by: @trouble
PB: have you seen this paper. It suggests a FA synthsis regulatory role for DHA in liver and adipocytes.

The effect of dietary docosahexaenoic acid on the expression of porcine lipid metabolism-related genes. J. M. Hsu, P. H. Wang, B. H. Liu and S. T. Ding. J. Anim. Sci. 82:683-689 2004.

To study the effect of dietary docosahexaenoic acid (DHA) on the expression of adipocyte determination and differentiation-dependent factor 1 (ADD1) mRNA in pig tissues, weaned, crossbred pigs (30 d of age) were fed either 2% (as-fed basis) tallow or DHA oil for 18 d. Body weight of the pigs was not affected by different dietary fatty acid (FA) compositions. The plasma and liver FA composition reflected the composition of the diet. The adipose tissue and skeletal muscle FA composition only partially reflected the diet, indicating either a slower FA turnover or that a greater proportion of the FA in these tissues is from endogenous FA synthesis. The ADD1 is an important transcription factor that modulates transcription of FA synthase to regulate the endogenous FA synthesis in the liver and adipose tissue. The ADD1 mRNA was decreased (P < 0.05) in the liver of DHA-treated pigs compared with that of the tallow-treated pigs. The diets did not have an effect on the ADD1 mRNA in pig adipose tissue. The ADD1 transcript was not detected in pig skeletal muscle. These results indicate that significant enrichment of liver DHA content inhibits the expression of ADD1 mRNA. Such an effect is similar to that reported in porcine differentiating adipocytes cultured with DHA. The liver and muscle acyl CoA oxidase mRNA concentration was increased (P < 0.05) by DHA oil treatment, suggesting that DHA treatment may increase peroxisomal fatty acid oxidation in these two tissues. Our present observations demonstrate that dietary DHA enrichment not only affects tissue DHA concentration but also mildly modifies the expression of genes related to fatty acid metabolism in the porcine liver and skeletal muscle.

I think you might find this interesting. Vanderbilt clinical nutritional research investigator, Mike Freeman, is working on the following: "It is hypothesized that DHA induces Nrf2 (a master regulatory protein) –dependant synthesis of glutathione. This increase in the concentration of the antioxidant leads to a decrease of the concentration of reactive oxygen species, which prevents activation of Calcium/calmodulin-dependent protein kinase II (CaMK II). Because activation of CaMK II is associated with tachyarrhythmia, it is proposed that DHA would lead to prevention of the arrhythmia.."

Calcium channel effects, via glutathione. This would effectvely control ion flux imbalances in many cells types, myocyte and adipocyte.

I'm sorry I didn't see this earlier. Yeah DHA I'm sure has some effect on glutathione because it is involved with cysteine formation in tissues. Plus all those cytochromes in the ECT need it. Not to mention the cysteine iron centers of the krebs cycle.

However, the challenge these omega 3s face is getting out of the liver similar to vitamin A.

Speaking of calcium movement I'm pretty certain its reputation as a calcium channel blocker comes from its downregulation of phosphoinositol.


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