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Par Deus

The Carb Up (2001)

In the last episode of The CKD Files, Derf and Dan Jr. had just returned home from the gym following their two hour glycogen depletion workout and had subsequently commenced preparations for the ensuing carb-up. 

Setting: Daytime in a living room

DERF: Typical musclehead, 240+ lbs, sub 6% bodyfat, head shaved to hide the consequences of years of 5-alpha reductase activity, rummages through a tackle box full of pills, vials, and syringes.

DAN JR: who couldn't grow on a gram of tren a day, sits, rolling a joint.
 
 
DERF
Dude, I'm low on gear.

 
 DAN JR. 
Yeah, me too. We should go back by the gym and see BigWill after we smoke this.
 
He takes a puff and hands it to Derf, who does the same.

 
DERF 
I'm gonna need to eat first.

 
DAN JR.
(annoyed) 
Did you take your shot already??
 
He nods, a bit woozy. Dan just shakes his head, grabsa syringe, and stands up. 
 
Derf passes out. 
 
Dan heads to the kitchen and returns with a bottle of glucose. He draws some into the syringe and injects it into one of the giant veins on Derf's arm.
 
He comes to.

 
DERF 
Thanks, dude. Let's hit McDonald's.

 
DAN JR.
(shakes his head)
That's far too high in fat. Glycogen storage and amino acid uptake are optimal right now -- We need high Glycemic Index carbohydrates. A post workout drink of dextrose and whey is ideal.

 
DERF 
Bullshit. I haven't had anything except whey and flaxfor the last two weeks. I want some food.

 
DAN JR. 
Fine. But, we're not eating McDonald's -- we'll go toan all you can eat place.
 
Dan takes out a syringe and injects himself in thethigh. 

 
DERF 
Nubain?

 
DAN JR. 
Insulin.
 
Derf nods. Dan pulls out another.


DERF 
Nubain?


DAN JR. 
GH.
 
He injects it and pulls out another.


DERF 
Nubain?


DAN JR. 
Yep.
 
 
Setting: Daytime at all All-You-Can-Eat Restaurant

They walk into the restaurant, anxious to begin refilling of glycogen stores and raising leptin levels. There are a couple of people in line in front of them, so they step back. 

They stand there for a moment, already impatient, when an OBESE WOMAN waddles up and cuts in front of them in line. 

They give each other a "What the fuck?!" look, then stare at her back, in a rage fueled by low blood sugar, serotonin depletion, and supraphysiological androgen levels.


DAN JR.
Did that chubby bitch just cut in front of us? 


DERF 
Yeah. 


DAN JR. 
Does she think we're just standing here to greet people as they walk in the door?
 
Derf shrugs.


DAN JR. 
She doesn't need to be getting seconds anyway. 


DERF
Nope. 


DAN JR. 
How much do you think she weighs?


DERF 
Three hundred? 


DAN JR.
I'm thinking maybe as much as four bills. But it's pretty hard to tell when they get that big... I'd say she's definitely pushing at least three and somechange... You'd think they'd have some kind of width limit to eat at all-you-can-eatrestaurants. You know? 


DERF
(laughs) 
Like the height requirements for rollercoasters? 


DAN JR.
Yeah. They should have a sign when you first walk in the door with a guy holding his arms out that says: 
 
Dan holds his arms out really wide. 


DAN JR. 
"You must not be this wide to eat at this restaurant." -- 'Cause if you are, you damn sure don't need to be eating at an all-you-can-eat restaurant.
 

DERF 
She needs some EC.


DAN JR. 
Fuck EC, she needs DNP and some meth. 


DERF 
Maybe she just has low leptin levels. 


DAN JR. 
Yeah, and maybe she swallowed a guy who swallowed a fly, but I fucking seriously doubt it. It takes a concerted effort to get that fat. You don't go to sleep one night looking like a normal human being and wake up the next day with 54% bodyfat. That doesn't happen. It takes years of determination and willpower. To look like that, there can be no skipping meals, no going to bed hungry, no exercise. Shit, just walking from the couch to the kitchen must burn more than a hundred calories when you weigh that much... I bet she keeps a crate of Krispy Kremes, in her fucking living room, so she can grab a box whenever the urge should strike... Low leptin levels my ass. I guarantee you that bitch gets three tiers of food on her tray. 


DERF
(smiles) 
She's just got more to love, that's all.
 
Derf walks up closer to her back. He pretends to spank her.


DERF 
Big is beautiful. Ain't it baby. 


DAN JR.
(shaking his head) 
Fat is not beautiful unless you're a sick, deviant motherfucker with a fetish for that shit. It just isn't aesthetically pleasing.
 
The Obese Woman continues piling food on her tray.


DAN JR.
I mean, granted, culture and normal personal preferences play a role incertain aspects of what is considered beautiful at different times. For example: Hairstyles and fashion change -- certain trends are hip for a while, but fiveyears later are atrocious -- the 1980's come to mind.

But some things are universally beautiful. And certain things are universally not beautiful in any way, shape, or form. 


DERF 
Like what? 


DAN JR. 
Things like Nicole Bass, and pimples, and warts, and melted flesh from third degree burns... And well-fed bitches like her.


DERF 
You make a good argument.


DAN JR. 
Don't kid yourself, Derf. I'm not finished. I haven't yet begun to ridicule.


DERF 
Oh. 


DAN JR. 
You know it's gotta be unsanitary. I mean, can you imagine what kind ofbacteria and yeast and STD's and shit are spawning and fermenting betweeneach and every fucking chub roll on that immense body? 


DERF 
It's a sick thought. 


DAN JR. 
Of course, it is. And the other day I heard on Oprah something about "foodaholism". Like it's a fucking disease, like cancer. Like they can't help. Like it's not their fault. 


DERF 
I did read on MFW about a study linking obesity to a virus. 


DAN JR. 
Well, then the CDC needs to come out here and quarantine this bitch. 


DERF 
(laughing) 
If it was a virus, what do you think they'd call it. 


DAN JR. 
There's already a name for what she has. It's called "gluttony". 
 
The Obese Woman turns around with two trays full of food, each with plates piled one on top of the other like a pyramid.


 DAN JR .
(as she walks by) 
How now, brown cow. 
 
She doesn't respond. Derf laughs, and they finally approach the windowto order their long-awaited food.

The End.
 
 
The following was a fictional skit. Any resemblance to actual people, be they from your local gym or alt.support.fat-acceptance, is purely coincidental.

Par Deus

The following is an interview with TC Luoma. TC is the editor of TestosteroneMagazine, former editor of Muscle Media 2000, bodybuilding pioneer, and badass. 

 

THE LESBIAN PIMP
How are you doing today, TC?


 

TC LUOMA

Man, I accidentally used too much Androsol this morning -- it's got me almost homicidal. I had to stop by a biker bar and kick some ass o­n my way out here. 

 

THE LESBIAN PIMP
Really?


 

TC LUOMA

Oh yeah. This is powerful stuff. I can literally feel the increased protein synthesis - in fact, I've gained 29 grams of rock solid mass in the last 2 hours. 

 

THE LESBIAN PIMP
Very impressive. Actually, you've made a number of impressive claims as far as results from different supplements over the years - it seems as though you should be vying for the Mr. O by now, yet looking at you, I can't really tell you work out.


 

TC LUOMA

Yeah, a lot of people say that. But, I'm 173 lbs at less than 13% bodyfat, so I just don't get it. And frankly, it pisses a T-dude off. In fact, if this Androsol wasn't wearing off, you'd be dead right now... just for bringing it up. 

 

THE LESBIAN PIMP
I see. Why did Charles leave T-Mag?


 

TC LUOMA

I can't go into that too much, for legal reasons. 

 

THE LESBIAN PIMP
Most of us assume that all of the hype and bullshit left him with a Biotest stank that he could no longer wash off of himself each night, even with Lava. And that has pumice, so it must have been really bad.


 

TC LUOMA

No. That's not it at all. It didn't have anything to do with Biotest. He--


(TC stops)
 

Let's just say he saw something that made our business relationship uncomfortable. 

 

THE LESBIAN PIMP
Like pissing in the Methoxy-7 or what??


 

TC LUOMA

Like I said, I can't really say too much - so I'll just leave it at this: "Me, Tim, full body latex, and a tub of vanilla Grow." 

 

THE LESBIAN PIMP
Fascinating. What was your relationship with Bill Phillips like?


 

TC LUOMA
(Getting teary eyed) 
 

I loved that man. Bill Phillips was a great man in the early years - when he still cared about the sport. But, then came the fame, then the drugs and the fitness bimbos... And after he started those physique transformation contests... he just turned into a completely different person. 
 

(TC breaks out crying) 


 

THE LESBIAN PIMP
There. There. It's gonna be okay.


 

TC LUOMA

He made me eat out of a dog bowl. 

 

THE LESBIAN PIMP
I see... Wait, he what?... Nevermind.

 

(TC calms down a bit) 

 

So what does the "T" in "TC Luoma" stand for, TC? I assume it must be something pretty bad if it made you go through life just using your initials - 'cause "TC" really sounds pretty stupid itself. I bet it's a hermaphroditic name- that would explain a lot of the machismo - you know, like a coping mechanism for sharing your name with a girl. Is it Terry?... Tracey?

 

(He bursts out crying again) 

 

TC LUOMA

Bill used to call me that... Are you clean, Tracey? Are you wearing my favorite dress??... Who's ass is this, Tracey?!
 

(he continues crying)
 

It's your ass Bill -- It's your ass! 
 

(He's hysterical)
 

Okay, I'll call you daddy -- please, just don't hit me again!

 

THE LESBIAN PIMP
Okay. I think that will just about do it. Thank you for coming by today, TC. We look forward to talking with you again soon.



Obviously, this has been a fictional skit -- it is parody, co-written by The Lesbian Pimp and Par Deus, and is not intended to be taken at all seriously, nor is it intended to imply anything about the sexual inclinations of the real TC Luoma, Tim Patterson, or Bill Phillips.

Par Deus
I have previously stated that I believe transdermal prohormones to be the most effective supplements ever to hit the market. That statement must now be amended. Transdermal prohormones are indeed the most effective MUSCLE BUILDING supplements ever to hit the market. But, topical fat loss products have the potential to be an even bigger overall breakthrough in the never ending quest to improve body composition.

There are four areas that need to be addressed in regards to topical fat loss products and so called "spot reducers" in general. First, one needs to distinguish between the products that are merely diuretics and those that the manufacturer (assuming they have a brain) actually thinks might significantly reduce body fat. Second, we have to have an understanding of the andrenergic system, which is primarily what these products attempt to manipulate in order to aid lipolysis Thirdly, we must have an understanding of transdermal/percutaneous delivery, in order to understand why a topical formulation could present advantages vs. orals, as well as to understand why every product of this kind currently on the market, other than LipoDerm-Y, fails. Within this category there are 2 issues -- getting adequate amounts past the skin barrier and localizing its distribution to adipose tissue. And, finally, there is the issue of Yohimbine HCl vs. yohimbe. After reading this, you should have an understanding of why true "spot reduction" is physiologically quite possible, as well as enough information to make an informed decision as to which products can and cannot accomplish it.
 
 
Fatloss Agents vs. Diuretics
 
Assuming we are not preparing for a photoshoot or competition, a product that merely acts as a diuretic rather than significantly aiding actual lipolysis is basically worthless. "Cutting Gel" belongs in this category -- its active ingredient is aminophylline:

Aminophylline is a xanthine derivative, similar to caffeine, which is not a particularly potent fat burner. In rat studies, it has shown good thermogenic properties due to blockade of adenosine receptors (which provide one of the negative feedback mechanisms for catecholamine induced thermogenesis) and inhibition of phosphodiesterase (which degrade cyclic AMP) -- but this is at extremely high doses, which would kill a human, so it is not applicable (1,2). At therapuetic doses, only adenosine blockade occurs, which will act to increase norepinephrine levels (3)-- but as you will see norepinephrine stimulates alpha 2 receptors (bad) in addition to beta 2 receptors (good) -- and in stubborn fat, alpha 2's outnumber beta 2's (4). 

Like caffeine, it is a good diuretic (5), which would account for the girth loss in the study they reference, which did not measure actual fat loss (6,7). One study did look at fat depth after use of an aminophylline cream, and no difference was found vs. control (8). As a local diuretic, it might be effective, but as a true fat loss agent, it quite likely is not.

Precontest, such a product could be extremely beneficial if it would truly localize the water loss, as it would allow one to get rid of extracellular water with out the total body dehydration produced by drugs such as Lasix -- thus, one could have fuller muscles, less cramping, etc. I am not particularly familiar with the physiology of diuresis, as I have not researched it to any great extent, so I don't know if it could actually be localized.

Products such as LipoDerm-Y, Impact's DermaLean, and S.A.N.'s LipoBurn (basically any of the products with yohimbine and a handful of other ingredients) fall into the latter category. They are intended to manipulate the adrenergic system, thus, theoretically, such products could cause true localized fat loss if formulated properly:

The Adrenergic System: Introduction
 
One of the major contributors to body weight homeostasis in the human body is the adrenergic system. There are two types of adrenergic receptors, alpha and beta, as well as subtypes of each -- and depending on which are activated, lipolysis (breakdown of fat) can be either stimulated or inhibited.

The most well-known adrenoreceptors to bodybuilders are the beta receptors. These can be divided into subtypes 1, 2, and 3 -- and it is through these receptors that drugs such as the ephedrine/caffeine stack and Clenbuterol exert their effects. While Clenbuterol acts directly on beta 2 receptors, ephedrine exerts its effects indirectly by stimulating the release of norepinephrine (NE), the body's primary endogenous thermogenic hormone. Unlike Clenbuterol, NE is not selective in its binding. In addition to binding to the beta 2 receptor, it also binds to both alpha receptors, as well as the beta 1 and 3 receptors. It is in regards to its binding to the alpha 2 receptor that yohimbine comes into play.

Norepinephrine and Yohimbine
 
Activation of the alpha 2 receptor inhibits the release of NE. Thus, by binding to this receptor, NE functions as its own negative feedback signal. In other words, it shuts off its own release. Obviously, this is not a good thing for fat loss. This is particularly true at rest (which, unless you are a marathon runner is 95% of your day) -- this is because alpha 2 receptors are activated at lower catecholamine levels than are the beta receptors (9). Thus, thermogenesis is basically always turned off. It is the differences in regional distribution of alpha 2 and the beta receptors that is responsible for the gender differences in bodyfat storage (4). Basically, females have a large number of alpha 2 receptors and few beta receptors in the gluteofemoral area (hips, thighs, and butt), while men have the same problem in the midsection. With exercise or the use of compounds such as the ephedrine/caffeine stack, catecholamine levels can be increased to a point where the alpha 2 induced inhibition of lipolysis is partially overcome (9). However, even then, the alpha 2 receptors ARE still acting to reduce lipolysis.

Yohimbine is a selective alpha 2 antagonist (10) and can thus short circuit this feedback loop, maximizing NE levels, thus maximizing fat loss, particularly in these problem areas -- and even more so if we can achieve high levels of yohimbine and NE in the adipose tissue. Unfortunately, to do so with orals, or any other method that results in high blood levels means that we will also have high levels in the heart and CNS -- thus, we will also have unpleasant and dangerous side effects. Considering the subject of this article, I obviously believe the solution lies in transdermal administration, but more on that in a bit.

Blood Flow
 
A second, more indirect, mechanism by which Yohimbine can aid lipolysis via the adrenergic system is by increasing peripheral blood flow (11, 12). Adipose tissue is known to have rather poor vascularity. When triglycerides are broken down into free fatty acids and glycerol during lipolysis, they must also be transported away from the fat cell or they risk being reincorporated into adipose tissue. Beta receptor activation causes vasodilation, thus increasing blood flow, however, it does not increase enough to remove all of the free fatty acids released during lipolysis (13). Alpha 1 and 2 receptor activation, on the other hand, causes a decrease in blood flow (4, 14). Thus, antagonism of the alpha 2 receptor with yohimbine would be expected to increase blood flow, and thus increase the mobilization and disposal of these FFA's, further aiding fat loss. And, again, the more we can get in the adipose tissue without it reaching the heart and CNS, the better.

Percutaneous Delivery
 
Though the terms are often used interchangeably in the literature, there are two distinct forms of drug delivery through the skin. The first, and most common, is "Transdermal Delivery" -- this involves a drug bypassing the skin barrier in order to be taken up into the bloodstream and distributed systemically (15). This basically does the same thing as oral delivery, but it is inherently time released and avoids first pass metabolism in the liver which can limit bioavailability and cause hepatotoxicity, so it is is advantageous for delivering many drugs. 

The second is "Percutaneous Delivery" (15)-- with this method, one bypasses the skin barrier, but with the purpose of delivering the drug to specific target tissues in the body, while AVOIDING uptake into the blood and subsequent systemic delivery. In the pharmaceutical realm, this has been pursued primarily for antibiotics and NSAIDS -- the former, to avoid destruction of systemic microflora (so-called "good bacteria"), and the latter to avoid hepatic recirculation, which is responsible for gastrointestinal problems. 

Unfortunately, the people who have developed most of the topical fat loss products thus far either do not know about or understand this difference or they do not understand its paramount importance in regards to adrenergic modulators such as yohimbine. With prohormones, systemic uptake and distribution is our goal -- they have poor oral bioavailability, so we are just trying to avoid the liver in order to get significant amounts in the bloodstream. 

However, with yohimbine and other adrenergic agents, oral bioavailabilty is not the issue -- at about 22%, it is more than adequate (16). We can readily achieve adequate blood levels with oral usage. The issue with these is that as we increase dosages (and thus blood levels) in order to increase distribution to adipose tissue to aid fat burning, we also increase distribution to the heart and CNS where we create numerous unwanted side effects such as rapid heart rate, high blood pressure, and overstimulation, which is particularly noticeable with exercises. Yohimbine is also used clinically to produce anxiety (17). Ideally, we want our drug to reach fat cells in high doses, without the dangerous side effects of high levels in the heart and central nervous system.

So, how do we do this?? Unfortunately, it is easier said the done. Typically, drugs that penetrate the skin barrier and traverse the epidermis and dermis are rapidly taken up by the dermal microvasculature, where they are delivered systemically (just like with orals) -- this is well characterized in the literature (15,18,19) -- with direct tissue penetration being limited to 1-4 mm, which obviously is not exactly deep into the adipose tissue. And, considering that these substances have good oral bioavailability, if the dermal microvasculature is not taken into account, we end up with a product that not only does not localize delivery, it does not even deliver it systemically as efficiently as an oral would do. Considering these products cost far more than there oral counterparts, and could also be thought of as inconvenient in that you have to rub them on your body, any supplement developer who doesn't take dermal uptake into account has obviously missed the boat quite badly. And, guess what... Not one single product other than LipoDerm-Y does. And guess what else -- they probably are not going to because we have filed a use patent on the one carrier that has been shown in the literature to effectively accomplish this.

Targeted Delivery
 
Let's now take a look at the literature that supports the idea of tissue specific delivery of therapeutic substances. As mentioned previously, when it comes to targeted delivery, the pharmaceutical realm, and thus the literature, has primarily concerned itself with antibiotics/anti-fungals and NSAIDS. We will look at the three most important ones.

Editors note: I am not going to give the name of the substance that has been shown to be effective as a vehicle for local delivery at this time. I may do so when the product comes out, as it has to listed on the label. Though we have filed a patent on it, there are many companies whom that will not stop from attempting to steal our intellectual property. They lack the intelligence and creativity to discover this sort of thing on there own (as well as the integrity to think such things matter) so they choose to make their money in this manner.

The first study (19b) involved the NSAID indomethacin as the drug to be delivered. The drug was given orally (O) , topically without the "special delivery solvent" (WO), and with the "special delivery solvent" (W). The topicals were applied to the shoulder. For the first two hours after administration, concentrations of the drug in the deltoid (which is obviously even deeper than adipose tissue) were 5 times higher in W than in either O or WO. After 4 hours, it was 3 times as high, and by 8 hours it was still twice as high. Obviously, the formulation containing the "special delivery solvent" was vastly superior at delivering the drug to the target tissue. But what about delivery to unwanted tissues? If it was just a case of the "special delivery solvent" allowing more drug to cross the skin, this would not be a big deal -- we could just use more. What we also need is for a minimal amount of the drug to be delivered systemically, and once again, the "special delivery solvent" was shown to be superior. Maximal blood levels of all three compounds occurred at the 2 hour mark. W displayed levels about 1/3 that of O and 1/2 that of WO. 

If the significance of this is not clear, it basically means that localized delivery (what we want) per unit systemic delivery (what we don't want) for W was 15 times that of O and 10 times that of WO -- and this was to the muscle. Considering the adipose tissue is closer to the skin (which had levels 10 times as high as the muscle) and that the joint capsule (which is below the muscle) had levels 1/3 that of the muscle while with WO there were equal levels at the muscle and joint, the ratio of delivery to adipose tissue vs. systemic delivery for W is likely significantly higher.

The second study (19c) utilized the antibiotic erythromycin as the delivery drug. Formulations for W and WO were identical to the above study. Oral administration was not tested. Exact counts of the concentration in muscle tissue was not reported, but the authors stated that after 4 hours, there was a major increase in the muscle mass below the site of application (I have contacted the authors to try to get exact data). Kidney and liver levels (indicative of systemic distribution) were significantly lower for W than WO -- about 1/2 for the former and 1/4 for the latter over 24 hours.

The third study (19d) we will look at utilized the antifungal griseofulvin as the delivery drug and compared W with oral intake. The formulation for W was the same as the previous two studies. The accumulation of the active compound in the area of application for W was several hundredfold greater than that which accumulated in the organs, and brain levels were non-detectable, which is extremely important considering we are trying to avoid excessive CNS stimulation -- and all of this was a full four days after application. Compare this to oral delivery which showed concentrations that were approximately identical in all areas, which would be expected if systemic uptake occurred.

Penetration Enhancement
 
I think it should be clear from the previous studies that it is quite possible to achieve targeted delivery. However, if we cannot get adequate amounts of our substance past the skin barrier, it is a mute point. And, considering one of the skin primary purposes is as a water barrier (20), hydrophilic substances such as yohimbine do not readily pass through (21, 22,23). Thus, we need to turn to the topic of penetration enhancement (for a more thorough presentation, see my previous article Transdermal Delivery. 

Yohimbine HCl, with a LogP of about .75 (24), is fairly polar/hydrophilic, thus penetration enhancers should be chosen accordingly -- namely we want those which affect the polar route. This rules out many commonly employed penetration enhancers -- a fact many companies do not seem to be aware of. Since there is very little direct data on penetration enhancement with Yohimbine HCl, we will look at data when substances with similar physical properties were used.

One promising chemical in this area is the terpene, l-menthol. Polar molecules undergo significant hydrogen bonding in the stratum corneum, which is the primary reason for their poor passage through the skin barrier (23). Because of the presence of a hydroxyl (OH) group, l-menthol should bond to these hydrogens (25), leaving our drug free to more easily traverse the skin barrier. And, indeed the data has supported this. It increased the permeability coefficient of mannitol 100 fold vs. control (26). In a study using Propranolol HCl which has a partition coefficient almost identical to yohimbine (Log P .74 vs. .75), it increased flux 1000 fold vs. control and also displayed the shortest lag time of all terpenes tested (25). This is in contrast to d-limonene, almost identical, structurally, to l-menthol, with the exception of lacking the afore mentioned hydroxyl group, which has been shown to much less effective for polar compounds (25, 27).

A second chemical is laurocapram. It too has been shown to be quite successful with polar drugs (23,28,29) likely due to its increasing the water content of the lipid phase of the stratum corneum. In one study, it enhanced the flux of mannitol in a propylene glycol vehicle by over 350 fold (23). Unfortunately, it displays a significant lag time -- meaning it can take as much as 10 hours before it starts to work (30, 31, 32). Consider most of us shower daily, this is not acceptable.

That brings us to n-methyl-2-pyrrolidinone (NMP). In combination with laurocapram, in a study using morphine hydrochloride, which has physical properties similar to Yohimbine Hydrochloride -- both polar molecules, molecular weight of 322 vs. 390 -- and is thus quite applicable, NMP was shown to significantly reduce the lag time (down to as low as 2 hours) as well as increase the rate of penetration for the drug as indicated by blood levels that were several thousandfold high than controls (32). In addition, it has been shown in several other studies to enhance penetration of polar molecules on its own, including a 256 fold increase with mannitol (23).

Finally, we have also added glycerol, which provides dual functions. First, it helps to counter any skin irritation that might be caused by the alcohol carriers. This is due to its increasing the water content of the skin, and as alluded to in regards to laurocapram, this increase in water content has the added bonus of increasing penetration for polar molecules such as yohimbine (33, 34).

Yohimbine vs. yohimbe
 
Quite a bit of confusion seems to exist about the difference between Yohimbine and yohimbe. Yohimbine is the principal alkaloid from the herb P. yohimbe. However, there are 31 other yohimbane alkaloids that can be present in herbal yohimbe preparations. Some of these have different and unknown selectivities and potencies (and thus, effects) at the adrenergic receptors (35, 36) -- in addition, these preparations vary greatly from brand to brand and even from batch to batch, as no standardization for extraction exists. In fact, a recent investigation found that most over the counter preparations have little to no actual yohimbine (37). And, even in the more potent preparations, most people find a higher degree of undesirable effects with the herb vs. pure Yohimbine (due to the afore mentioned 31 other yohimbane alkaloids that can be present). With LipoDerm-Y, you are guaranteed 25mg of pure, pharmaceutical grade Yohimbine HCl per milliliter, without the added side effects from other alkaloids - thus, allowing safer, more reliable dosing.

Dosing
 
Because some people are unusually sensitive to yohimbine, I would recommend that one start with a small dose -- 3-4 squirts (50 mg) and then increase the dosage by 25-50mg each day until side effects become unacceptable. Dividing it into two doses would be ideal, but probably not necessary. In our beta testing, we have gone as high as 400mg/day without significant side effects. I have personally done this along with an EC stack, and the only time side effects were particularly noticeable was during workouts.

Another thing to be considered when using yohimbine is that insulin blunts its lipolytic effects. Because yohimbine is not reaching the pancreas in significant amounts as it would with oral administration, insulin levels will not be as high for a given amount of carbohydrates, but they will still be elevated. Thus, it should ideally be used on a low-carb/ketogenic diet, or at the very least, one should do moderate aerobic activity for an extended period first thing in the morning on an empty stomach.

Conclusion
 
I think it should now be exceedingly clear that all topical fat loss products are not created equal -- and you should now be equipped to make an informed decision on which one to use. To sum up:
  • The formulation should contain active ingredients that are significantly lipolytic rather than mere diuretics.
  • The formulation should use yohimbine hydrochloride rather than the yohimbe herb.
  • The formulation must not only include penetration enhancers, but they must be appropriate for polar a molecule.
  • The formulation must avoid uptake by the dermal microvasculature or it will merely be an expensive, inefficient version of a pill.
The formulation that meets these criteria is LipoDerm-Y.

 
References:

1. Dulloo AG; Seydoux J; Girardier L. Potentiation of the thermogenic antiobesity effects of ephedrine by dietary methylxanthines: adenosine antagonism or phosphodiesterase inhibition? Metabolism 1992 Nov;41(11):1233-41.

2. Lee TF; Li DJ; Jacobson KA; Wang LC. Improvement of cold tolerance by selective A1 adenosine receptor antagonists in rats. Pharmacol Biochem Behav 1990 Sep;37(1):107-12. 

3. Tung CS, Kuan CJ, Tarng JL, Tseng CJ. Effect of adenosine blockade on plasma renin activity and catecholamines. Proc Natl Sci Counc Repub China B 1993 Jan;17(1):21-8

4. Millet L, Barbe M, Lafontan M, Berlan M, Galitzky J. Catecholamine effects on lipolysis and blood flow in human abdominal and femoral adipose tissue. J Appl Physiol 1998; 85(1):181-188.

5. Pretzlaff RK, Vardis RJ, Pollack MM Aminophylline in the treatment of fluid overload.Crit Care Med 1999 Dec;27(12):2782-5

6. Greenway FL, Bray GA, Heber D. Topical fat reduction. Obes Res 1995 Nov;3 Suppl 4:561S-568S 

7. Greenway FL, Bray GA.Regional fat loss from the thigh in obese women after adrenergic modulation.Clin Ther 1987;9(6):663-9 

8. Collis N, Elliot LA, Sharpe C, Sharpe DT. Cellulite treatment: a myth or reality: a prospective randomized, controlled trial of two therapies, endermologie and aminophylline cream. Plast Reconstr Surg 1999 Sep;104(4):1110-4; discussion 1115-7

9. Arner P, Kriegholm E, et al. Adrenergic regulation of lipolysis in situ at rest and during exercise. J Clinical Invest 1990; 85:893-898.

10. Goldberg MR Robertson D. Yohimbine: a pharmacological probe for study of the a 2-adrenoceptor. Pharmacol Rev 1983;35:143-180.

11. Berlan M, Galitzky J, Riviere D, et al. Plasma catecholamine levels and lipid mobilization induced by yohimbine in obese and non-obese women. Int J Obesity 1991; 15:305-315.

12. Galitzky J, Taouis M, Berlan M, Riviere D, et al. a 2-Antagonist compounds and lipid mobilization: evidence for a lipid mobilizing effect oral yohimbine in healthy male volunteers. Eur J Clin Invest 1988; 18:587-594.

13. Hodgetts V, Coppack S, Frayn KN, Hockaday TDR. Factors controlling fat mobilization from human subcutaneous adipose tissue during exercise. J Appl Phys 1991; 71:445-451.

14. Ruffolo RR, Bondinell W, Hieble JP. a - and b -Adrenoceptors: From the gene to the clinic. 2. Structure-activity relationships and therapeutic applications. J Med Chem 1995; 38(19):3415-3444.

15. Roberts MS. Targeted drug delivery to the skin and deeper tissues: role of physiology, solute structure and disease.Clin Exp Pharmacol Physiol 1997 Nov;24(11):874-9 

16. Le Corre P, Dollo G, Chevanne F, Le Verge R. Biopharmaceutics and metabolism of yohimbine in humans. Eur J Pharm Sci 1999 Oct;9(1):79-84

17. Joly D D, Sanger DJ Social competition in dominant rats can be attenuated by anxiogenic drugs. D.Behav Pharmacol 1992 Feb;3(1):83-88 

18. Singh P, Roberts MS. Skin permeability and local tissue concentrations of nonsteroidal anti-inflammatory drugs after topical application. J Pharmacol Exp Ther 1994 Jan;268(1):144-51

19. Singh P, Roberts MS Dermal and underlying tissue pharmacokinetics of lidocaine after topical application..J Pharm Sci 1994 Jun;83(6):774-82

19b. Mikulak SA, Vangsness CT, Nimni ME. Transdermal delivery and accumulation of indomethacin in subcutaneous tissues in rats. J Pharm Pharmacol 1998 Feb;50(2):153-8

19c. Peng L, Nimni ME. Delivery of erythromycin to subcutaneous tissues in rats by means of a trans-phase delivery system. J Pharm Pharmacol 1999 Oct;51(10):1135-41

19d. Nimni ME, Ertl D, Oakes RA. Distribution of griseofulvin in the rat: comparison of the oral and topical route of administration. J Pharm Pharmacol 1990 Oct;42(10):729-31

20. Ranade VV. Drug delivery systems. 6. Transdermal drug delivery. J Clin Pharmacol 1991 May;31(5):401-18

21. Peck KD, Ghanem AH, Higuchi WI. Hindered diffusion of polar molecules through and effective pore radii estimates of intact and ethanol treated human epidermal membrane.Pharm Res 1994 Sep;11(9):1306-14.

22. Hansch C, Dunn WJ 3rd. Linear relationships between lipophilic character and biological activity of drugs.J Pharm Sci 1972 Jan;61(1):1-19

23.Barry BW, Bennett SL. Effect of penetration enhancers on the permeation of mannitol, hydrocortisone and progesterone through human skin.J Pharm Pharmacol 1987 Jul;39(7):535-46 

24. Interactive LogKow Demo website: http://esc.syrres.com/interkow/kowdemo.htm

25. Kunta JR, Goskonda VR, Brotherton HO, Khan MA, Reddy IK. Effect of menthol and related terpenes on the percutaneous absorption of propranolol across excised hairless mouse skin. J Pharm Sci 1997 Dec;86(12):1369-73

26. Katayama K, Takahashi O, Matsui R, Morigaki S, Aiba T, Kakemi M, Koizumi T. Effect of l-menthol on the permeation of indomethacin, mannitol and cortisone through excised hairless mouse skin. Chem Pharm Bull (Tokyo) 1992 Nov;40(11):3097-9

27. Koyama Y, Bando H, Yamashita F, Takakura Y, Sezaki H, Hashida M. Comparative analysis of percutaneous absorption enhancement by d-limonene and oleic acid based on a skin diffusion model. Pharm Res 1994 Mar;11(3):377-83 

28. Lambert WJ, Higuchi WI, Knutson K, Krill SL.Dose-dependent enhancement effects of azone on skin permeability. Pharm Res 1989 Sep;6(9):798-803

29. Goodman M, Barry BW. Action of penetration enhancers on human skin as assessed by the permeation of model drugs 5-fluorouracil and estradiol. I. Infinite dose technique. J Invest Dermatol 1988 Oct;91(4):323-7 

30. Hosoya K, Shudo N, Sugibayashi K, Morimoto Y.Effect of Azone on the percutaneous absorption of 5-fluorouracil from gels in hairless rats. Chem Pharm Bull (Tokyo) 1987 Feb;35(2):726-33

31. Sugibayashi K, Hosoya K, Morimoto Y, Higuchi WI. Effect of the absorption enhancer, Azone, on the transport of 5-fluorouracil across hairless rat skin. J Pharm Pharmacol 1985 Aug;37(8):578-80 

32. Sugibayashi K, Sakanoue C, Morimoto Y. Utility of topical formulations of morphine hydrochloride containing azone and N-methyl-2-pyrrolidone. Sel Cancer Ther 1989;5(3):119-28

33. Bettinger J, Gloor M, Peter C, Kleesz P, Fluhr J, Gehring W Opposing effects of glycerol on the protective function of the horny layer against irritants and on the penetration of hexyl nicotinate. Dermatology 1998;197(1):18-24 

34. Gloor M, Bettinger J, Gehring W Hautarzt Modification of stratum corneum quality by glycerin-containing external ointments.1998 Jan;49(1):6-9 

35.. Ruffolo RR, Bondinell W, Hieble JP. a - and b -Adrenoceptors: From the gene to the clinic. 2. Structure-activity relationships and therapeutic applications. J Med Chem 1995; 38(19):3415-3444.

36. Goldberg MR Robertson D. Yohimbine: a pharmacological probe for study of the a 2-adrenoceptor. Pharmacol Rev 1983;35:143-180.

37. Betz, JM, White KD. Gas chromatographic determination of yohimbine in commercial yohimbine products. J AOAC Int. 1995; 78:1189-1194.
Par Deus
Well, the real write-up for our semi-new topical fat loss product, FL7 is here, at long last. Since the initial write-up many months ago, I have done a great, great deal more research and developed a much greater understanding of the systems it effects and, probably more importantly, discovered just how significant these systems are for modern man -- and woman, though to a lesser extent -- but, your lower bodies are the ideal target for LipoDerm-Y, so don’t be greedy :)

In this time frame, we have also introduced FL7 II (same active ingredient, but with a carrier designed for localized delivery of the active to the area of application). FL7 II has since been rechristened as the more clever, and more appropriate, “Ab-Solved”. 

As you may know, the “7” is from 7-oxo-DHEA. Obviously, 7-oxo-DHEA is nothing new, but as with prohormones and Yohimbine, swallowing a pill isn’t always the best approach. Opting out of the Chicken without a Head School of Supplement Design, we have journeyed deep into the literature, analyzed it exhaustively, and figured out a better line of attack. So, instead of offering up a tired, unspectacular product, we have housed the active comfortably in two of our miracle gels and Voila’...water to wine. 
 
Editors Note: For those unfamiliar with the science behind our topical gels, I direct you to “The Science of Topical Fat Loss”, “The Battle of the Topical Prohormones”, and “One+ vs. The Competition."

Because FL7 and Ab-Solved utilize the same mechanisms (other than delivery), we will cover both in today’s article. We will first address the basics, after which we will get into specific differences and uses of each. 
 
Editors Note: 7-oxo has far fewer studies on it than plain DHEA, but it is widely agreed, in the literature, that 7-oxo mediates a great deal of DHEA’s metabolic effects of interest, with 7-oxo being about 2.5 times to an order of magnitude stronger than plain DHEA, but without the effects on sex hormones.

There are three major systems that 7-oxo positively modulates to aid body composition improvement – Thyroid, PPAR, and Glucocorticoid. As you will see, there is a decent bit of crossover among them, in general. 

Thyroid Activity
 
The most well-known and directly researched aspect of 7-oxo is its effect on thyroid activity. Its primary action, in this regard, overwhelmingly seems to be potentiating the effect of t3 that is already present. Two of the principal markers of thyroid-induced thermogenesis are malic enzyme and glucose-6-phosphate dehydrogenase (GPD). You can probably guess what else has been found to increase these enzymes….

Yep: 7-oxo.

It has been postulated that 7-oxo’s effects on thyroid occur only in the liver, thus arguing against transdermal usage. However, injections of DHEA (which would also bypass the liver) were found to increase malic enzyme activity in the liver nine-fold in just one week; interestingly, levels had not yet peaked at this point. This is the same increase produced by t3.

Given the mechanism by which 7-oxo apparently manifest its effects on t3, the increase in activity is going to occur in all t3-responsive cells, such as adipose and muscle, in addition to the liver; more specifically, it will occur at the mitochondrial level of these cells.

7-oxo and the Fed cell
 
Malic enzyme (l-malate: NADP+) is an oxoreductase that generates NADPH. Though considered a lipogenic enzyme, because it furnishes NADPH, I think “fed” enzyme more appropriate. We know t3 is far from lipogenic and we know it is high in the fed state and low when dieting. 

7-keto uncoupled oxidative phosphorylation and increased proton motive force, similar to t3, in the euthyroid state, and did so in hypothyroid, as well, when succinate was added to the medium. It also increases proton slip/leak; this results in inefficient production of ATP, which the body would avoid, for obvious evolutionary reasons, unless properly fed. 

Succinate, a potent ATP substrate, mimics the effects of t3 and 7-oxo on mitochondrial membrane potential – which is basically just the ability to take ADP added to the medium (high ADP and AMP indicate ATP hydrolysis, which signals low energy availability in the cell) and return potential to the state characterized by high ATP. 

Recall, also, that adequate liver ATP is necessary for conversion of inactive t4 to active t3. Finally, ATP levels are highly correlated with indices of the fed state.

So, clearly, 7-oxo is facilitating the induction of a high-energy consumptive state, in the mitochondria, which is also characteristic of the fed state.

PPAR
 
PPAR-alpha is best known as the target of fish oils and fibrates. They have a remarkable, and very well documented, effect on oxidation of fatty acids and insulin sensitivity. Both DHEA and 7-oxo induce PPAR-alpha expression, with the latter compound, as expected, being significantly more potent.

PPAR-alpha treatment shows a profound effect on fatty acid oxidation vs. incorporation into TG, increasing complete oxidation of oleate as much 2-fold and partial oxidation 3-fold, while decreasing TG by 50%--all in all, showing a maximal TG:oxidation ratio difference of 4-fold. It also decreased the number of lipids with large lipid droplets (which is associated with insulin resistance), as well as the better known, and also desired, effects of Malonyl coA decarboxlase and CPT-1 (rate-limiting for fatty acid uptake).

Finally, 7-oxo has been found to have positive effect on HDL-C and Apo A-I, both of which are affected in the same manner, by PPAR-alpha stimulation. PPAR-alpha also decreases 11beta-HSD-1 activity (which you will soon learn much more about), so we have another nice 7-oxo tie-in.

There is also data suggesting 7-oxo might directly inhibit PPAR-gamma expression (PPAR-gamma is a potent stimulator of adipocyte differentiation, lipogenesis, and is considered a major player in the dreaded “thrifty” phenotypes) – this has been found for DHEA, as well as 7-oxo metabolites, though I have not seen a direct study on 7-oxo. Regardless, PPAR-alpha activation inhibits PPAR-gamma.

So, how does DHEA and 7-oxo potentiate t3 and increase PPAR-alpha expression? Unfortunately, the literature does not know. Fortunately, I believe I do.

Retinoid X
 
I propose that 7-oxo, or a metabolite, is an agonist for the Retinoid X receptor (RXR). The RXR is a member of the nuclear family of receptors that is known to form heterodimers with several other receptors, potentiating their activity. Among these are the thyroid receptor, the PPAR-receptors (which we have covered), the vitamin D receptor, and the Liver X receptor (which we will not cover).

Because they share dimerization with RXR, thyroid and PPAR-alpha generally antagonize each other’s effects, due to competitive inhibition. However, as we have shown, 7-oxo increases the activity of both, which argues strongly against direct activity at one or the other, and argues fairly strongly for RXR activation.

DHEA and thyroid also share G-3-DP (triglyceride metabolizing enzyme) activation, and 7-oxo has been found to be a much more potent stimulator of G-3-DP than DHEA. PPAR alpha (fibrates) and thyroid also have increases in fatty acid coA oxidase in common.

Cortisol/the HPA axis
 
The final, and IMO, the most important, aspect of 7-oxo is its modulation of cortisol equilibrium. Before we address the hows and whys, let’s take a look at the system, so you’ll know why you should care.

The HPA axis stands for the Hypothalamus-Pituitary-Adrenal axis. This is a bit of a misnomer, as the renin-angiotensin-aldosterone system, the sympathetic nervous system (SNS), and other parts of the brain are also heavily involved. However, damn near every system is a misnomer, because of the ubiquitous interconnectedness and cross-signaling that has come to light in the last 3-4 years, so it is forgivable.

The purpose of the HPA and friends is to differentially mediate cellular metabolism in different tissues in response to stress—both physical and emotional—acutely, as well as to prepare to handle future occurrences of such stressors.

The two primary HPA stressors our ancestors would have encountered are lack of food and the need to fight/protect themselves. You may note that the former is rather male specific. Not surprising, males encounter far more problems from this system in the modern world than do females.

Females also have their own large stressor: pregnancy. However, I suspect that fuel supply in this situation is largely mediated by the alpha 2 adrenergic receptor, which is why women carry a lot of lower body fat, and why us guys love us a J-Lo ass (even if we hate her and her music and her acting).

But, the alpha2 receptor is not the topic for today (read my Science of Topical Fat Loss in Issue #3 of M&M for a bit on that).

Cortisol’s role in the body is often greatly misunderstood in the bodybuilding community (and certainly elsewhere). It has a very strong reputation as an evil catabolic hormone. While this certainly is true, there is much more to cortisol than this. It is also quite necessary for survival and stress responses, and it is a big part of the trigger for the anabolic response following exercise, including the arachadonic/prostaglandin cascade.

The HPA Proper
 
At the most simplified level, cellular or emotional stress triggers the release of Corticotrophin Releasing Factor (CRF), which triggers the release of Adrenocorticotropic Hormone (ACTH), which triggers the release of adrenal steroids, including the glucocorticoids and DHEA.

Acutely, the former results in increased fuel availability in the blood, for use in tissues that need the extra (muscles when exercise, brain when starving), and decreased fuel uptake in those that do not (fat when exercising, as well as the immune system, bone, and muscle, when starving). The organism takes care of business (TCB), a negative feedback signal is sent centrally, via the GR, and things return to normal.

But, as we said, and as you should know by now, it is not nearly so simple. Not only are there many more players, but in the modern world, we very, very regularly encounter the “anomaly” of being highly stressed and well-fed, at the whole-body and the cell level, at the same time. 

This results in a biochemical state quite different from having high levels of stress hormones (and the resulting elevated output of fuel to plasma from the liver and decrease in unnecessary disposal) while taking in little to no fuel while starving or burning large amounts of fuel chasing dinner across the open plains (and subsequent fuel used by highly consumptive reparations processes from the exercise stress).

Cortisol, VAT and The Liver
 
The previously all too often ignored hepatoportal glucose sensor system will now get a bit of time in the sun. There are direct nerves between the portal vein to the adrenal medulla, as well as the liver and the hypothalamus. These communicate the blood glucose status of the body to the brain and allow for rapid mediation, via the HPA (brain glucose levels are too important to depend on the rest of the body, for the most part, so it is more tightly regulated, thus its levels do not accurately reflect changes in metabolic needs, peripherally.) Instead, this is signaled by the liver (recall the mention of liver glycogen and the “fed state” from our leptin articles and discussions.)

Reduced liver glycogen, due to chronic lack of food, or rapid upregulation of glyogenolysis, from increases in activity, signal the stress response, in the hypothalamus and adrenals -- and an increase in free fatty acid release, from the VAT, into the portal vein, further stimulates it. Neural communications back and forth between the parties, initiates as positive feedback cycle, which we will detail, a bit later, which liberates fuel, to meet the increased metabolic demand.

Indeed, stress-related increases in cortisol have been found to 1) promote glucose cycling via glycogenolysis, 2) greatly inhibit peripheral glucose utilization (in “dormant” tissues), 3) increase hepatic gluconeogenesis, primarily through enhanced substrate delivery to the liver, and 4) increase free fatty acid release from VAT

This is most helpful, when one is actually prone to shortages of metabolic fuel, and when one receives a negative feedback signal telling it to relax. But, when one follows a meeting with the Board of Directors or a deadline with a supersized Big Mac Value Meal, day in and day out, and never simulates (at the cell level) the thrill of war or the hunt, this is not so good.

Under these conditions, the VAT and liver are still pumping out fuel, and the VAT storing it (we’ll get to this), cortisol is still inhibiting uptake of nutrients where it is not needed (which includes your muscles, and to a lesser extent, your sub Q adipose), all the while you are taking in an excess of nutrients. Thus, you end up with very elevated blood glucose, TG’s, and fatty acids, which are free to exert their anabolic effects in the artery walls, instead of muscle tissue

And, Holy Shit!, that looks an awful lot like the Metabolic Syndrome and NIDDM. 

Mostly because it is. Mostly.

11-beta-HSD-1 over expression results in hyperphagia (i.e. increased food consumption), even with hyperleptinemia, as well as metabolic syndrome – and, insulin resistance and metabolic resistance go hand in hand. Interestingly, a reductive cellular redox state is conducive to PTP1B activation, which is known to decrease insulin and leptin signaling. 

A recent review by Arch called the 11-beta-HSD over expressing mouse “possibly the most important transgenic model of obesity so far created” because it models the metabolic syndrome, in humans.

11-beta-HSD-1 knockout mice represent an “atheroprotective phenotype” – when ad-lib fed (meaning all they want, of yummy foods), they have lower TG levels, higher HDL, CPT-1, and insulin sensitivity.

Thus, the beauty, and importance, of 11-beta-HSD-1 inhibition would extend well beyond a bit of cosmetic improvement – it could save your life, particularly, if you are male or prone (via genetics or lifestyle) to cardiovascular disease and insulin resistance/metabolic syndrome.

And, with that, let’s talk about the 11-beta-HSD-1 complex.

 

11beta-hydroxysteroid Dehydrogenase
 
Glucocorticoids exist in humans in two primary forms, the inactive cortisone and the active (and dreaded) cortisol. These exist in the body, in a constant state of flux, depending on the enzyme situation. 
 
Editors note: The rat counterparts to Cortisol and cortisone are Corticosterone and 11-dehydrocorticosterone. Their mechanisms, in regard to equilibrium/metabolism and signaling are the same, and they are studied interchangeably within the literature, so we will just use the human terms here, to avoid confusion.

What is of note is that the two isoenzymes, 11-beta- hydroxysteroid Dehydrogenase type 1 (11b-1) and type 2 (11b-2) that convert one to the other have vastly differing concentrations in different tissues. For example, in differentiated adipose tissue, only the first isomer of 11-beta-hydroxysteroid dehydrogenase (11b-1) is found. 

The type 2 enzyme exists in tissues expressing the mineralcorticoid receptor (MR), such as kidney and hypothalamus, where it deactivates it, to protect the receptor from high levels of cortisol (which has affinity for the MR equal to that of aldosterone).

Despite the name,11-beta-hydroxysteroid Dehydrogenase type 1 generally acts as a reductive enzyme, converting Cortisone to Cortisol. It can also act as a dehydrogenase in some tissues, under some conditions, but in intact, differentiated human adipose tissue and skeletal muscle and liver, it is always acts as a reductase, converting cortisone to cortisol. 

It also appears that there is a third enzyme in the complex, which also possesses both reductase and dehydrogenase activity, depending on the NADPH/NADP+ ratio, and it, too, is likely modulated in the same manner, by 7-oxo.

NADs and 11beta-hydroxysteroid dehydrogenase
 
The oxoreductive function of 11-beta-HSD is largely determined by the NADPH: NADP+ ratio, with a high ratio promoting reductase activity and reducing dehydrogenase activity, and vice versa. The same seems to hold for 11-beta-2, in regard to NADP:NAD+. As mentioned, reductase activity by 11b-hsd promotes the formation of active cortisol from inactive cortisone and dehydrogenase activity results in oxidation to the inactive compound.

This had some very nice evolutionary advantages, in regard to adaptations to stress responses. Namely, when stressed, the organism would release large amounts of corticosteroids, which would liberate large amounts of fuel, peripherally, in conjunction with the Sympathetic nervous system. Eventually, the stress response would end, and you would eat. 

NADPH formation is dependent on hexose-6-phosphate and Glucose-6-phosphate, which are stimulated by carbohydrates and insulin. Thus, co-enzymes would shift to a reductive state, which would shift 11-beta-HSD toward reductase activity, which would convert the cortisone to cortisol and promote differentiation of pre-adipocytes to full-fledged adipocytes and an increase in triglyceride storage. This would ultimately result in increased nutrient stores for the next round of stress, and proved quite beneficial for survival, back in the day.

In other words, the system evolved to provide a readily available depot for cortisol and NE/E to quickly mobilize Free Fatty Acids (FFA) and get it into the portal vein and the blood stream, as part of the fight or flight response, in order to get nutrients to the needed tissues, rapidly. 

Stress, in the absence of exercise, or with an abundance of food, is what causes the problems and the epidemic.

The Stress Response
 
It is most fascinating that the systems that were some of the most important for the survival of our ancestors, are some of the most problematic for our health and happiness, today. 

Thrifty genotypes have facilitated an epidemic of obesity in developed countries, as well as provided endless frustrations in our efforts to achieve our ideal physique. The seeking and reward signals, which evolved for acquisition of food and mates, have led to rampant drug use, and the city of Chatsworth, California. I will leave it up to our good readers to render judgment on these two :) 

The stress response is at least as important, and at least as problematic as many other more well known modulators of thrifty phenotypes. So, put your science hat on, and get comfy, because it is a rather complex and intricate system, with a pathology that is even more so. 

You should probably read these next few sections twice (actually, 3 times, and read the whole article twice), as one cannot talk about the process, without referring to several systems, and one cannot detail the systems, within the processes, without making you forget what we were even talking about :)

Fortunately, the solutions are a bit more simple.
 
Editors Note: Yes, I am referring to Ab-Solved and FL7, so sod off :)

As with many other systems, it has become apparent that the stress response is initially a positive feedback one. As we have mentioned, the stressor can be emotional, or it can be metabolic, and it seems to manifest itself a bit like so:

Metabolic stress signals CRH release in the hypothalamus (PVN) with emotional stress originating in the amygdale, with the latter receiving serotonergic input from the Dorsal Raphe, and both receiving contextual input from the Hippocampus, which also receives signals from those structures (this part is “learned” and becomes hard-wired, which will be very important shortly, as it leads to hypersensitization). 

CRH triggers the release of ACTH in the pituitary, which releases glucocorticoids from the adrenals. This results in a number of peripheral effects, which we will cover, but for now, we are concerned with the CNS. The glucocorticoids make there way into the brain, where they act in several structures.

In the Dorsal Raphe, cortisol potentiates serotonin signaling in the amygdala, which results in an emotional response in the organism (which is sent to the hippocampus to be remembered for future needs, in order to facilitate a stronger and more rapid response next time around). 

In the amygdala, serotonin potentiates the cortisol response, which potentiates serotonin, and so on. Both of which stimulate GABA, which inhibits NMDA firing and release GABA inhibition (via GABA autoreceptors) of dopamine, thus relaxing the organism, emotionally – i.e. producing an “in the zone” state.

Meanwhile, in the hippocampus…. 

Cortisol is undergoing a positive feedback cycle (as long as it is receiving the input to do so from the PVN and/or amygdala), which results in levels of up to 20-40 times normal, which results in a signaling cascade that increases signal transduction rate and amplitude (IP3 and DAG and NMDA), which consumes the extra metabolic fuel that cortisol and friends have liberated. 

This is all generally a good thing, for the organism, in the short-term, as the brain will just work faster. In addition, bursts of elevated serotonin and cortisol are strongly associated with dominant behaviors, so it helps you kick ass, in order to do away with the stress signals that initiated the cycle, in the first place.

But, what happens if the stress signal never really goes away. 

Glad you asked:

Defeat Stress
 
In the Amygdala (essential for processing and conditioning of fear-type stimuli), 5-HT is elevated (300%) and quickly falls, in rats, with escapable shock treatments (i.e. acute stress), but is elevated continuously, with inescapable shock (i.e. chronic stress), and only falls to 150-175% even 2 hours after termination of “treatment”– they also exhibit exaggerated levels to subsequent shocks 24 hours later (sensitization). Cortisol, not surprisingly, given the aforementioned 5-HT potentiation of the HPA, mirrors the fate and effects of 5-HT.

Point is: stress increases Cortisol and 5-HT output, and they both further potentiate each other’s release – all the while, they act synergistically to increase the activity of inhibitory GABA neurons. Continuous firing of GABA eventually depletes it from the neurons, while downregulating GABAb. 

Thus, the inhibition they both exert on NMDA is lost (and, recall that this inhibition also activated dopaminergic firing), transforming the calming, dominant effect they exert with acute elevations (fight or flight) to a state of continuous anxiety and, likely a result of negative feedback via energy depletion via NMDA cellular hyperactivity, triggering of an adenosine mediated “circuit breaker” in the cell, as a protective measure against cell death, from “starvation”, takes place. This results in hypoactivity and an inability to form coping strategies. This is known as “defeat stress” or “learned helplessness”, within the literature. And, indeed, it has been found to be reversed by the adenosine antagonist caffeine.

For further evidence of this phenomenon, I invite you to read the alt.support.fat-acceptance newsgroup for 10 minutes. 

And, we’ll cover why being fat, in itself, stimulates this vicious cycle by the HPA.

Receptor downregulation
 
But do not fret, it gets worse. In the presence of chronically elevated cortisol levels, the Mineralcorticoid receptor (MR), which centrally modulates much of the negative feedback signal, is downregulated greatly. Indeed, the chronically stressed and the obese are insensitive to hydrocortisone infusion, at night, which has the lowest level of MR occupancy, normally. The Glucocorticoid receptor (GR) is downregulated as well, but it has much higher affinity, so it still manages to transduce undesirable excesses in cortisol signaling, peripherally, in the muscle and adipose. So, you are insensitive to negative feedback in the brain via the MR (high affinity, low saturation point), but you are still fairly sensitive peripherally, because of the high saturation point of the GR, so you can still store plenty of fat, for the next time you “need” it.

Hypersensitization
 
It was also quite beneficial to our ancestors’ survival to have an elevated response to subsequent stressors. If a rhino is charging, one can certainly see how it would be helpful, but if you are in the 2nd year of a 30-year mortgage you can’t afford, “not so much”, as they say. This is mediated centrally, in the hypothalamus, with input from the hippocampus, via the signaling cascades we discussed.

Drugs
 
Given some of the players involved in said signaling cascades, you should not be too surprised to learn this hypersensitization can be primed by recreational drugs. Indeed, they greatly increase cortisol release and cortisol strongly mediates the reward cascade and signaling of alcohol, dopamine, amphetamine, opiates, and GABA/benzos – several of these have also been found to downregulate the GR and MR, thus reducing negative feedback inhibition, in addition to increasing hypersensitivity to the initial response.

Another one that you might not normally think of as a drug, is the tried and true EC stack, and its more recent dieting playpal, Yohimbine, which provides a nice segue for us to talk about the adrenergic/sympathetic part of the fight or flight response, in a bit more detail.

Sympathetic nervous system activation is a strong sensitizer of the stress response, in the PVN portion of the hypothalamus. This should not surprise, given its strong role in the fight or flight response, and the fact that this is how we have learned the system behaves. This is modulated via the sympathetic nodule, at the base of the brain. It has direct connection to the PVN and delivers norepinephrine directly to it. This is in addition to the stimulatory response that would be provoked via increased liberation of fatty acids from the VAT to the portal vein.

For even more detail, take a look at an excerpt from part 6 of Spook’s leptin article, which I see no real way to improve upon:
 
Adrenal Regulation:
adrenals.gif
Corticotrophin Releasing Factor (CRF) secretions for the PVN are controlled directly by CRF, NPY, GABA, Nor-Epinephrine (NE), Arginine-Vasopressin (AVP) and leptin.

CRF promotes its own release (5,6). Injection of either CRF or a beta-adrenoeceptor (B-AR) agonist in to the PVN of rats promotes CRF secretion by altering DBH protein in the neural bundles (6). Sympathetic Nervous System (SNS) projections run from the spinal column and the basal sympathetic nodule directly to the PVN. These neural circuits sense immunological stress, physiological stress, or stimulants.

In vivo, most regulation is accomplished by the alpha2-adrenoreceptor (A2-AR) and not the B-AR. NE binding to A2-AR sites in the PVN dramatically increase CRF production (7). The effects of NE on the PVN are not temporary either. By altering DBH protein in the neural bundles the PVN is sensitized to activation of the Hypothalamus – Pituitary – Adrenal (HPA) Axis. The effects of direct injection into the PVN of rats lasted 3 weeks. The effects may have lasted even longer, however at this time they had terminated the rats to examine their brains (6). 

NE is also delivered to the PVN by afferent projections from the Locus Coeruleus (LC) (8). The LC is an extremely complicated neural structure. It is extensively studied as abnormalities in the LC often result in psychological disorders. For our purposes we may consider the LC to be the psychological stress response center. 

The LC is one of the brain regions that is strongly correlated with brain wave patterns. This is one reason that even small amounts of sleep depravation result in highly elevated levels of corticosterone and cortisol. When we enter slow wave sleep patterns, NE delivery to the PVN is reduced. It is also reduced during times when we do not have to pay very close attention to things. NE release from the LC is strongly correlated with attention, vigilance, and psychological stress. Thus we can conclude that brain wave patterns are a pretty good indicator of NE activity in the PVN.

Leptin directly increases corticosterone and epinephrine production through multiple pathways. First by lowering VMH derived GABA delivery to the PVN it increases firing rate in the PVN, resulting in increased CRF secretion. Leptin also enhances secretion of AVP (9). It further upregulates the V1 AVP receptor, promoting additional CRF release from the PVN (10). 

AVP and CRF act at the pituitary to increase adrenocorticotropin (ACTH). However their effect is not additive, but is in fact synergistic. AVP strongly potentiates CRF-induced release of ACTH. Thus leptin is a potent activator of the HPA.

The Beer Gut
 
Ever wonder from whence the Boomhauer physique originates? Skinny, with a big belly, for those who are not K.O.T.H. fans. Once, again, it is an HPA/VAT issue. As we mentioned, alcohol and its signaling pathways (dopaminergic, opiate, GABAergic) directly activates the HPA, in addition to producing the hard-wired hypersensitization. 

The fact that a 12 pack has about 1500 calories (which only covers the first 2-3 hours of drinking), and greasy foods taste really good, when drunk, does not help matters, as it will push the NAD co-enzymes to the reductive state and further trigger the HPA with the dumping of fatty acids into the portal vein.

And, if that was not enough, ethanol has been found to directly inhibit 11-beta-HSD-2’s dehydrogenase activity, via increase it oxidation products, which causes it to form an inactive dimmer. In addition, the 11-beta-HSD-1 enzyme participates in xenobiotic carbonyl compound detoxification in the liver – ethanol and its acetylaldhyde metabolite fit this structure – thus, occupying the enzyme. 

And, guess what, 11-beta-HSD-1 activity is already reduced, in the liver, in chronic stress, and visceral obesity. This is a protective measure, to prevent cortisol output, particularly, to the kidneys and the brain, where high levels could damage the MR, but unfortunately, it will just result in greater output of cortisone, which will be converted to cortisol, in the VAT, and other tissues, where it will reek havoc.

Androgens and VAT
 
It is well documented, in the literature, that males are far more prone to visceral obesity, and VAT related insulin resistance and cardiovascular disease and death. Estrogens and preferential storage of fat, in the lower body, via alpha2 receptors confer some protection to females, but the main culprit in this dichotomy is higher levels of androgens, in males.

VAT already exhibits increased beta receptor density, which is largely responsible for its increased lipolytic rate, and androgens are well known to increase beta receptor density, thus it promotes the gender differences we have mentioned – and, exogenous androgen administration would exacerbate this.

In addition, androgens decrease 5-alpha reductase activity, and 5-alpha reduction of cortisone produces a metabolite that cannot be recycled back to cortisol. Thus, relatively high natural androgen levels, or really high androgen levels, from steroid use -- and, if they are non-aromatizing, they will also take out the protective effects of estrogen, and one could speculate that they might increase the problems exponentially, due to the relatively far greater levels) -- means more cortisol, which means more VAT, and greater peripheral nutrient insensitivity, In other words, addressing this issue won’t just shrink your waist, it will go a long ways toward saving your ass.

 

Cortisol and Adipose Stores
 
Now that we have established how and why the system can become proper fucked, let’s take a look at what happens, once it does. 

As we have mentioned briefly, Cortisol stimulates lipolysis, short-term (6hrs or so), as would be seen with fight or flight bursts to free up fatty acids and glucose, for fuel, in numerous studies, thus a facile search of pubmed would likely leave one feeling confused, if not hoodwinked. That the cells are cultured at fasting insulin concentrations and euglycemia, in most of these studies, which does not mimic the real world, where we eat and such, also helps skew the picture. With chronically elevated levels, as seen in chronic stress or visceral obesity, in conjunction with real-life feeding pattern, the balance of lipolysis to lipogenesis shifts decisively to the latter. 

Chronically, cortisol inhibits basal and catecholamine induced lipolysis, as well as dramatically upregulating LPL, which is a rate-limiting step, in fatty acid uptake and triglyceride formation, particularly in the presence of insulin.

Adipogenesis involves differentiation of preadipocytes into adipocytes. Cortisol inhibits proliferation of preadipocytes, which tips the balance towards differentiation. In other words, cortisol promotes the formation of new fat cells. And, as we know, empty adipose cells make wonderful sponges for tryglicerides – i.e. terminal differentiation of adipocytes is associated with a dramatic increase in lipid production within the cell.

But, the situation is actually even worse. We have covered this, but as a refresher, in preadipocytes, 11-beta-HSD acts as a dehydrogenase, which increases cortisone, which promotes proliferation of these pre-adipocytes (meaning more of them), until the cell gets adequate fuel to shift redox state to reductase, and turn them into full-blown adipocytes. And, as we have established, it just gets really ugly from there – and, 11-beta-HSD upregulates proportionally to glucocorticoid levels, so there is no real brake on this spiral, other than rationally addressing the problem, or death.

 

Sub-Q adipose
 
While the primary effect of cortisol, is in VAT, it can also cause problems in subcutaneous adipose (particularly abdominal), especially as the system gets worse, due to obesity or stress. Sub-Q adipose tissue 11-beta-HSD activity has been found to be positively correlated with BMI, waist to hip ratio, % bodyfat, and insulin resistance, in both males and females 

Obese women were found to have higher abdominal Sub-Q fat, as well as a positive correlation between BMI and 11-beta-HSD activity.

Finally, anyone who has ever been on prednisone (me)/dexamethasone or seen someone with anorexia (which is strongly associated with HPA dysfunction) has almost certainly noticed preferential storage of subcutaneous abdominal fat.
 
 
Good news
 
Because VAT has extremely high FFA turnover (the median effective dose for suppression of lipolysis was almost fourfold higher in the visceral adipose bed than for whole-body suppression of lipolysis), it will quickly dump its FFA in to the blood stream. Reduction in local cortisol  will stop VAT differentiation, increases VAT apoptosis, and decrease triglyceride storage. In addition to this, all cells in the body turnover, meaning they die and are replaced. If we inhibit the formation of new fat cells (via inhibiting cortisol activity in the fat cell), given that fat cell death remains constant, we would have ourselves a very modest, on-going liposuction effect. This would ultimately lead to significant losses in adipose cell number, adipose mass, and fatty acid output, especially in VAT.

Skeletal Muscle
 
Muscle is responsible for the majority of non-oxidative glucose disposal. As discussed, glucocorticoid excess causes insulin resistance, peripherally, in skeletal muscle by directly inhibiting the translocation of the GLUT4 glucose transporters to the plasma membrane in response to insulin. Further, cortisol inhibits glycogen synthesis, peripherally. What’s more, stress hormones (cortisol, adrergics, glucagon) decrease ribosome formation, a reflection of protein synthesis , IN VIVO, in skeletal muscle. Skeletal muscle was found to have 11-beta-HSD activity comparable to other tissues, so the potential for excess is most certainly there. Thus, dysfunction of the system can cause problems with nutrient partitioning and LBM accrual.

Stress, cortisol, and testosterone production
 
As one might expect, chronically elevated cortisol also has negative effects on testosterone production – after all, such a situation, in evolutionary terms, indicates getting one’s ass kicked by life – and, in modern studies, the birth of a child ranks in the top 3 of scales of stressor events – thus, it was not, and is not, generally, a good idea to introduce this “hassle” into an already bad situation, thus reproductive drive and function, is inhibited.

Consulting the literature, we find that 1) high cortisol inhibits test production in the testis, 2) psychosocial stress has been found to decrease sperm count, 3) High cortisol also can cause Leydig cell death – latter only 5-10 times above basal (stress increases it up to 40 fold). And, finally, it can also cause inhibition of sex steroids, centrally, via CRF and LH interactions.

So, that is just one more thing to add to the list.

The anti-cortisol, 7-oxo
 
”So, that’s real interesting and all, but WTF does it have to with FL7 and Ab-Solved?” 

Well, the active ingredient in each—7-oxo-DHEA—decreases 11-beta-HSD-1 reductase activity. In fact, it appears to promote general dehydrogenase activity, at the expense of reductase, within the entire 11-beta-HSD complex.

A quick check of pubmed will reveal that there are no direct studies on 7-oxo DHEA and inhibition of 11beta-HSD-1. There are however, several studies with DHEA (and, recall that DHEA must be used in massive amounts to significantly exert its effects, as opposed to several of its metabolites). There is also speculation by researchers that concurs with the idea of 7-oxo and 7-OH metabolites of DHEA as modulators of 11-beta-HSD activity. 

And, most importantly, there is the elegant, and scientifically masturbatory (in the good way) explanation, which I shall present, based on my new favorite bit of biology, REDOX—bigger than leptin and Jesus :)

REDOX
 
For those unaware, REDOX is simply the removal or acceptance of an electron by a molecule. Reducing agents donate electrons; Oxidizing agents accept electrons, becoming, themselves, reduced. In biological systems, oxidation and reduction are always coupled, thus “REDOX.”

Oxidation is generally a catabolic process, liberating energy for ATP production, or for the formation of reducing equivalents. Reduction is involved in biosythensis—i.e. anabolic processes, including lipogenesis.

7-oxo and REDOX
 
DHEA release, like glucocorticoids, is stimulated in the adrenals, via ACTH. It is metabolized locally, in microsomes of tissues such as the liver, adipose, brain, etc. by the CYP-450 system. Two of the participating enzymes are 11beta-HSD and 7alpha-HCD, with 7-hydroxlated and 7-oxygenated metabolites as major products of its metabolism.

DHEA has been directly found to inhibit the reductase activity and promote the dehydrogenase activity of 11-beta-HSD, on cortisol, in multiple studies. This reaction results in the formation of 7alpha-OH-DHEA (7a-OH), suggesting 11-beta-HSD directly reduces it to this compound (i.e. its inhibition of reductase activity on cortisol is via competition for the enzyme). This is supported by studies with inhibition of 11-beta-HSD, which drastically reduced 7a-OH formation.

7a-OH and 7-oxo have been found to interconvert, to one another in several studies. A recent study sheds a great deal of light on why. In the presence of the dehydrogenase promoting NADP+ (and to a much lesser extent, NAD+), 7a-OH is oxidized to 7-oxo by 11-beta-HSD. This is decreased by 11-beta-HSD inhibition and does not take place with NADPH. IOW, it is competing with cortisol for the dehydrogenase activity of 11-beta-HSD – this would increase cortisol. 

7-oxo, in the presence of the reducing equivalent NADPH is converted back to 7a-OH via the 11-beta-HSD enzyme. This is decreased by 11-beta-HSD inhibition and does not take place with NADP+. IOW, like DHEA, it sacrifices itself on the alter of 11-beta-HSD reductase activity – this would decrease the formation of cortisol.

To put in a bit of English, DHEA is converted to 7a-OH by the mechanism than converts cortisone to cortisol, 7a-OH is converted to 7-oxo by the mechanism than converts cortisol to cortisone, and, like DHEA, 7-oxo is converted to 7a-OH by the mechanism that converts cortisone to cortisol. 

IOW, interference with the direction of the cortisol to cortisone ratio in one direction, results in the formation of a compound that interferes with the enzymes activity in the opposite direction.

REDOX, baby, REDOX.

Advantages vs. Oral
 
That is all well and good, but why not just take it orally?? There are two primary and very significant reasons: 

Number one is increased bioavailability. You get far more 7-oxo in your system, mg/mg than with oral.

Furthermore, with oral usage, we suppress 11-beta-HSD-1 activity in the liver. This increases the output of the inactive, dehydrogenase product, cortisone in the body, thus lowering systemic cortisol. This is good right?? Nope. Unfortunately, this results in an increase in systemic cortisone to serve as substrate for formation of the dreaded cortisol in the oxoreductase-only adipocyte and other tissues.

Worse, yet, as we alluded to, the 7-oxo will be converted to the 7-alpha-OH compound, which will enter the bloodstream, and increase the reductase activity of the 11-beta-HSD complex, thus INCREASING formation of cortisol from cortisone in peripheral tissues such as adipose and muscle, as well as in the brain, where it will reek havoc, on the long-term functioning of the system.

Ugh.

Never fear. Topical administration eliminates this problem by avoiding the liver, so 7-oxo is not working against itself.

FL7 or Ab-Solved

 

bottle-fl7.jpgFL7 – excellent on a mass phase for fat gain prevention, current androgen use, recently stressed, near maintenance/with LeptiGen, or in cases of obesity. 

Ab-Solved –excellent when dieting or on a mass phase, for combating ‘roid gut, previous high stress or cortisone use.

Those who are most likely to respond very well would be anyone that caries their fat in the midsection, endomorphs, older people, and anyone with above average test levels. This will be particularly effective if you have the more distended stomach look.

It will also be extremely effective in helping women with abdominal obesity as well. 

Those who have more problems with subcutaneous adipose tissue could still get results from Ab-solved, yet Lipoderm-Y is the better option if their midsection fat is more mediated by adrenoreceptors than it is cortisol. This would however apply to a very small percentage of males.

Conclusion
 
7-oxo exerts its positive effects via the thyroid, PPAR-alpha, 11-beta-HSD-1 (redox, local activity), and through its positive impact on stress levels and VAT.  7-oxo is excellent for combating obesity, reducing VAT, while using androgens (previous users should opt for Ab-Solved, current users for FL7), for stress, and to minimize the negative effects of drug use. Users are advised to eat a low fat diet supplemented with fish oil when using Ab-Solved (will be releasing plenty of FFA from VAT) and/or FL7.
Par Deus

LeptiGen Write-Up (2004)

LeptiGen ushers in new paradigm in science and supplementation

by

Par Deus

 

O happy day!

LeptiGen - Prototype 2 has finally pulled into the gate, after much anticipation and much delay.

You, our dearest customers, will obviously be the final arbiter as to whether it was worth the wait, but we are certainly feeling pretty good about our formula and ourselves J

 

 

Introduction

LeptiGen - Prototype 2 represents far more than a shift in trends in the bodybuilding and performance supplementation realm. What it represents is a fundamental shift in the way one understands and conceptualizes the human body (and basically all biological processes). Basically, I am proposing a new, comprehensive, and unified paradigm concerning all things biological J

It encompasses and integrates research and theory from numerous disciplines and sub-disciplines -- everything from exercise science to biochemistry to evolutionary biology to molecular biology to philosophy to Holistics to “old-school”, to things generally thought best left to hippies – and, the full gamut from basic in vitro research to anecdotal reports on message boards.

But, before you can understand and appreciate the breakthrough that LeptiGen p2 represents, you will first need to be introduced to, and indoctrinated in, the new Gospel of Par Deus.

It is the paradigm from which LeptiGen p2’s design, as well as the design of our products in the foreseeable future, takes form.

It is a synthesis of the two equally short-sighted and misguided perspectives prevailing in the literature, and reflected in our little world, on several different levels. We have elucidated and shall unveil, about 10 theorems, that, on their own, would generally be major breakthroughs, in our world, but we have unified it all under a single, beautiful paradigm, which WILL be a breakthrough, in the literature, when they figure it out, in 5 years.

As with all things that push the boundaries, large amounts of direct evidence is lacking in certain areas of our research (or it wouldn’t exactly be revolutionary). As you will see, there is, however, a truly prodigious amount of indirect evidence, which, when analyzed as a whole, with the help of our friends logic, critical analysis and creative genius, is both loud and eloquent in its support of our argument.

Editors Note: Before we move further, I cannot emphasize enough the importance of the whole for understanding the parts and vice-versa. And, I mean this well beyond distinctions of in vitro vs. in vivo. As this is best viewed as a collected body of work, it will be presented as such -- it will be organized into major points, with the data in support presented as a semi-organized whole because it defies typical uni-directional linear representation because the body does signal either linearly or uni-directionally. The relatively abbreviated nature of “teaser”, reinforces this set-up. I have tried to stick to the theory in the text, with examples here and there, as opposed to detailing a study every other line (that write-up is in the works) – instead, I have just placed references at the end of the write-up, summarizing the significance of each one, and divided them into groups, based on the aspect of the paradigm they provide support for.

So, with that aside:

 

Survival, Reward, and You

The essence of biological systems is survival and propagation, basically by definition. Billions of years of evolution created us and genetic coding that sent reward signals for anti-life behavior would result in extinction, and has thusly been generally eliminated at the genetic/instinctual level. So, everything we do, scientifically, will be with survival advantage for the organism omnipresent in the back of our minds (alas, their will be no Creationist themed Avant Labs products in the near future).

We humans should add "happiness" to that, as should we bodybuilder (yes, it has positive repartitioning effects), because it is signaled by the same reward pathways. So, let us look at the nature of our survival, propagation, and happiness in greater detail.

 

 

The War Machine

There is exactly one good reason to be “one with nature” – to dominate it.

Life is essentially a war of all against all -- even within one’s own body (bacteria, viruses and cancer, are such examples of warring agents). Natural selection IS war, survival, and propagation -- from the first atoms that found it "beneficial" to form a molecule, then a cell, and so on, to the current penultimate organism, Rational Man and his Empire.

At the macro level, it is obvious – “Mother” Nature sends us pestilence and famine and natural resources galore, we counter with the insertion of our intellect into matters. We are occasionally more civilized when warring with each other, but most still prefer versions of force over the thought and reason, and considering that is all life had to work with for the first 99.99999% of evolution, it should not surprise that a lot of this is still wired into our genetic code.

Not so obvious, is what goes on at the micro level, between body and environment. Examining the nature of the skin barrier, Phase I and II acute “xenobiotic” responses (everything is a “xenobiotic”, as with war, we keep the spoils, destroy and discard the rest), inflammatory cytokines, local expression, leaves one with the impression they are housing World War III, 24-7.

We would do very well conceptualize biological systems as such in our mind’s eye, and we would do very well to treat the matter as such, in our attack.

One does not just send a single plane with a nuke in, except when it is time to fuck something up proper. Our goal is supraphysiological health, aesthetics, and performance, which requires a bit more strategery than that. Instead, we should attack the problem from multiple fronts and with multiple tactics, like an army -- and like the human body (“community effect” and “entourage effect” are two terms in used the literature).

 

The Homeostatic Imperative

What our means of defense aims to do, ultimately, is produce homeostasis (make a note, ‘tis Way Important ™ ) -- we adapt to weight training, because it is an attack on the status quo at numerous levels -- electrical, mechanical, chemical, etc., which cells perceive as “uncool”. So, they produce pain so you won’t do it again tomorrow (and probably does some long-term coding in the brain as well), and then supercompensates, because billions of years of evolution has shown that we’ll not only do it again, but that it is beneficial for survival and propagation (and that some us will even schedule our life around purposely doing it, day after day).

Let us call this the Homeostatic Imperative.

Interestingly, one the way body does so, in regard to weight training, is to make the muscle fiber resistant to the cellular stress response evoked from training, but that is a topic for another day.

 

 

If There Were a Magic Bullet…

I can think of exactly two places where your magic bullet properly belongs, and neither of them are a scientific discourse on the betterment of a biological system.

The body is profoundly redundant in its setup and operation. Basically, we just evolved one system on top of another, as it proved useful for survival. The previous system, however, did not just disappear, as if the higher system or organism were created anew by magic. Instead, it stuck around and just helped with the same job. That extreme redundancy might be most beneficial for survival, in case the foodstuffs containing essential micronutrients become unavailable during the days before science and supermarkets, does not take a fantastic leap of logic.

And, in combination with the homeostatic imperative, it does not take a great leap of logic to suggest that the Magic Bullet and the related Godfather Hormone approach is inherently retarded, on multiple levels (yeah, I know I greatly helped propagate the latter in my Leptin articles and postings).

Unfortunately, this is the dominate medical approach, and, as such, it is the current dominate academic paradigm.

How the idea that simple, massive, overconsumption of a nutrient might not be the best approach for manipulating a system whose nature is specifically to prevent massive overstimulation of ANY signaling pathway has not occurred en masse – be it due to conspiracy or myopia or lack of talent or whatever – I am not sure. I mostly know it’s retarded. Mostly.

 

Yin-Yang in this Thang

Such, is just not how the body chooses to do business. It does so via the manipulation of countless LOCAL signals, modestly elevated or reduced, working in unison. Under such conditions, quite a bit of evidence exists that, contrary to the wrath of protective feedback inhibition, when proper substrate is available in PHYSIOLOGICAL amounts, a positive feedback cycle is produced.

We witness this phenomenon with the inflammation/anabolic response to exercise, with sex hormone action (and I think pulsatile release is an artifact of this phenomenon, but I lack sufficient evidence), with tumors, prostate hypertrophy, hair-loss, body-hair growth, or in any situation when there occurs a loss of control of substrate imbalances.

The body is quite good at preventing this (truly, profoundly, remarkably so, in fact), but it is not perfect – chronically place excessive pressure on any system, and it will eventually fail.

So quite abusing it.

I am not directing this comment at the slothful and gluttonous -- I am speaking about We of the Bodybuilding and Human Performance persuasion. Let us cease looking for the magic pill and the magic routine, and start looking at how genotype met environment to produce the phenotype you see looking at you in the mirror, how it does so in others, and why.

Chances are 100% that you are doing a bunch of stuff right (what "works for you"), but without having a clue as to why, while also doing a bunch of stuff wrong (which works for lots of others), because without the “why” and “how” , you cannot take context into account -- and, context is EVERYTHING to the cell.

Environmental encounters will have dramatically different effects depending on the existing biochemistry (be it mostly genetic in origin, or otherwise). It thus follows, that without a true understanding of wherefores, whatnots, and how-so's, one is going to draw false conclusions from study after study, and experience after experience. If the core determiner of biochemical reaction is not understood, its subsequent manifestations cannot be either.

You have hopefully noticed that the same environment will not only produce very different results in say the DoWA mesomorph vs. the "hardgainer" ectomorph , so too will it produce different results in you, given your current biochemical profile (on 1g of test per week, for example, vs. “clean”, or even at high body fat vs. 10 weeks into your diet.

IOW, the Chicken Without a Head Approach to Diet and Exercise ™ almost certainly leaves you greatly lacking in efficiency and results.

 

Phenotype = Genetics + Environment

Everything the body does, it does for a reason. Namely, perceived survival benefit. If fatty acid oxidation and protein synthesis decreases, and your sex drive goes away, it is because your cells are getting signals that your body is starving and not getting signals of the opposite nature.

The last thing you would need, is the inefficient, DOMINATE phenotype and another mouth for the village to feed, because right now, nutrient signaling pathways are indicating that life is kicking your ass.

Furthermore, it does its bidding through specific pathways -- though prodigious in complexity, it is not random. Transduction, translation, and transformation are the result of specific FOOD DERIVED NUTRIENT SIGNALS – everything else just influences those.

Change the signals, you change the phenotype. Good genetics are most welcome, but clearly, we can influence the phenotype, for good and for bad, by changing our lifestyle. The pathways and signals responsible for production of the phenotype are rapidly being uncovered , so one would do very well to take them into consideration. Look at why what works does in fact work. Meaning, analyze the signaling mechanisms involved, and manipulate them as efficiently as possible through properly designed exercise, diet, and supplementation for your situation.

You could save several years by letting us do most of the legwork for you, which is what we have done with LeptiGen -- and what we will do beyond. Though, methinks it a fairly magnificent beginning, LeptiGen Prototype II truly is but the beginning of what we are going to do in the near future.

 

Mmmmm…… Cocoa Pebbles

Before rational man, the organism needed a very strong signal to let it know what it needed to do for proper living, particularly in times of scarcity. Things have strong tastes for a reason. Unfortunately, one’s goals and needs are generally not in harmony with one’s genetic tendencies, nowadays, so the issue is far more complicated than “yummy = good for you” (ancestors) and vice-versa. This situation has literally caused an epidemic in times of plenty, as the genetic coding that calorie dense foods are precious and wonderful is still very much existent and active, but it now takes essentially zero effort (physical and otherwise) to attain this nourishment.

Don’t fret, it gets much worse J -- many have come to possess a "thrifty" genotype. Unfortunately for these individuals, large amounts of muscle and high rates of FFA oxidation and lack of need/desire to eat are the thrifty genotype’s antithesis, so the nutrient partitioning situation can get ugly. Compare this, for example, to the West African, badass genotype (gorillas, rhinos, lions, elephants, pro-athletes), which evolved with continuous abundance.

Fortunately, these same signals also open up quite a few avenues of attack. The body has a fair number of reward signals that indicate living right, as well as a vast number of pathways that mediate these reward signals (and, which these reward signals conversely mediate -- did I mention that EVERYTHING is connected). This same reciprocal, intertwined signaling extends to the process of telling the organism to stop a behavior that is anti-life as well.

Dopamine, opiates, GABA, NE, Cannabinoids, PEA, NMDA and more are part of this reward signal, but, again, balance is key. Get something too high or run out of a needed substrate, and the organism shuts down those processes to avoid damage. And because these bodily functions are all interrelated, this shutdown of one process will often take the good stuff with it (like protein synthesis or nutrient uptake).

There is far too much info to get 100% precise on our approach without a computer algorithm of some sort (Spook and I have that on the agenda – mostly him). Worrying that we do not know every pathway in its entirety is akin to fretting over atomic physics in regard to its application in hitting a baseball.

If we take the big and small picture into account — in vitro and in vivo -- the macro and the micro— the forest and the trees –- real world and the lab -- wecan clearly see pattern after pattern, and pathway after pathway, many screaming to be rationally manipulated for nutrient repartitioning. So, if we are vigilant in cultivating an awareness of these patterns, we can carefully manipulate them via little pushed and pulls in the proper directions and do infinitely better than the 2/3 blind approach that is currently being employed.

This, of course, begs the question: what are these so-called “patterns”, of which you speak? And, of course, what are the proper directions in which we need to push them in order to attain the DOMINATE phenotype?

 

Phenomorphosis

The Fed State

Well, this is for LeptiGen, so let us start there. As you recall, the point of LeptiGen is to trick the body into thinking it is being fed when it is not. We have discussed the fed state in regard to metabolic parameters of an organism, in our “Leptin” series. Namely, the fed state is conducive to fast, muscular, and “metabolically inefficient” phenotypes, with the vice-versa also holding just as true, if not more.

However, this phenomenon is actually signaled at the cell level, and the fed cell is a metabolically active cell, in regard to overall metabolism, fatty acid oxidation, protein synthesis, and much more.

Obesity does not occur in the wild (animals eat what they need, then get a signal to stop). But, keep Rover and Kitty’s bowls full, with delicious vittles, and it is a different story. Obviously, that communication between nutrient signaling and calories and reward is proper fucked in an even larger percentage of human people.

But, what does that have to do with We, the Lean??

Everything.

We too, are very oft not getting the proper "fed" signal, though, our is a result of self-imposed starvation, to a great extent (as far as calories) – again, read my leptin articles if unaware of the negative partitioning invoked by the starvation response.

What we are not aware of, is that calories are almost meaningless, per se -- it is the strength of the signal sent at the protein level and in what tissues it is signaled that determines the phenotype. It is indeed foodstuffs and their metabolic byproducts (along with other aspects of environment, which we will not get into too much (sunlight, oxygen, pathogens) that determine this signaling, so adjusting caloric intake will affect all of this to some extent, but it is not going to be remotely linearly correlated (unless you have the perfect diet -- which you don't), because quality is what is of absolute, prime importance.

Which gets us to our paradigm (in relation to our products, at least) -- namely -- via supplementation, we intend to invoke the fed state by providing the body with those metabolic byproducts that signal it, but which contribute fewer calories per unit fed signal then glucose.

Thus, the body will continue FFA oxidation and protein synthesis at high rates, but instead of having the excess calories, which you previously needed to reach this state, spill over into adipose, we will get the signal at a calorie deficit or near maintenance, instead of with massive over feeding, so the body will draw on existing fat stores to provide substrate/ATP for these processes, giving long-term repartitioning.

We also intend to push substrate flow to the proper tissues, via manipulation of pathways that favor muscle over fat.

 

Food and Mood

We talked about reward signals, quite a bit, in regard to the fed state, so I will just add that they are quite similar in nature, sharing neurochemicals and huge chunks of signaling pathways. This goes for responses to sex, to food, to drugs, and even great ideas.

For example, food-restriction increases the subjective reward response to both food and drugs. It also increases both dopamine and opiate activity. This makes sense, on the micro and macro level. First, food restrictions mimics food scarcity/starvation, so your reward signals would be low, so the receptors would upregulate simply due to diminished ligand binding. Secondly, the leptin receptor is found all over neurons for pleasure chemicals in the areas of the CNS that modulated food related behavior and, not surprisingly, leptin decreases the reward response to both food and drugs. Fed signals are then sent in 1000 directions and you are chemically satiated.

There are a number of pathways where the reward and fed response is imbalanced in the obese, and conveniently, they can be connected to leptin or dopamine with 1-2 steps. This includes opiate pathways, inositol pathways, and more.

 

Global Protein Synthesis

Protein synthesis is, essentially, a whole body process, though it is split up into converging and diverging pathways that make it seem more confusing. And, contrary to common misperception, significant portions of this signaling process are essentially immediate – so-called “fast transduction”.

The Mind signals the body, taste buds signal the body, the stomach signals the body, the liver signals the body, and so on –- and, of course, vice-versa…… and it is all at the cell level….. and it runs the gamut of tissues. All is interconnected (as you'll see), so anabolic conditions in one cell/tissue will push the entire body in that same direction (glucose and fatty acids in insulin resistance is one such obvious example).

This situation of global protein synthesis/anabolism applies to leptin and other peptide signals and structures like IGF-1, GH, insulin, etc, and likely to receptor expression as well (until negative feedback hits). IOW, it is far from confined to the kind that you flex, which is what we normally tend to think of too often.

 

The Anabolic Response

The anabolic/fed/protein synthetic response is basically the same for every component in the body: muscle, fat, the immune system, neurons, tumors, etc. In all of these systems, the pathways and cycles that determine the anabolic response (and are reflexively determined by it), including inflammation/cytokine/prostaglandins, mTor, ion transport, cell-swelling, 2nd messengers, and even mood chemicals, are virtually identical. These fundamental similarities in process transcend tissue/cell-type and they transcend species, from the most complex to some of the most simple.

As mentioned, previously, it is a positive feedback cascade, of nutrients/signals triggering their own release and the release of others that signal them, all the while creating more and more potent signals, branching out in a criss-crossing web, upregulating mRNA billions of times at a billion different points, until reaching the point where the fact that it is coupled tightly with the negative feedback side we are more familiar with, becomes apparent (only at the protein level much of the time, though most of us are familiar with pain, nausea, cyclic testicular shrinkage, etc. – all of which are negative feedback signals of one variety or another).

 

Yin-Yang Back in this Thang

Problems arise, in regard to health, body composition, mood, etc., when concentrations/signaling becomes unbalanced and askew. Basically, pretty much every bodily process has an “inverted U” concentration-response curve associated with it, which is made particularly manifest when essential co-substrates are lacking.

Proper balance is the key to overcoming the limitations of homeostasis. It should occur that nutrients might compete for absorption and uptake for a good reason. The body deals successfully with unfathomable amount our nonsense. Get things semi-right and transform the body is previously unimaginable ways via foodstuffs and exercise.

 

Nutrient Hierarchy

On the macro level, we note that the body has a hierarchy for nutrient distribution – and, again, in evolutionary terms, it makes perfect sense. It is more important for survival to provide nutrient to brain, muscle, organs, etc., than it is to provide it to fat tissue. This has profound and wonderful applications for Rational Man -- namely, uptake mechanisms are going to be more sensitive in these tissues, and adipose tissue will mostly get the spill over.

The literature on a number of systems backs this up as well, in cellular and whole-body nutritional states between obese and starving, the hormonal milieu activates catabolism of fat tissue in order to provide substrate for increased protein synthesis (PGF2a, testosterone) or to spare glycogen and muscle protein (AMPK, beta3, PPAR-alpha) at the expense of fatty acids.

 

Nutrient Repartitioning

Nutrient repartitioning is the key to rapid, long-term body composition manipulations. Obviously, maintain the fed state, proper, as mentioned -- balanced, full signaling at all pathways as ideal. The nutrient partitioning improvement lies primarily in the avoidance of the starvation response from suppressed signaling, as opposed to the achievement of supraphysiological levels.

And, as mentioned, strive to achieve this metabolic state without a calorie excess or even in a deficit, via manipulations in nutrient signaling pathways, using substances that send a stronger signal per calorie than glucose (or if you want to get fat, do the opposite), for the induction of long-term, steady repartioning

Finally, make a point to really focus in on the pathways/mechanism by which one can preferentially stimulate the anabolic response in muscle vs. fat. Exercise is the most obvious, since it is far easier to activate mechanoreceptors and induce ion flow (and the anabolic cascade that follows) in contracting muscle than in fat.

The rest is the essence of LeptiGen p2, and many products to follow.

 

Local Government

We have implied as much throughout, from start until present, but plasma levels of a nutrient or hormone in question are essentially meaningless (vasculature being a notable exception). The full machinery for synthesis and metabolism of essentially all of the important signals in the body exist locally. This applies not only at the tissue level but ultimately at the cellular and subcellular/protein level .

Local is EVERYTHING

 

Eggs and Omelets

Catabolism, oxidation, and the like, are all part of the anabolic trigger. It stimulates ion transport, nutrient uptake, cell-swelling -- any of this sounding familiar…..? J The key to harnessing the positive attributes activated by these processes lies, as always, in the attainment of balance through proper feeding (and filling) of the cell.

Many substances, such as NO, Vitamin C, and NAC can be both anti-oxidant and pro-oxidant, depending upon context. In addition, most of the signals we discussed in the “Anabolic response” segment, can be anabolic or profoundly catabolic, depending on context.

Ideally, one wants to obtain as much anabolic stimuli per unit of fiber damage, neurotransmitter depletion, high energy phosphate depletion, etc. (thus inroad to recovery) as possible. At a certain level, anabolism and uptake reaches a threshold, the muscle cell can’t expand anymore, ions are done being rapidly transported in and out of the cell, osmoltyes turn off their pager, and protein synthesis establishes a status quo for the time being.

Anything beyond that ceiling is overkill, as the extended anabolism of a “sore for a week” workout will not provide an Area Under Curve of anabolism to compensate for the catabolic hole you dug yourself.

The superiority of more numerous, less destructive workouts seems almost a given when one considers the homeostatic imperative.

 

The Data

Everything connected, everything in its place:

PubMed #
10386770 -- mechanotransduction (multiple cell types), local IGF-1

12490597 -- oxytocin, PGF2a, and Ca2+ transport

11976264 – Arachidonic Acid metabolites and penile dilation

12005362 -- DA receptor may have evolved from ATP/GTP receptors.

9560443 -- IGF-1, Ca+/calmodulin, alpha1, and K+ channels

12169444 -- leucine activates protein synthesis in all cell types tested

9227529 – Acetyl Choline stimulates release of NO and PG, causing vasodilation

2481442 -- NSAID blocks insulin stimulated mRNA synthesis

9044432 -- hypoxia, Arachidonic Acid, PGF2a, and glucose uptake

8468370 -- mechanical stimulation and 2nd messenger release in muscle (IP3 and DAG)

8141783 -- alkalosis and ATP increase IP3 and DAG

43142 -- hydrolysis of Arachidonic Acid from PhophatidylColine increased by histamine and retinoic acid, as well as PGE2 and PGF2a

12225698 – Acetyl-l-carnitine (ALC) increase dopamine (DA) and serotonin (5-HT)

8364354 -- ALC potentiates NE and DA increase in adenylate cyclase activity

8474576 -- ALC as stimulator of amino acid osmolytes

12580938 -- correlation between leptin and total body water

12565709 -- leucine promotes glucose uptake in skeletal muscle

 

Higher metabolites/nutrient signaling:

2412882 -- histamine stimulated by galactosamine

12716017 -- ALC and myo-inositol increase creatine phosphate.

7191117 -- DA stimulates fucose and mannose incorporation into glycoproteins in hippocampus

7907523 -- oral aminoglucose induced feeding suppression via histamine.

11818483 -- PPAR review

870654 -- leucine -- protein synthesis and nutrient signaling -- depressed food intake)

10762040 -- alpha1 adrenergic receptor modulates rewarding effetcs of DA and opiates

12199155 -- ALC prevents ATP depletion

12609753 -- histamine (H1) and leptin

9387093 -- acceleration of TCA cycle increases protein synthesis by increasing ATP.

 

Protein Synthetic Machinery:

11790952 -- muscle protein synthesis and amino acid availability

11498025 -- requirements for protein synthesis -- differences in mTor linked pathways

11242477 -- dietary protein and the IGF-1 system

12423332 -- regulation of translation by nutrients -- review

12501002 -- leucine, insulin, signal trasduction, exercise

9597174 and 1772873 and 2661928 -- minerals and growth -- deficiency at cellular level before loss from muscle lowers protein synthesis

3521317 -- Ca, Mg, thiol proteases and protein breakdown

12388166 -- mTor and leptin

12080086 -- mTor and IP3 dependence in cell growth

9814971 -- leucine requires other amino acids for maximal activation of mTor -- effects linear at physiological concentrations

6694002 -- leucine effects linear until maximal protein synthesis is reached

12417714 -- TOP mRNA's controlled by IP3, not mTor

12217881 – Essential amino acids and protein synthesis

 

Food and Mood

11324170 -- Histamine (like leptin) blocks DA steorotypy

11249972 -- DA and Histamine

10683850 -- Histamine (like leptin) modulates striatal DA activity

12417657 -- NE, DA, and cysteine

10336518 -- DA as alpha 2c ligand (like NE) -- negative feedback mechanism

11507683 – PGE1 increases beta-endorphin, which increases glucose disposal

9443837 -- insulin downregukates alpha2 in CNS

11919655 -- tyramine and octopamine -- compete for DA Transporter

12573518 -- DA, insulin, leptin – CNS - food/reward/metabolic parameters

11272151 – Histamine(1) necessary for leptin's effects

11349397 -- augmentation of drug reward with dieting via DA(1)

8205479 -- augmentation of drug reward with dieting – opiate/endorphin

8947935 and 12387683-- more food and mood

973122 -- tyramine conversion to dopamine via CYP-45- enzymes

11897683 – DA(2) required for proper IGF-1 functioning

11744219 -- DA and IGF-1

10422653 -- 5-HT potentiates bradykin induced muscle pain

 

Adenosine Triphosphate

12351422 -- ATP and nutrient signaling 

12387821 -- adenine and methionine restore hepatic ATP and protein synthesis.

2339278 -- ATP substrates

12398110 -- ATP stimulates arachidonic acid release

9595270 -- ATP as mitogen

11509496 -- creatine reduces leucine oxidation 20% in men

11018652 -- ATP, swelling, and Cl- channnels

 

Cell-Swelling/Volume

11125222 -- insulin, cell-swelling, and nutrient signaling

12696593 -- cell-volume and insulin signaling

11530937 -- diuretic increases proteolysis

12688629 -- swelling releases ATP, activates Cl- channels

8889186 -- proline as "compatible osmolyte”

12355187 -- taurine as osmolyte

11881930 -- .5% betaine as nutrient partitioner in pigs

12563517 -- glutamine as nutrient signal equal to glucose, in importance

12153571 -- glutamine synergistic with leucine/insulin in promoting anabolic state

12001166 -- glycine-betaine, asparagine, and glycine as osmolytes

11533303 -- glutamine and nutrient signaling, via cell swelling, in liver

12606317 – Reactive Oxygen species mediate taurine release

11500954 -- cell-swelling and proliferative signal transduction

10806336 -- cell-volume and protein synthesis

 

Minerals/Ion Transport

10381146 -- Mg and Vanadate synergistic in glucose disposal

11963837 -- increased Mg improves recovery of ATP and protein synthesis and NO after glucose-oxygen deprivation

11831463 -- zinc in signaling, proliferation and differentiation of mammalian cells. 

10871879 -- Ca2+ transport in the Sarcoplastic Reticulum

10071779 -- Calcium signaling and gene expression.

9124303 – Arachidonic acid and Na+ channels

8926370 -- ion transport -- correlations to cell volume, hormone actions, and metabolism

3544865 -- ion transport systems during cell volume regulation

1721542 -- swelling activates ion channels

12688629 -- glucose, ion channels, and cell-swelling

10893434 -- Ca2+ and muscle

11509825 – reactive oxygen species, Ca2+, cell-growth and differentiation

12440694 -- glucose, Na+, cell-swelling

11015618 -- exercise and K+

 

Prostaglandins/cytokines/Inflammation

12611772 -- glutamine potentiates exercise effect on IL-6

10233023 -- cytokine induced glucose uptake redox sensitive

11257454 – Arachidonic acid, PGF2a, glucose uptake and adipose differentiation

12581497 -- histamine and NO

12600796 -- 5-HT, histamine, ATP, PGE1 and muscle pain

10940341 -- fatty acids and the immune response -- review

9928421 -- inflammation/immune response and protein synthesis -- review

8781295 -- TNF-alpha increases glucose uptake

9375864 -- cytokines stimulate connective tissue

6053649 and 940231 -- 5-HT and skeletal muscle

12205200 -- inhibition of prostaglandin and NO decreases blood flow from exercise

11557312 -- vitamin C and NAC increase exercise induced muscle damage

9839076 -- exercise and cytokines

11303145 -- exercise and IL-6 (produced locally)

10762721 – Arachidonic acid and cell-swelling

 

2nd Messengers/signal transduction

11493020 -- IP3 essential for protein synthesis and glucose uptake

9932214 -- IP3, insulin, cell growth, and anti-apoptosis

12115906 -- alpha1 adrenergic activation increase IPs 8-fold

10720331 -- IPs and gene expression

8626564 -- inositol, Na+, glucose -- uptake/transport

12457379 -- amphetamine increases IP activity

1575723 -- insulin mediators

9165224 -- IPGs as insulin mediators

10212830 -- IPGs and growth factor signaling

 

Anti-oxidants and co-factors

11050172 -- thiols and redox

10491755 -- lipoic acid prevents H2O2 downregulation of glucose uptake -- vitamin C and E unable

11976222 -- ALC and lipoic acid

11792699 -- free radicals down-regulate PPAR-alpha -- anti-oxidant protects

12071973 -- cellular stress inhibits protein synthesis.

10842745 -- Cellular thiols and redox-regulated signal transduction.

6231057 -- vit E protects Ca2+ transport system against oxidized free fatty acids

7547850 -- lipid peroxidation with fish oil and depletion of Arachidonic acid stores blocked with vitamin C and selenenium

 

 

 

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