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Par Deus

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  1. Hopefully, we will get quite a few people to come back and start posting, again. Having trouble with the mass emailing, because a lot of people's registration emails were University emails or companies no longer around, so getting a ton of bounced emails, which triggers an automatic suspension of account with Amazon Web Services. I thought that all got worked out with the one I sent a month ago, because the software automatically removes the bad emails, but it had gotten suspended 1/3 of the way through the list, so there will still a bunch left when I sent it out, today, and it got zapped, again, half-way through the member list.
  2. calcium

    Some more calcium goodness from Neobium write-ups: "Increasing dietary Calcium produced a reduction in weight gain and fat pad mass of 26-39% with a 51% inhibition of adipocyte fatty acid synthase expression and activity, while stimulating lipolysis by 3 to 5-fold (195). In another study, an almost 50% increase in weight loss was found (196). A high-Calcium diet decreased fat gain by 55%, stimulated adipose tissue uncoupling protein (UCP2) and skeletal muscle UCP3 expression, increased thermogenesis and lipolysis, while lowering fatty acid synthase expression and activity (197, 198). Calcium also elevated peptides GLP-1 and GLP-2, which increase satiety and decrease food intake (199, 200). Calcium improves intestinal permeability, strengthens the mucosal barrier, reduces inflammation, and alleviates colitis (201). Prebiotics have actually been found to have negative effects on intestinal permeability and inflammation without Calcium Phosphate rather than the positive effects produced when it is present (202, 203). This protection is dependent on Phosphate, thus Calcium likely pulls it into the colon, improving luminal buffering capability (204). This is because SCFAs produced by prebiotic fermentation could lower pH too much in its absence. Finally, Calcium is necessary for the Calcium/Calmodulin-dependent Protein Kinase Kinase 2 (CaMKK2) mediated AMPK signaling and barrier maintenance produced by Glutamine (205)." http://neobium.org/product-line/primer/
  3. vinager

    Some stuff on acetate and other short-chain fatty acids from Neobium write-ups: "One of the primary ways that probiotic bacteria work their magic is by fermenting prebiotics and producing SCFAs (primarily acetate, butyrate, and propionate), so we are going to talk about those, and how they work. They primarily work through two mechanisms: 1) activation of free fatty acid receptors, FFA2 and FFA3. 2) Decreasing inflammation and permeability in the gut. SCFAs protect against obesity and insulin resistance. Butyrate and propionate induce anorectic gut hormones, while acetate does so without reducing food intake (Supplementary 1). FFAR2 deficiency results in obesity on a normal diet, whereas with overexpression, subjects remain lean, even on an obesity promoting high-fat diet. Activation of FFAR2 suppresses insulin signaling in adipocytes, which inhibits fat accumulation in adipose tissue and promotes the metabolism of lipids and glucose in other tissues such as muscle (S2). Propionate and butyrate activate intestinal gluconeogenesis. Butyrate does so through AMPK, while propionate works through a gut-brain neural circuit involving FFAR3 (S3). Propionate is sensed in the portal vein walls via FFAR3, initiating intestinal gluconeogenesis. This glucose then triggers a signal to the brain to modulate hunger sensations and normalize whole body glucose homeostasis (S4). In a fasting state, as much as 62% of infused propionate is converted to glucose, accounting for 69% of total glucose production (S5). This is quite applicable to lower carb diets. Basically, it makes your brain think you are plenty fed with carbs/glucose, so it signals not to eat more, as well as not to produce or pump out more glucose into the blood. SCFAs also stimulate the release of anorectic and satiey inducing peptides like GLP-1 and PYY via FFAR2/3 (S6, S7). Activation of FFAR3 by SCFAs inhibits insulin secretion and increases sympathetic outflow. This raises energy expenditure and help to protect against obesity (S8, S9). Acetate has been found to increase brown adipose tissue, UCP1, and mitochondrial biogenesis via FFAR2 (S10). Short-chain fatty acids also improve intestinal barrier function via activation of AMPK (S11). Sodium butyrate has been specifically found to be an AMPK agonist (S12). And, butyrate increase tight junction assembly, thus improving barrier function, specifically through AMPK (S13, S14)." http://neobium.org/product-line/suprabiotic/
  4. Some AMPK stuff from the Neobium write-ups: "AMPK is a primary signaler in the maintenance of tight junction integrity and intestinal barrier function. It is one of the most important pathways in preventing the “leaky gut” we have spoken of earlier in regard to LPS and other inflammatory and infectious molecules escaping into the body to wreak havoc (S15, S16). Modern food processing and the Western diet is a particularly egregious malefactor in this (S17). In addition to its involvement in barrier function, AMPK activation is extremely positive for the great bacteria that we can’t get commercially. Metformin increased Akkermansia 18-fold through AMPK activation. Also, against a high-fat diet, it restored Bacteroides levels and the Firmicutes:Bacteroides ratio to that of lean subjects (S18-S20). It inhibited LPS induced inflammation and gut permeability increases, while improving glucose uptake and insulin sensitivity (S19). Akkermansia increases are likely at least partially due to greatly elevated production of its favorite food, mucin, which is stimulated by AMPK. It also reduces insulin resistance and adipose tissue inflammation in a high-fat diet (S20)." http://neobium.org/product-line/suprabiotic/
  5. 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.
  6. Primer (tm) Ingredients

    Primer™ Ingredients As Primer™ is primarily a prebiotic, let’s start with those. Prebiotics have come a long way since oat bran and psyllium husks. Beginning with inulin, a huge array of oligosaccharide and glycan type compounds have been found to be fermented and fed on by intestinal bacteria. These newer prebiotics tend to be basically tasteless and dissolve effortlessly, which is quite handy. With the importance of microbial diversity for optimal gut and body health, we want a number of different prebiotics for them to feed on. Likewise, we want to choose the ones that best increase the bacteria we want to increase, rather than just randomly feeding all of them. Galacto-oligosaccharides (GOS) GOS reduced fat mass, food intake by 14%, and elevated expression of pro-satiety peptides. Combining them with Calcium increased propionate formation (116). In addition to reductions in food intake, appetite, bodyweight, and inflammation are also decreased (117). GOS increase beneficial bacteria, particularly Bifidobacterium, with 5-10 fold increases in some subjects being noted (118-121). They also raise Bacteroides levels (121). They are long-acting, providing prebiotic effect throughout the entire length of the colon, while strongly inhibiting pathogenic bacteria (122). This owes to high resistance to conditions early in gut digestion (123). GOS provide direct enhancement of intestinal barrier function through interaction with goblet cells, separate from SCFA or anti-inflammatory mediated mechanisms. They also showed a 2-4 fold mucin elevation, which would create a positive environment for mucin feeders such as Akkermansia and Bacteroides (124). They inhibited inflammatory responses, augmented protein junction assembly by 85%, and prevented loss of barrier function (125). GOS displayed a microbiota independent increase in tight junction assembly and improved barrier function (126). Finally, they mitigate LPS induced inflammation and protect against stress induced LPS activity (127, 128). Arabinoxylan-oligosaccharides (AXOS) AXOS are strongly Bifidogenic. They increase satiety inducing peptides, while decreasing weight gain, fat mass, and insulin resistance (129). They raise butyrate levels along with Bifidobacterium suggestive of subsequent cross-feeding to butyrate producing bacteria (130). They also reduce protein fermentation in the gut (130, 131). This spares amino acids for more useful purposes as well as preventing toxic breakdown products. AXOS are long-acting, with bacterial fermentation occurring throughout length of colon. They significantly promote Bacteroides as well as Lactobacillus (132). They are even better than inulin at providing fermentation products to the distal portions of the colon (133). AXOS elevated Roseburia and butyrate levels, with total SCFA increases as high as 2-3 fold (134, 135). Finally, they increase tight junction proteins, improve barrier function, and inhibit inflammation in adipose tissue (129). Xylo-oligosaccharides (XOS) XOS increased Bifidobacterium along with acetate and butyrate. Combining with inulin further augmented butyrate formation, as well as increasing propionate, suggesting cross-feeding to butyrate and propionate producing bacteria like Roseburia and Bacteroides (136, 137). And, XOS have indeed been found to promote both Roseburia and Bacteroides, as well as improving the Firmicutes:Bacteroides ratio (138, 139). Bacteroides possess special xylan degrading enzymes, making them a preferred fermenter of XOS (140). Elevated Bacteroides and butyrate from XOS protected against genotoxicity in a colonic simulator (141). They also decreased LPS and increased epithelial cell proliferation (137, 142). Lactulose Lactulose inhibits adipogenesis and fat accumulation, down-regulates adipogenic genes, and reduces caloric extraction efficiency, while increasing energy expenditure and lipolysis (143). It also improves post-prandial blood glucose and insulin levels (144, 145). Lactulose raises Bifidobacterium counts, particularly of the ideal cross-feeder B. adolescentis, as well as Akkermansia (146-148). Finally, it decreases intestinal permeability and proteolysis of amino acids in the gut (147, 149). Inulin Inulin improved glucose uptake in insulin resistant cells, and activated AMPK (150). It increases Bifidobacterium and butyrate, while reducing protein fermentation (151, 152). It has a prolonged Bifidogenic effect, with more distal fermentation and SCFA production vs. fructo-oligosaccharides, particularly of butyrate and propionate – again, suggestive of cross-feeding (153, 154). In fact, it was found to increase B. adolescentis more than 4-fold and F. Prausnitzii by 50% (155). It also increased Roseburia, while augmenting mucin production 6-fold, leading to large elevations in Akkermansia and propionate, distally (156). Resistant Starch 3 (RS3) Resistant Starch 3 is formed when starchy foods such as potatoes and rice are cooked and then cooled. This turns formerly digestible starches into resistant starches via a process called retrogradation. RS3 is particularly, and somewhat uniquely, highly prebiotic for Ruminococcus bromii, with increases up to 4-fold (157-159). R. bromii has superior ability to degrade this resistant starch, which is the most prevalent fermentable carbohydrate in the average diet, making it a “keystone species” by acting as a cross-feeder for other species (160, 161). It was also found to be readily consumed by Bacteroides, elevating faecal propionate, rather than butyrate as is often observed following resistant starch feeding of other types. This propionate formation reflects a gut community dominated by the Bacteroides, and it actually became the primary lineage in this study (162). Amylopectin Amylopectin was found to be superior to several other prebiotics for increasing butyrate, as well as butyrate producers F. prausnitzii and Roseburia (163). It also raises Bacteroides, with increases in Roseburia and Bacteroides being found to be proportional to the amylopectin content of barley and oats (164, 165). Mucin Mucin is the glycoprotein constituent of the mucus which lines the wall of the intestines and protects it. Several species of bacteria, including some of the really good ones, feed off of it. Akkermansia is the most well characterized mucin consumer (166, 167). Verrucomicrobia, of which Akkermansia is the primary genus, was increased from .03% to 5.25% by mucin, and in combination with inulin, Bacteroides was raised as well (168). Bacteroides thetaiotamicron is a known mucin degrading specialist (169-171). Bacteroides fragillis consumes mucins as well (172, 173). Roseburia intestinalis also colonizes the mucosal layer and feeds on mucins (174). With these bacteria colonizing the mucus and being close to the epithelium, particularly with the butyrate producers, bioavailability for epithelial cell regeneration and barrier function is enhanced. Rhamnose Rhamnose is a preferred sugar for the propanediol pathway of propionate production by Roseburia inulinivorans (175, 176). It is quite selectively metabolized to propionate (177, 178). It is much more selective for propionate formation than lactulose or glucose, which utilize different, less selective pathways, resulting in 4 times more propionate than with lactulose or glucose (179). Rhamnose was also found to decrease triglyceride synthesis and serum triglyceride levels, likely due to propionates effects on the SCFA receptors FFAR 2/3 (180). Glutamine Glutamine is the primary substrate of rapidly diving cells, a category to which the epithelial cells of the digestive tract belong. It increases tight junction protein production (181). It does so by activating the mammalian target of rapamycin (mTOR) cell signaling in enterocytes. It enhances intestinal growth, enterocyte proliferation and survival, and regulates intestinal barrier function in injury, infection, stress, inflammation, and other catabolic conditions (182). It is basically both the leucine (protein) and the glucose (carbohydrate), to go along with butyrate as the fat, for the fueling of survival, growth, and reproduction of the enterocyte. This makes it quite possibly the most important nutrient for intestinal barrier health and function. Glutamine also reduces utilization of other amino acids (asparagine, aspartate, serine, lysine, leucine, valine, ornithine, and arginine) in the gut, preserving them for more useful things while reducing toxic metabolites (183, 184). It decreases intestinal permeability and enhances intestinal mucosa and barrier function (185). Glutamine improves intestinal barrier impairment and quells the LPS mediated inflammatory cascade (186). It also prevents mucosal injury and promotes recovery from LPS induced inflammatory damage, as well as downregulating TLR-4 expression (187, 188). Inflammatory conditions increase the requirements for Glutamine to maintain the intestinal barrier (189). It has specifically been shown to protect the intestinal barrier against processed, Western diet style foods (190). AMPK mediates its enhancement of tight junction integrity and barrier preservation (191). Conversion to glutamate and subsequent cellular uptake is a pivotal step in its protective effects (192). Monosodium Glutamate has been found to promote the colonization of F. prausnitzii and Roseburia (193). And, finally, L-glutamate enhances barrier function (194). Calcium Phosphate Increasing dietary Calcium produced a reduction in weight gain and fat pad mass of 26-39% with a 51% inhibition of adipocyte fatty acid synthase expression and activity, while stimulating lipolysis by 3 to 5-fold (195). In another study, an almost 50% increase in weight loss was found (196). A high-Calcium diet decreased fat gain by 55%, stimulated adipose tissue uncoupling protein (UCP2) and skeletal muscle UCP3 expression, increased thermogenesis and lipolysis, while lowering fatty acid synthase expression and activity (197, 198). Calcium also elevated peptides GLP-1 and GLP-2, which increase satiety and decrease food intake (199, 200). Calcium improves intestinal permeability, strengthens the mucosal barrier, reduces inflammation, and alleviates colitis (201). Prebiotics have actually been found to have negative effects on intestinal permeability and inflammation without Calcium Phosphate rather than the positive effects produced when it is present (202, 203). This protection is dependent on Phosphate, thus Calcium likely pulls it into the colon, improving luminal buffering capability (204). This is because SCFAs produced by prebiotic fermentation could lower pH too much in its absence. Finally, Calcium is necessary for the Calcium/Calmodulin-dependent Protein Kinase Kinase 2 (CaMKK2) mediated AMPK signaling and barrier maintenance produced by Glutamine (205). Multi-Berry Powder Multi-berry powder has the power of berries!! A day’s worth of Primer™ is equal to ¼ cup of mixed berries. It has the polyphenols and fiber and such that berries have, but it is mostly in here because it gives it a nice, subtle berry flavor. Conclusion Primer™ takes the concept of prebiotic far beyond where anyone has previously taken it before. It starts by carefully and selectively feeding the most beneficial bacterial species, including novel probiotic species that you cannot attain, anywhere. It does so in a way that no other product comes even close to doing. It protects against dysfunction of the gut and microbiota to promote better health, better appetite control, better metabolism, and better fat loss. Finally, its supporting ingredients go to work on making your inflamed and leaky gut as good as new, leaving your body functioning in the optimal way it is intended to. Primer™ is a gourmet meal for your microbiota and a happy-ending massage for your gut. It is a one of a kind product that fits in perfectly with and enhances any diet and exercise program, any supplement regimine, any lifestyle. For references, see "View Full Science Write-Up" here: http://neobium.org/product-line/primer/
  7. The Best Bacterial Species That Money Can’t Buy. Unfortunately, several species of bacteria with some of the very best data are not available commercially, due to regulatory issues and well as practical challenges such as stability and viability of the bacteria themselves. We are working on these, as are several other groups, but it will happen later rather than sooner, at best. Fortunately, there are a myriad of ways to specifically target and increase these strains using methods that ARE available. And, that is exactly what we have done. So, let’s take a look at these novel wonder-bacteria, and then we will get to the data on B. adolescentis as the ultimate cross-feeding probiotic. Genus Bacteroides Bacteroides are butyrate and propionate producing. Levels were 6-fold higher in lean vs. obese subjects, as well as being reduced in obese patients, in general, compared to control populations (60-63). The Firmicutes:Bacteroides ratio was also significantly worse in obese patients, even in comparison with the merely overweight (65, 66). It has a negative correlation with fat mass and waist circumference (66, 67). It was also 60% lower in obese pigs – yeah, apparently that is a thing (68). Bacteroides levels in Type-2 diabetes were only half that of those with normal glucose tolerance (69). Lower Bacteroides was correlated with increased energy intake (70). Additionally, it was decreased after smoking cessation similar to differences in obese compared to lean subjects suggesting a link between Bacteroides and the weight gain of smoking cessation (71). Among various species in the Bacteroides genus, B. uniformis reduced bodyweight gain, triglycerides, and adipocyte volume while improving insulin and leptin sensitivity. It also lowered LPS and other inflammatory signals (72). Bacteroides acidifaciens decreased bodyweight and fat gain, while increasing fatty acid oxidation via PPAR-alpha (73). In addition to an elevated Firmicutes:Bacteroides ratio, B. vulgatus levels were found to be lower in the obese (74). B. fragilis releases a symbiotic immunomodulatory anti-inflammatory factor called Polysacharride A (75). This activates TLR-2, which releases anti-inflammatory interleukins. PSA is basically the opposite of LPS, and TLR-2 the opposite of TLR-4 (76). This has been shown not just to prevent but to cure experimental colitis, an extreme version of a leaky, inflammatory gut (77). It has also been shown to prevent demyelination of neurons in the central nervous system, indicative of protection against inflammation well outside of the gut (78). A few of the Bacteroides species bind to mucins for colonization and consume these mucin polysaccharides (79, 79b). Bacteroides species also have greater glycan degrading capability than Firmicutes, thus they are preferentially increased by polyphenols (80). Primer™ contains both mucin and polyphenols. Faecalibacterium prausnitzii Faecalibacterium prausnitzii is butyrate producing and is considered a physiological sensor and marker of human health (81). It does not get much more important than that. It is lower in the obese and type-2 diabetics (82-84). Conversely, it is higher in normal glucose tolerance vs. prediabetic subjects (85). Faecalibacterium prausnitzii is also negatively correlated with inflammatory markers and sharply decreased in inflammatory bowel diseases (84, 86). It is greatly reduced in ulcerative colitis and less abundant in Crohn’s disease (87, 88). As would be expected from the above, it improves intestinal barrier function (89). Akkermansia muciniphilia Akkermansia muciniphilia is mucin degrading, meaning it feeds on mucins (90). Levels are higher in lean subjects than the general population (91). It is also decreased in obesity and type-2 diabetes. Its administration reduced fat mass, adipose tissue inflammation, and enhanced insulin sensitivity. Along with this, improved gut barrier function and increased intestinal endocannabinoid levels were seen (92). This species is also inversely related to fasting glucose, waist-to-hip ratio, subcutaneous adipocyte diameter, plasma triglyceride levels, visceral adipose tissue mass, and insulin resistance (93). Along with enhanced glucose tolerance, it reduced adipose tissue inflammation (94). Akkermansia levels are higher in normal glucose tolerance vs. pre-diabetic subjects (95). It decreased inflammatory cytokine production and protected intestinal barrier function in experimental colitis (96). Finally, its levels are reduced in ulcerative colitis (97). Roseburia Species Roseburia species are butyrate producing (98). An increase in this species is associated with decreased body weight, fat mass, insulin sensitivity, and triglycerides -- independent of calorie intake (99). Increased Roseburia correlated with reduced body weight, improved profile of lipid and obesity related gene expression, along with a normalized inflammatory status (100). It is also lower in type-2 diabetes (101). Levels are increased by a Mediterranean diet, as is insulin sensitivity (102). Roseburia is enriched in healthy populations vs. those with atherosclerosis (103). And, its levels display an inverse correlation with disease activity in ulcerative colitis (104). High protein/low carbohydrate diets, which are so effective and popular, reduce Roseburia and SCFA levels (105, 106). This does not mean don’t use them, it just means make sure you make a point to get fiber/prebiotics to feed your good bacteria that produce SCFAs. Butyrate is especially important amongst the SCFAs, as it the preferred energy source, along with Glutamine, for epithelial cells in the colon (107). Butyrate is basically the fat to Glutamine’s protein and carbohydrate as far as feeding these cells. We will talk more on Glutamine in the Primer™ write-up. Bifidobacterium adolescentis as Cross-Feeder As mentioned, B. adolescentis is hugely important in helping to feed other bacteria, specifically the really good ones that we just talked about, which we cannot get commercially. B. adolescentis is superior to other potential cross-feeding Bifidobacterium in that it provides a slow, steady degradation of oligosaccharides for a long, continuous release of substrate for these various bacteria to feed on. It is essentially time-released, allowing acetate feeding, butyrate producing bacteria to grow and thrive throughout the entire length of the gut (108). Faecalibacterium prausnitzii is almost fully dependent on acetate, which B. adolescentis supplies. F. prausnitzii converts it to butyrate with 85% efficiency, and its growth is enhanced by co-culture with B. adolescentis (109, 110). Roseburia is also an acetate user (111). It is, in fact, generally required for growth (112). In addition to acetate production, B. adolescentis increases Roseburia via partial breakdown of oligosaccharides, which it can then utilize (113). Cross-feeding with Bifidobacterium modulates the prebiotic effect of inulin and arabinoxylan-oligosaccharides on Roseburia and F. prausnitzii by making acetate available (114). Roseburia was able to grow in pure complex carbohydrate cultures, which it cannot metabolize on its own, owing to cross-feeders (115). Short Chain Fatty Acids (SCFAs) One of the primary ways that probiotic bacteria work their magic is by fermenting prebiotics and producing SCFAs (primarily acetate, butyrate, and propionate), so we are going to talk about those, and how they work. They primarily work through two mechanisms: 1) activation of free fatty acid receptors, FFA2 and FFA3. 2) Decreasing inflammation and permeability in the gut. SCFAs protect against obesity and insulin resistance. Butyrate and propionate induce anorectic gut hormones, while acetate does so without reducing food intake (Supplementary 1). FFAR2 deficiency results in obesity on a normal diet, whereas with overexpression, subjects remain lean, even on an obesity promoting high-fat diet. Activation of FFAR2 suppresses insulin signaling in adipocytes, which inhibits fat accumulation in adipose tissue and promotes the metabolism of lipids and glucose in other tissues such as muscle (S2). Propionate and butyrate activate intestinal gluconeogenesis. Butyrate does so through AMPK, while propionate works through a gut-brain neural circuit involving FFAR3 (S3). Propionate is sensed in the portal vein walls via FFAR3, initiating intestinal gluconeogenesis. This glucose then triggers a signal to the brain to modulate hunger sensations and normalize whole body glucose homeostasis (S4). In a fasting state, as much as 62% of infused propionate is converted to glucose, accounting for 69% of total glucose production (S5). This is quite applicable to lower carb diets. Basically, it makes your brain think you are plenty fed with carbs/glucose, so it signals not to eat more, as well as not to produce or pump out more glucose into the blood. SCFAs also stimulate the release of anorectic and satiey inducing peptides like GLP-1 and PYY via FFAR2/3 (S6, S7). Activation of FFAR3 by SCFAs inhibits insulin secretion and increases sympathetic outflow. This raises energy expenditure and help to protect against obesity (S8, S9). Acetate has been found to increase brown adipose tissue, UCP1, and mitochondrial biogenesis via FFAR2 (S10). Short-chain fatty acids also improve intestinal barrier function via activation of AMPK (S11). Sodium butyrate has been specifically found to be an AMPK agonist (S12). And, butyrate increase tight junction assembly, thus improving barrier function, specifically through AMPK (S13, S14). This seems like as good of a place as any to add a bit more about AMPK, as it is one of the major targets in all of this. AMPK AMPK is a primary signaler in the maintenance of tight junction integrity and intestinal barrier function. It is one of the most important pathways in preventing the “leaky gut” we have spoken of earlier in regard to LPS and other inflammatory and infectious molecules escaping into the body to wreak havoc (S15, S16). Modern food processing and the Western diet is a particularly egregious malefactor in this (S17). In addition to its involvement in barrier function, AMPK activation is extremely positive for the great bacteria that we can’t get commercially. Metformin increased Akkermansia 18-fold through AMPK activation. Also, against a high-fat diet, it restored Bacteroides levels and the Firmicutes:Bacteroides ratio to that of lean subjects (S18-S20). It inhibited LPS induced inflammation and gut permeability increases, while improving glucose uptake and insulin sensitivity (S19). Akkermansia increases are likely at least partially due to greatly elevated production of its favorite food, mucin, which is stimulated by AMPK. It also reduces insulin resistance and adipose tissue inflammation in a high-fat diet (S20). For references, see "View Full Science Write-Up" here: http://neobium.org/product-line/primer/
  8. It is such a religion at this point with the liberals. The way I see it, there are primarily 3 factions amongst the Dems (though, they have some obvious cross-over besides hatred of Trump/cisiWhite male Christians). And, they are fighting over the party, right now, which could bring some good things (in addition their self-destruction. 1) Hillary Faction -- Establishment, pure Neo-Liberal, Imperialist Corporate Globalist (they want the whole world to be American Democrats -- essentially identical to the Neo-Cons). Identity politics based, but with greater emphasis on Women and LGBT vs. People of Color 2) Obama Faction -- Fairly Establishment, Neo-Neo-Liberal, Anti-Colonialist Imperialist Globalist (they want the whole world to be 3rd world). Identity politics based but favoring People of Color over Women and LGBT 3) Bernie Bros -- Anti-establishment, 60s Liberal, Anti-Colonialist/Imperialist/Globalist (They want real European Socialism/Communism in America). If they could abandon Identity Politics in favor of 60s Class based politics, things could get interesting, as there is potential to meet half-way with the Alt-Right. Basically, if they become Blue Dog Democrats more like 90s Bill Clinton and before that. On the Republican Side, you also have 3 main factions 1) Neo-Cons -- Establishment, pure Neo-Liberal, Imperialist Corporate Globalist (they want the whole world to be American Democrats -- essentially identical to the Neo-Cons). They are less identity politics based that Hillary Faction Neo-Libs. 2) True Cons (Evangelical Right plus Tea Party who have not made the switch to Alt-Lite/Alt-Right, yet) -- God, Guns, and Small Government (the voters moreso than the leaders) 3) Trumpers/Alt-Lite and Alt-Right -- Anti- Establishment, anti-Imperialist Globalist. Identity Politics based, though not by choice. Also, literally Hitler frog posting fascists. Could team up with True Cons, and could possibly compromise with Bernie Bros and accept some socialism if they dropped the anti-White male Christian identity politics and favored pre-1965 Americans In any case, both parties are hugely split, and they could go the way of the Whigs and Tories. Interesting times.
  9. Primer(tm) -- Part 1

    Primer™ Microbiomic Superfuel™ Bacteria need to eat, too. Pamper them. A well fed microbiome is a happy and healthy microbiome. Give them the gourmet shit. Primer is a generously portioned blend of 11 prebiotic dishes and desserts meticulously chosen to entice the good bacterial denizens and citizens of your gut to feed and breed, prodigiously, while starving and poisoning unwelcome pathogenic bacterial inhabitants. Grow your own, right at home. Currently, probiotics are mostly thought of and used in relation to a healthy digestive system (reducing upset stomach, gas and bloating, diarrhea, and IBS type symptoms) and the immune system (coughs, colds, and general sinus and respiratory health). While they certainly are indeed useful for such applications, the ramifications of an unhealthy gut and microbiota go far, far beyond that. The gut and its microbiome are essentially a massive endocrine organ, controlling and influencing basically your entire body and brain. And, given that all of the trillions of bacteria that call it home originally came from outside your body – and entered without your permission – it is by far the most important organ in which we can take steps to manipulate and take back control. We will first look at some basic science and data on how this all works. Then, we will look at studies that have shown alterations in the microbiotic make-up of the gut, and the correlations they display in health and disease, suboptimal and optimal fitness, and just general things that everyone would consider part of good or bad life outcomes. It is a massive subject, far too much to discuss in complete depth, here, so we’ll do our best to keep it as short and sweet as possible while still giving you enough background in this field to understand the shocking reality, scope, and importance of this microscopic invasion. Subsequently, we will get down to business and specifically get into the science of Shock Treatment™, the first step in the process of making yourself king or queen of your own castle, again. We’ll show you how it can immediately ameliorate symptoms, while preparing the gut for a permanent fix, with special emphasis on a lean, healthy body. Deus Vult! The Basics It basically works like this. The Western lifestyle, including diet, lack of exercise, and alcohol use (and, in all likelihood, genetics, though the data just isn’t there, yet) leads to an imbalance of the bacterial composition of the gut (1,2). This results in the excess production and release of inflammatory signals, such as Lipopolysaccharide, TNF-alpha, interleukins, and prostaglandins, which subsequently escape the gut and enter the rest of your body (3). Though, they all contribute to the pathologies we will cover in various ways, it is Lipopolysaccharide (LPS) that we will focus on the most. Within the gut, this leads to the general digestive issues and inflammatory bowel syndromes like IBS and colitis that you have commonly known probiotics as being used to alleviate (4). While fixing digestive disorders will come along for the ride, our primary focus is going to be on body composition and metabolic health. In other words, we want to make you leaner, protect against diabetes, and help keep you from having a heart attack or stroke. However, there really is so much more to it than that, as a few quotes from the literature aptly demonstrate: “Changes in the composition of the gut microbiota (dysbiosis) may be associated with several clinical conditions, including obesity and metabolic diseases, autoimmune diseases and allergy, acute and chronic intestinal inflammation, irritable bowel syndrome (IBS)…” (5) “In this milieu… disturbance of the gut microbiota balance and the intestinal barrier permeability is a potential triggering factor for systemic inflammation in the onset and progression of obesity, type 2 diabetes and metabolic syndrome.” (6) “Through these varied mechanisms, gut microbes shape the architecture of sleep and stress reactivity of the hypothalamic-pituitary-adrenal axis. They influence memory, mood, and cognition and are clinically and therapeutically relevant to a range of disorders, including alcoholism, chronic fatigue syndrome, fibromyalgia, and restless legs syndrome… Nutritional tools for altering the gut microbiome therapeutically include changes in diet, probiotics, and prebiotics.” (7) As you can see, alterations in the microbiota can affect basically everything, but that there is also hope for change. Getting back to the gut and body composition, the aforementioned Lipopolysaccharide (LPS) leads to overactivation of cannabinoid receptor 1 (CB1) within the gut, which causes an increase in intestinal motility (speed of food going through) in the proximal parts of the intestine. This leads to less absorption of nutrient feedback signals that tell the brain you are well fed, and that it is time to stop eating (8). Concurrent with this is an increase in transit time in the colon, which results in a greater total harvest of caloric energy from your food (9, 10). In other words, the signal your brain is getting is that you are not getting enough food, while you are actually extracting more calories from what you eat. This not only directly leads to more fat accumulation from harvesting more calories, it lends itself to over-eating. This aggravates the cycle further, as overeating and increased adiposity are themselves inflammatory. So, what you have is more inflammation, more dysfunction, greater food intake, greater extraction of food, more fat accumulation, then REPEAT! The carnage does not even end here. Along with this inflammatory state is a disruption in the intestinal barrier. Intestinal permeability is increased and these inflammatory agents spill out systemically. This is often called a “leaky gut”. This results in a low-level inflammatory state in the entire body. The biggest culprit here is, once again, LPS (11). LPS activates CB1 receptors in the body and brain, just as in the intestine. In the fat tissue, this leads to activation of PPAR-gamma, and an upregulation of triglyceride synthesis, fat cell formation, and fat storage (12). In the brain, activation of CB1 increases orexegenic pathways, thus increasing appetite, hunger, and ultimately, food intake (13). This should not much as much of a surprise considering “the munchies” that accompany intake of famous cannabinoid receptor agonist, marijuana. And, LPS is not done yet, not at all. It also activates Toll-like Receptor 4 which, along with other inflammatory signals (TNF-alpha, interleukins), promotes both insulin and leptin insensitivity, peripherally and centrally (14, 15). At this point, your adipostat (the thermostat for your body fat level) is wrecked. Your ability to control food intake is gone, and you are a fat storing machine. Obviously, this is not what you want your body doing to itself. It is not what you want it doing to you. It is not what you want it doing to your life. Oh, and to top it off, atherosclerosis, heart disease, and stroke are promoted by these same inflammatory pathways. Combined with the increased body fat and insulin resistance, you officially have all of the perfect ingredients for the dreaded Metabolic Syndrome (16, 17). And, it is just a bunch of microscopic bacteria that call your gut “home” causing all of this devastation. General Data The most well-known genera of bacteria in commercial probiotics are Lactobacillus and Bifidobacterium. They are also among the most common in the body, along with several other ones which are not commercially available, but which we can manipulate with supplementation. We will talk about these in length in the SupraBiotic™ and Primer™ write-ups. Unfortunately, Lactobacillus belong to the Firmicutes phylum which has been found to be associated with weight gain and obesity (18-20). Just a 20% increase in Firmicutes (which Lactobacillus is usually the primary genus) with an equal decrease in Bacteroides results in an increased energy harvest of 150 calories per day in humans (21). That is equal to 15lbs of fat per year! The Western style diet promotes these negative changes in microbial proportions (22). Thus, one can plainly see why it can be so difficult to get lean, as well as how easily obesity has become an epidemic. Interestingly, smoking cessation produces the same negative changes in bacterial composition, while gastric bypass surgery improves it (23-24). The well-known effects on weight with both of these further highlights the negative body compositional effects of this intestinal dysbiosis. In addition, probiotic treatment with several Lactobacillus species that are in a great number of commercial formulations, including Lactobacillus acidophilus, Lactobacillus fermentum, and Lactobacillus ingluviei , have been directly associated with weight gain and obesity (25). Type-2 diabetics had significantly more Lactobacillus, with L. acidophilus being particularly bad in this regard (26). Further, L. reuteria and L. sakei have been found to be positively associated with obesity and body mass index (27-29). They probably don’t tell you that on the label. More powerful evidence of the profound effect of the microbiota on body weight and metabolism come from studies on “fecal transfer”. And, yes, that is exactly what it sounds like – transferring poop from one subject’s intestine to another’s. In twins, transfer of an obese microbiota to lean mice was accompanied by an increase in bodyweight, fat mass, and a dysbiotic alteration of the Firmicutes:Bacteroides ratio to reflect that of the obese model (30). A similar transfer replicated the obese phenotype with increased weight gain, lipogenesis, adipogenesis, overeating, and lower satiety, as well as inflammation and hyperglycemia in formerly lean, healthy subjects (31, 32). On the other side of the coin, transferring the intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome, as well as reversing obesity and gastrointestinal issues (33). It also reduced markers of metabolic syndrome, inflammation, and oxidative stress in animals challenged with high-fructose diets (34). Obviously, while it highlights the science, doing a fecal transfer is not terribly practical, appetizing, or readily available -- unless maybe you are in California. Fortunately, there is good news. While several species and strains of lactobacillus have been found to promote weight gain, several have also been found to protect against it. And, of course, we only used the good ones. Furthermore, Bifidobacterium have shown only positive effects to a remarkable extent. Bifidobacterium are anti-obesity and lipid lowering, decreasing fat weight, blood glucose, cholesterol, and triglyceride levels (35). They are higher in lean subjects, as well as being lower in obese (36, 37). They are significantly lower in type-II diabetics and have been shown to improve glucose tolerance as well to decrease inflammatory signaling (38-40). In addition, they increase levels of EPA, DHA, and CLA in fat tissue and the brain (40). They have also been found to decrease with aging (41). We can also readily manipulate levels of the good bacteria that are not commercially available such as Bacteroides species, Akkermansia Muciniphilia, Faecalbacterium Prausnitzii, and Roseburia via supplementation of ingredients that ARE available. So, let’s get to it. You may have noticed that almost no probiotic formulas contain just a single species of bacteria, nowadays. And, if you did not, I will just say that it is for a good reason. They work better in combination. This applies to the prebiotics that feed them as well. You need a variety of prebiotics to grow a variety of probiotic bacterial species. First of all, microbial diversity seems to be good, in and of itself. Essentially, a diverse gut is a healthy gut (42). Obesity has been associated with a lack of microbial diversity and, as you might expect, lean subjects have greater microbial diversity in the gut (43-45). Insulin sensitivity is also improved along with diversity increases (46). Finally, in the interesting but not terribly shocking category, exercise increases microbial diversity (47, 48). Increased diversity also works to specifically create an environment where probiotic bacteria can thrive, thus enhancing their ultimate performance (49). Compared to individual strains alone, this diversity increases adhesion to intestinal mucus, which is necessary for most survival, growth, and activity (50, 51). Conversely, bacteria inhibit adhesion of pathogenic bacteria better when in combination (52, 53). However, you do not want to just try to have every single species and strain in existence growing inside of you. It needs to be done rationally. If not, they can interfere with each other’s actions and compete for space and resources (54-56). But, maybe the most interesting benefit of supporting a combination of bacteria is through cross-feeding. This is when one bacterial species produces metabolic substrates the other species and strains use for fuel (57, 58). Bifidobacterium adolescentis is the most interesting and important species in this regard as it functions as THE archetypal cross-feeder for several of the most important and impressive strains of bacteria. And, those strains are not commercially available. B. adolescentis produces acetate and oligosacharrides which are then consumed by these acetate utilizing, butyrate and propionate producing bacteria (59). For references, see "View Full Science Write-Up" here: http://neobium.org/product-line/primer/
  10. 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: 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 FL7 – 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.