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Par Deus

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  1. 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/
  2. 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.
  3. 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/
  4. 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.
  5. 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). Pomegranate Extract Pomegranate Extract is an extremely rich source of polyphenols. Polyphenols are generally prebiotic for good bacteria (Bifidobacterium, Akkermansia, Bacteroides, and Roseburia), and antibacterial for less favorable and pathogenic ones (189-191). Fruit/berry based polyphenols seem to be particularly favorable toward Bacteroides, the Firmicutes:Bacteroides ratio, and Akkermansia compared to other polyphenol sources. Lactobacillus (Firmicute) lack glycan degrading enzymes, thus do not grow on them particularly well compared to the others (192). Strawberry polyphenols elevate Bifidobacterium and Bacteroides, butyrate and propionate, as well as decreasing Firmicutes (193). Red wine polyphenols raise Bifidobacterium and Bacteroides as well (194, 195). Polyphenols improve the Firmicutes:Bacteroides ratio, while also increasing Roseburia (196, 197). Akkermansia REALLY loves polyphenols (198). Grape polyphenols gave a 10-fold increase in Akkermansia and decreased the Firmicutes:Bacteroides ratio, while also reducing weight gain, triglyceride storage, insulin resistance, LPS, and inflammation (199). Cranberry polyphenols produced a 30-fold increase in Akkermansia and decreased weight gain, visceral adipose tissue, triglyceride synthesis, insulin resistance, LPS, and inflammation (200). Finally, Pomegranate Extract, itself, produced a massive 33 to 47 fold increase in Akkermansia (201). Caffeic acid, a component of Pomegranate Extract, increased Akkermansia 15-fold vs control and several hundred fold vs. subjects with induced colitis! It also improved the Firmicutes:Bacteroides ratio (202). Polyphenols activate AMPK, enhancing intestinal barrier function (203). They increase tight junction proteins, decrease tight junction pore formation, and ameliorate inflammatory bowel disease (204). Pomegranate Extract activates AMPK at 2 times the potency of metformin (205). It also displayed extremely potent alpha-glucosidase inhibitory activity (this is an ezyme that metabolizes carbohydrates to glucose), being 10 times as potent as acarbose, lowering blood glucose after sucrose intake, but not after glucose (206, 207). It consistently decreases glucose levels, as well as being anti-inflammatory (208, 209). Fermented Herbs Fermentation of herbs results in much higher concentrations of active compounds compared to unfermented (210). This same fermentation is done in the body, but it is highly dependent upon the microbial make-up of the individual’s gut, so it can vary widely from person to person (211, 212). As just one example, a fermented herb preparation inhibited LPS mediated inflammatory damage, while the unfermented was ineffective (213, 214) Fermented Kudzu Kudzu is a group of polyphenol rich plants belonging to the pea family. Its administration reduced body weight, fat mass, and lipogenesis while stimulating lipolysis and thermogenesis (215). It also lowers body mass index and visceral fat (216). Kudzu increased fatty acid oxidation, and decreased weight gain, triglyceride levels, and visceral adipose tissue on a high-fat diet (217). In addition, it improves insulin sensitivity and lipid metabolism (218). Kudzu is anti-inflammatory, with components inhibiting LPS, TNF-alpha, and ROS induced inflammation (219, 220). It is also a potent inhibitor of COX-2 (221). In addition, Kudzu reduced intestinal permeability and improved intestinal barrier function (222, 223). Finally, it reduces expression of the dreaded TLR-4 (224, 225). Fermented Ginseng The anti-obesity effect of unfermented ginseng was shown to be dependent on bacterial make-up of the microbiota (226). It increased mucins (the Akkermansia and Bacteroides food) by 50% (227). It is metabolized by Bifidobacterium as well as Bacteroides. There is a dramatic difference in levels of those bacteria between metabolizers and non-metabolizers, suggesting strong prebiotic specificity toward them (228). And, it was indeed found to enhance growth of Bacteroides (229). Absorption of one of its main active ingredients, Compound K, is increases by prebiotics (230). And, there are plenty of those in Primer™. Fermented Ginseng decreased bodyweight, fat mass, and food efficiency, while improving insulin and leptin sensitivity (231, 232). In addition to reduced body weight, decreases in fat mass, adipocyte size, and glucose uptake were also observed. And, all of these effects were superior with fermented vs. regular ginseng (233, 234). Finally, it decreases inflammatory cytokines and protects the intestinal barrier (235, 235b). Mulberry Extract SupraBiotic™ contains an industry-best Mulberry Extract, standardized to over 5% 1-Deoxynojirimycin (1-DNJ) and containing relevant amounts of d-Fagomine, as well. Like all berries, it also has high polyphenol content, the benefits of which we have already talked about. 1-DNJ 1-DNJ is a naturally occurring carbohydrate mimic. Its use significantly lowered body weight, blood glucose, and serum insulin levels, and it conversely improved glucose tolerance and insulin sensitivity (236). It increased the insulin and leptin sensitizing peptide adiponectin (which activates AMPK), reduced visceral adipose tissue, adipose mass, triglycerides, lipid accumulation, and increased fatty acid oxidation (237). It is remarkably potent, elevating adiponectin, GLUT4, and AMPK at just .5uM (238). This is 1000 times as potent as metformin. Along with increasing AMPK, it improved mitochondrial function and lipid metabolism (239). Finally, it is a more potent alpha-glucosidase inhibitor than acarbose, which futher helps with glucose and insulin (240). D-fagomine D-fagomine is also a naturally occurring sugar mimic. It reduced weight gain, plasma triglycerides, glucose, and enhanced leptin and insulin sensitivity (241). It attentuated fat gain on high-fat diet (242). D-fagomine was also found to inhibit intestinal sucrase, lowering post-prandial glucose levels (with either sucrose or starch), as well as modulating bacterial adhesion, inhibiting pathogenic ones without effecting Bifidobacterium or Lactobacillus (243). Selenium Selenium increases microbial diversity, and it is synergistic with probiotics for this gut bacteria modulation (244, 245). It works by enhancing the fermentation activity of gut bacteria resulting in better bacteria growth as well as output of SCFAs (246). Queen’s Bee Acid (10-hydroxy-2-decenoic acid) QBA is a medium chain fatty acid from Royal Jelly. It is a very potent AMPK agonist, being effective at just 20uM. This is 25 times as potent as research standard AICAR and the pharmaceutical metformin. (247) We have mentioned it over and over, but it bears repeating more about the machinations that result in the vicious cycle of gut dysbiosis. Inflammation in the gut, followed by low-level but constant systemic inflammation, PRECEDES obesity and insulin/leptin resistance. It is what gets them started. If you are not either quite lean, or have been on a diet long enough that fat loss has basically stopped, insulin and leptin resistance are already at work, particularly in the brain/adipostat (248). This is bad news for appetite control, metabolism, and body weight regulation. LPS levels of just 2 to 3-fold above normal, which occur during a Western-style/high-fat diet, initiate the low level inflammatory response that leads to reduced insulin and leptin senstivity, and ultimately type-2 diabetes and Metabolic Syndrome. And, again, this happens before the weight gain starts (249). It sets you up for it to begin in earnest. AMPK is one of the primary brakes on this ride. It inhibits the LPS induced inflammatory response, as well as the leaky gut. Super potent AMPK agonist, like 1-DNJ and QBA, are basically airbrakes on a runaway train. QBA inhibits LPS induced cytokine production (250). It increases GLUT4, glucose uptake, and insulin signaling (247). It enhances intestinal barrier function and tight junction assembly in an AMPK dependent manner (251-253). AMPK activation also improves LPS induced blood-brain-barrier disruption much as it does with the intestinal barrier (254). This improves central insulin and leptin signaling, keeping your adipostat functioning properly. Palmitoylethanolamide (PEA) PEA is a naturally occurring cannabinoid-like lipid, from a class called acylethanolamides. It is a competitive FAAH inhibitor (this is the enzyme that breaks down endocannabinoids). Decreased levels of endocannabinoids lead to upregulation of cannabinoid receptors, which leads to the increased activity at CB1 via LPS that gets the increased fat storage and over-eating part of the vicious cycle really going into overdrive. Endocannabinoid activation of CB2, along with PEA/acylethanolamide activation of PPAR-alpha, normally keeps this inflammatory response balanced and in check, but when it gets out of whack, LPS à CB1 reigns supreme. Let’s take a closer look at all of this and what PEA does to fix it. Intake of dietary fat stimulates production of PEA, and the other acylethanolamides (255, 256). They increase satiety, and reduce food intake and body weight (257, 258). It creates satiety via activation of PPAR-alpha in the intestine followed by direct vagal signal to brain -- i.e. immediate, no gene transcription needed (259, 260). This is one of the steps in which fast transit times in the proximal small intestine become problematic. You get less PEA, thus less satiety signaling to the brain. In addition, PEA specifically decreases this intestinal transit rate, so it is double plus good on appetite and satiety signaling (261). It both directly makes you feel full and prolongs its own duration of activity in doing so. PEA does, in fact, ultimately reach the brain, where it is active in nM concentrations through gene transcription (258). But, you would have already finished eating too much at that sitting, and each of your other meals, before it did anything, centrally. In addition to the appetite side of things, PEA decreases intestinal inflammation and permeability. It does so through CB2 and PPAR-alpha as this is blocked by antagonists of either one (262, 263). It is also anti-inflammatory in the intestine via selective targeting of TLR-4 (263). All sounds great, right? Well, the problem is that with a Western-style or chronic high-fat diet, the PEA release trigger becomes desensitized, ultimately resulting in reduced levels (256, 259, 265). This disrupts normal functioning of the whole system, leading to LPS induction of CB1 becoming dominant. And, this is on top of losing its direct beneficial effects on satiety and food intake. An increase in inflammation happens in parallel with decreases in PEA, endocannabinoids, and FAAH – and, an upregulation of the cannabinoid receptors (266). It all happens together, at the same time, because they are all connected. And, FAAH inhibitors restore levels of all of these and suppress this inflammation (266). FAAH inhibitors also decrease intestinal motility, as we would expect (267). They do so by restoring PEA and the endocannabinoids, thus normalizing the system. The final bit of evidence on how this operates is that chronic administration of tetrahydrocannabinol (THC), the main active ingredient in marijuana, reduces weight gain, fat mass gain, and energy intake in obese but not lean mice, despite an initial increase in food consumption (268). This is because it is both a CB1 and CB2 agonist. So, you have anti-inflammatory CB2 activation by THC snuffing out the inflammatory LPS pathway, as well as it down-regulating and competing for CB1, such that LPS cannot act on it to wreak its havoc, unchallenged. This THC administration even improved select gut microbiota profiles. It increased Akkermansia by 4-fold, and improved the Firmicutes:Bacteroides ratio by 6-fold (268). It did not have these same effects in lean subjects because these pathways were not messed up to begin with for them. So, you can see that PEA helps correct the system at basically all levels that we have been talking about. One more thing of note is that, as we mentioned with high protein diets negatively altering the bacterial make-up of the microbiota if one does not make a point to get plenty of fiber/prebiotics, the high-fat side of such diets will negatively affect PEA levels, long-term, thus the entire system will be functioning sub-optimally. Again, I am not bashing these diets at all, they are quite effective. Consuming an excess of glucose and/or fructose is the worst thing you can do to your body as far as inflammation and insulin and everything we have been talking about, just to be clear. But, we want to be optimal, and we can be, quite easily with supplementation. Ginger Extract (20% Gingerols) Ginger is well known as a digestive aid. The extract is an all-around nice ingredient, aiding through several pathways, and it is particularly effective as an anti-inflammatory and protector of barrier function. The primary component of the extract is 6-gingerol, though 8-, and 10-gingerol, as well as 6-, 8, and 10-shogaol are present in significant, pharmacologically relevant numbers. They all pretty much do the same thing, just at different potencies. Mechanistically, it is primarily an anti-inflammatory and antioxidant. It decreases basically all inflammatory cytokines (269, 275, 276). It inhibits LPS induced inflammation as well as TNF-alpha (270). It reduced interleukins 3-fold at just 50uM, and its COX inhibition is comparable to aspirin (271-273). It also displays extremely potent anti-oxidant activity, being effective against various radicals at just 1-25uM (274). Gingerols activate PPAR-alpha, as well as AMPK, with 5 times the potency of metformin and AICAR in suppression of inflammatory cytokines (275, 276). They increase tight junction proteins and integrity via protection against inflammatory assault (277, 278). They suppress colitis via anti-inflammatory and anti-oxidant activity (279). Gingerols enhanced the survival and proliferation of intestinal epithelial cells via reductions in pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β), while also elevating anti-inflammatory cytokines (IL-10 and IL-22) in colitis models (280). They also reduce spasms of smooth muscle in the digestive tract (281). In addition, gingerols displayed some modest inhibitory activity on α-glucosidase and α-amylase, being about 1/6 as potent as acarbose (282). Finally, it increased uptake of Calcium (100+%) and Glutamic acid (60%), both of which we will talk in detail about in the Primer™ write-up (283). CONCLUSION As you can see, SupraBiotic™ takes the concept of probiotic far beyond where anyone has previously taken it before. It starts with bacterial species carefully and purposefully selected to protect against dysfunction of the gut and microbiota to promote better health, better appetite control, better metabolism, and better fat loss. On top of this, SupraBiotic™ addresses and supports novel probiotic bacterial species that you cannot attain, anywhere. And, it does so in a way that no other product is even close to doing. Finally, its supporting ingredients crush inflammation and repair your leaky gut, leaving your body functioning in the optimal way it is intended to. SupraBiotic™ is a one of a kind product that fits in perfectly with and enhances any diet and exercise program, any supplement regimine, any lifestyle. See "Full Science Write-up" here http://neobium.org/product-line/suprabiotic/ for references.
  6. The Best Probiotics 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 (135-138). The Firmicutes:Bacteroides ratio was also significantly worse in obese patients, even in comparison with the merely overweight (137, 138). It has a negative correlation with fat mass and waist circumference (139, 140). It was also 60% lower in obese pigs – yeah, apparently that is a thing (141). Bacteroides levels in Type-2 diabetes were only half that of those with normal glucose tolerance (142). Lower Bacteroides was correlated with increased energy intake (143). 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 (144). 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 (145). Bacteroides acidifaciens decreased bodyweight and fat gain, while increasing fatty acid oxidation via PPAR-alpha (146). In addition to an elevated Firmicutes:Bacteroides ratio, B. vulgatus levels were found to be lower in the obese (147). B. fragilis releases a symbiotic immunomodulatory anti-inflammatory factor called Polysacharride A (148). This activates TLR-2, which releases anti-inflammatory interleukins. PSA is basically the opposite of LPS, and TLR-2 the opposite of TLR-4 (149). This has been shown not just to prevent but to cure experimental colitis, an extreme version of a leaky, inflammatory gut (150). 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 (151). Finally, a few tidbits that will make more sense after reading the Primer™ write-up. A few of the Bacteroides species bind to mucins for colonization and consume these mucin polysaccharides (152, 152b). Bacteroides species also have greater glycan degrading capability than Firmicutes, thus they are preferentially increased by polyphenols (153). Hint: Primer™ contains both mucin and polyphenols. Faecalibacterium prausnitzii Faecalibacterium prausnitzii is butyrate producing and is considered a physiological sensor and marker of human health (154). It does not get much more important than that. It is lower in the obese and type-2 diabetics (155-157). Conversely, it is higher in normal glucose tolerance vs. prediabetic subjects (158). Faecalibacterium prausnitzii is also negatively correlated with inflammatory markers and sharply decreased in inflammatory bowel diseases (157, 159). It is greatly reduced in ulcerative colitis and less abundant in Crohn’s disease (160, 161). As would be expected from the above, it improves intestinal barrier function (162). Akkermansia muciniphilia Akkermansia muciniphilia is mucin degrading, meaning it feeds on mucins (163). Levels are higher in lean subjects than the general population (164). 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 (165). 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 (166). Along with enhanced glucose tolerance, it reduced adipose tissue inflammation (167). Akkermansia levels are higher in normal glucose tolerance vs. pre-diabetic subjects (168). It decreased inflammatory cytokine production and protected intestinal barrier function in experimental colitis (169). Finally, its levels are reduced in ulcerative colitis (170). Roseburia Species Roseburia species are butyrate producing (171). An increase in this species is associated with decreased body weight, fat mass, insulin sensitivity, and triglycerides -- independent of calorie intake (172). Increased Roseburia correlated with reduced body weight, improved profile of lipid and obesity related gene expression, along with a normalized inflammatory status (173). It is also lower in type-2 diabetes (174). Levels are increased by a Mediterranean diet, as is insulin sensitivity (175). Roseburia is enriched in healthy populations vs. those with atherosclerosis (176). And, its levels display an inverse correlation with disease activity in ulcerative colitis (177). High protein/low carbohydrate diets, which are so effective and popular, reduce Roseburia and SCFA levels (178, 179). 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 (180). 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, the most important contribution of B. adolescentis is to feed other bacteria, specifically the really good ones that we just talked about and 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 (181). 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 (182, 183). Roseburia is also an acetate user (184). It is, in fact, generally required for growth (185). In addition to acetate production, B. adolescentis increases Roseburia via partial breakdown of oligosaccharides, which it can then utilize (186). Cross-feeding with Bifidobacterium modulates the prebiotic effect of inulin and arabinoxylan-oligosaccharides on Roseburia and F. prausnitzii by making acetate available (187). Roseburia was able to grow in pure complex carbohydrate cultures, which it cannot metabolize on its own, owing to cross-feeders (188). See "Full Science Write-up" here http://neobium.org/product-line/suprabiotic/ for references.
  7. SupraBiotic™ Ingredients 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 fish oils EPA and DHA, as well as conjugated linoleic acid (CLA), in fat tissue and the brain (40). They have also been found to be reduced with aging (41). We can also readily manipulate levels of the good bacteria that are not commercially available such as Bacteroides species, Roseburia species, Akkermansia Muciniphilia, and Facealbacterium Prausnitzii via supplementation of ingredients that ARE available. 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. 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). Combinations also work to specifically create an environment where probiotic bacteria can thrive, thus enhancing their ultimate performance (49). Compared to individual strains alone, it greatly increases adhesion to intestinal mucus, which is necessary for most survival, growth, and activity (50, 51). Conversely, they inhibit adhesion of pathogenic bacteria better when in combination (52, 53). However, you do not want to just throw every single commercially available species and strain into a product as so many companies do. They need to be rationally combined. If not, they can interfere with each other’s actions and compete for space and resources (54-56). But, the most interesting benefit of probiotic combinations is through cross-feeding. This is when one bacterial strain produces metabolites the others use for fuel (57). We will get into this in detail, in a bit. Right now, let’s get to the SupraBiotic™ probiotic combination. Bifidobacterium breve B. breve supplementation significantly suppressed the accumulation of body weight and fat mass, while improving serum levels of total cholesterol, fasting glucose, and insulin (58). The expression of genes related to fat metabolism and insulin sensitivity in both the gut and fat tissue was upregulated by its administration (59). It also improved lipid levels and insulin resistance while lowering bodyweight (60). In addition, B. breve combats the cycle of LPS inflammation, leaky gut, and insulin/leptin resistance. It reduced LPS activity 60% and quelled general colonic inflammation, particularly TNF-alpha, a downstream signal of LPS (61-63). It also upregulated anti-inflammatory pathways such as interleukin-8 and Toll-like Receptor-2 (64, 65). The latter having the opposite effect as TLR-4. Ultimately, it is reinforcing on intestinal epithelial cells and mucosa, improving the physical barrier of the intestine (66, 67). Bifidobacterium animalis subsp. lactis B. animalis subsp. lactis ferments a wide range of oligosaccharides quite extensively, so it is very versatile, being viable under numerous different conditions (68). It increased short chain fatty acid (SCFA) production to distal parts of the colon, meaning it has a long acting mechanism of action (69). We will discuss SCFAs a good bit more below, but they provide fuel for intestinal barrier repair, as well as having other metabolic benefits – and, their production is one of the main ways probiotics exert their positive effects. This species is negatively associated with body mass index in humans, and increased levels are associated with resistance to obesity (70-71). It prevents weight gain, reduces fat mass accumulation and LPS levels, while preserving glucose tolerance in the face of a high-fat diet (72, 73). Administration shifts the microbiota toward that of a lean phenotype while reducing inflammatory activity (73). Interestingly, it also improved the efficacy of diabetic drug and AMPK agonist metformin, suggesting potentiation with that pathway (74). Other direct metabolic improvements were enhanced energy and lipid metabolism, as well as an increase in markers of satiety (75). Switching to complementary mechanisms, B. animalis subsp. lactis limits increases of pro-inflammatory signals, supporting mucosal recovery to stress (76). It increases tight junction proteins, restoring normal intestinal permeability and preserving gut barrier function in the face of inflammation (77). Finally, it prevents translocation of pathogenic bacteria from intestine to body tissue, reversing inflammation induced insulin resistance (77). Lactobacillis Plantarum L. plantarum has a great deal of good data. Levels are higher in lean subjects than in the overfat (78). It lowered plasma glucose, insulin, triglycerides, and oxidative stress levels (78b). Further, it reduced lipogenesis and increased fatty acid oxidation via up-regulation of PPARalpha (79). It inhibits the formation of fat cells while decreasing adipose size as well as white adipose tissue mass (80, 81). L. plantarum also reduced weight gain and fat accumulation, upregulated fatty acid oxidation, while improving insulin and leptin sensitivity against an obesity promoting diet (82, 83). In addition to reducing weight gain and fat mass, it also lowered blood triglyceride levels, while improving leptin sensitivity and intestinal permeability (83). Remarkably, it led to a significant increase in leptin levels, concurrent with weight loss (84). Weight loss typically results in augmented leptin sensitivity, but decreased leptin levels, which is one of the primary causes of hitting the wall on fat loss with prolonged dieting. L. plantarum also improved glucose levels and insulin sensitivity – and, continuing with its remarkable effects, it increased weight with same body fat (85). This means it seemingly helped direct calories toward muscle formation instead of fat. It was more potent in combination with other probiotics as well as with polyphenols in reducing fat accumulation and improving metabolic alterations (86, 87). Another nice perk, in a comprehensive formula like SupraBiotic™, is that it increased levels of the genus Bacteroides while reducing the Firmicutes:Bacteroides ratio that is associated with obesity (88, 89). L. plantarum also displays potent anti-inflammatory actions, attenuating signaling of LPS and TLR-4, as well as COX-2, TNF-alpha, and inflammatory interleukins (90, 91). The reduction in inflammatory responses downstream of the LPS signaling pathway was consistently found in several studies (92, 93). Improvements of inflammatory colitis were also seen with L. plantarum (94, 95). Finally, it increased tight junction protein formation and improved intestinal barrier function (96-98). Lactobacillis gasseri L. gasseri is consistently associated with weight loss in both animals and humans in the literature (99). It mitigates bodyweight and fat mass increases in obesity promoting diets (100). It decreases body fat in both in visceral and subcutaneous adipose, while also increasing insulin and leptin sensitizing peptide adiponectin (100-101). This loss of visceral adipose tissue was associated with attenuation in inflammatory gene expression (102). This species elevated total energy expenditure, while diminishing body weight gain and improving glucose tolerance (103). It reduced bodyweight, triglycerides, and lipogenic genes, while augmenting insulin and leptin sensitivity (104, 105). Finally, L. gasseri increases tight-junction protein expression and improves intestinal barrier function (106). It elevated levels of the short chain fatty acid, butyrate, relieving inflammatory signaling (103). And, in kind, it decreases intestinal permeability, LPS production, and adipose tissue inflammation (107, 108). Lactobacillis Rhamnosum L. rhamnosum reduces fat mass, fat synthesis, and improves the obesity associated Firmicutes:Bacteroides ratio (109). It prevented weight gain in diet induced obesity (110). In women, it decreased fat mass, increased weight loss, and improved leptin sensitivity (111). Perhaps most notably, it reduced bodyweight and increased insulin and leptin sensitizing peptide adiponectin while also increasing leptin levels (112). As previously mentioned, leptin normally decreases along with metabolism and appetite control during weight loss, so this is a really nice effect. Administration of L. rhamnosum resulted in decreased weight gain, with enhanced fatty acid oxidation, insulin sensitivity, and adiponectin via activation of AMPK in both adipose and skeletal muscle tissue (113). It has also been shown to reduce bodyweight and adipose tissue, with increased conjugated linoleic acid (CLA) formation and upregulation of thermogenic protein UCP2 and leptin sensitivity (114, 115). On the inflammation and gut barrier side of things, L. rhamnosum decreased LPS and LPS induced systemic inflammatory markers including IL-6, COX-2, and TNF-alpha (116-118). Relatedly, it also reduces TLR-4 expression (119). Further, it increases tight junction proteins and restores intestinal barrier function, while inhibiting inflammation downstream of LPS (120-122). A novel action of this species is the production of soluble proteins, p40 and p75, which protect against tight junction and barrier function disruption (123). In addition, it raised Bacteroide levels, tight junction proteins, reduced inflammation, and protected barrier function against a high fructose diet (124). While this very likely goes for our other probiotic bacteria to some extent, L. rhamnosum has a good bit of data in regard to alcohol consumption. It protects against ethanol induced microbiomal changes, inflammation, and pathology (125). It is also protective against ethanol stimulated inflammation and damage via AMPK (126). Finally, it prevented not just inflammation but also gut barrier disruption in response to ethanol (127). Somewhat related, given alcohol’s use as self-medication, it increased GABA activity and was anxiolytic in response to stress (128). Bifidobacterium adolescentis B. adolescentis does not have a lot of direct data on body composition. It is higher in lean than obese populations and levels predict leanness, in general (129, 130). Administration resulted in reduction in bodyweight, visceral adipose tissue, and fat mass, while improving insulin resistance (131). It also is synergistic with polyphenols as an anti-inflammatory (132). See "Full Science Write-up" here http://neobium.org/product-line/suprabiotic/ for references.
  8. "Banhammer01@yahoo.com" Do you feel in charge?
  9. They literally never get a single dayNeighA single moment, offFrom their rage.For 7 more years.Even with Ronny Reagan and Bush the Lesser, they would have days, if not weeks, of just enjoying their hippie stuff, ghetto stuff, their bathhouse and/or foam parties, their barrio lowriders and chopshops, pooing in the street, their abacus/Go, their women's basketball, their dreams of more than 2 genders, the Great Satan, their (((Hollywood))).The violence against free speech, Republican Congressman, country music and church goers has just begun, kiddos.
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