Editors Note: Well, I didn’t quite get my shit done in time, so here is teaser until I do. This “teaser” is actually pretty scientifically dense and will be more than enough information for most, but I haven’t added the references, and it is still lacking about 30 more pages of details for the scientists and the skeptics, but that will be rectified, eventually.
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.
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….
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-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.
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.
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:
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.
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.
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.
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:
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.
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.
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.
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 🙂
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.
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.
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.