Rose Ellagitannins (RE)
The primary function of RE in this formula is DGAT inhibition.
Diglyceride Acetyltransferase (DGAT) is an enzyme which is vital to the process of forming adipose tissue. DGAT inhibition is an effective and unique angle for targeting fat loss. In fact, DGAT knockout mice (meaning they lack the DGAT enzyme) are resistant to obesity, and exhibit increased insulin and leptin sensitivity.
RE has been shown to significantly inhibit up to 96% of DGAT, which basically makes it super hard for your body to store fat (1). Which is not a suggestion to eat like an escaped convict, the take home point here is that when following a proper fat loss diet, controlling DGAT is going to be a big advantage.
Additionally, RE has some beneficial effects on blood lipids and inflammation. Specifically, lowering postprandial triglycerides and suppressing inflammatory cytokines like TNF-a, IL-6 and IL-1b (2). Also, give RE some bonus points for inhibiting growth of E. coli by 50% (3). Might as well improve health as you get ripped, right?
Gamma Mangostin 30% (GM)
GM is a dual PPAR-alpha and PPAR-delta agonist (4).
As for PPAR-a, its activation is directly involved with all three stages of fat burning, and is one of the most important players in lipid metabolism. It is triggered naturally during calorie deprivation and in severe carbohydrate restriction to aid in the production of ketones.
Regarding PPAR-d, increased expression of this nuclear receptor has been shown to increase fatty acid oxidation in skeletal muscle by shifting the body’s metabolic preference away from carbohydrate in favor of lipids.
This is favorable for multiple reasons. Obviously this means you’ll be burning more fat per unit of time, but one side effect of the body relying less on carbohydrate and more on fatty acids is that the latter is a cleaner burning fuel. During exercise you will produce less lactate, prolonging the accumulation of hydrogen ions as well as reducing the total ROS output. Burn more fat, better workout performance, quicker recovery.
Recent research shows that something called Lipopolysachharides (LPS), also known as endotoxins, will suppress PPARa gene expression. LPS elevation is linked with obesity, inflammation, and insulin resistance. Controlling LPS overproduction is a little-known way to assist in fat loss, and GM has been shown suppress LPS, in addition to directly boosting PPAR-a function (5).
Artemisia Iwayamogi 20:1 (AI)
Artemisia Iwayomogi (AI) is a Korean herb from the Asteraceae family, checking in as the second PPAR-d agonist in the DCP formula. It is made up of at least 20 known compounds, however it is not known exactly which and how many of these compounds are responsible for providing the numerous benefits.
As we know, herbs such as this are often far more than just the sum of their known parts; for this reason, a full spectrum 20:1 ethanol extract has been chosen for this formula.
AI is an exciting little herb, and although research in humans is in its infancy, the current published data have given us reason to expect big things with regards to accelerating fat loss and improving overall health.
In addition to the PPAR-d angle, AI offers the following benefits in regards to fat loss:
Increased expression of CPT1
AI has been shown to upregulate Carnitine Palmitoyl Transferase (CPT1B), which is a key reason why this herb is going to speed up the fat loss process (6).
CPT1’s are a class of mitochondrial enzymes, the “B” subtype are found in skeletal muscle as well as white and brown adipose tissue (WAT & BAT). This enzyme is responsible for transporting long chain fatty acids (LFCA’s) across the outer cell membrane so they can be delivered inside the cell to be oxidized. So simply put, more CPT1, more fat is handed to your furnace on a silver platter.
Increased expression of PDK4
Pyruvate Dehydrogenase Kinase Isozyme 4 (PDK4) is an enzyme that phosphorylates something called pyruvate dehydrogenase with the help of ATP, rendering it inactive. This process converts pyruvate to acetyl-coA, thereby increasing energy expenditure. AI has been shown to upregulate this enzyme (6).
Improves efficiency of two out of three steps in the fat burning process
For your body to actually “burn” fat, it has to go through a three step process. Step one is liberating the fat from stored tissue, known as lipolysis. Step two is transporting the fat; step three is actually using it as fuel, known as beta oxidation. AI encourages a higher rate of both transport and oxidation.
Scopoletin, one of the compounds found in AI, has been shown to be an intracellular antioxidant, suppressing ROS and superoxide anions in osteoclasts, and looks to be an important player in differentiation of these cells (7). Research also shows AI can actually stimulate osteoblasts to make new bone (8).
As we learn more about the vital role of bone on regulating full body metabolism and the importance of osteocalcin in this process through its interaction on adipokines such as adiponectin, this suggests a potential metabolic boost from another pathway (9). We will revisit this when we discuss Carnitine Fumarate.
Upregulation of secondary fat burning genes
AI has also been shown to upregulate several other genes affecting energy expenditure and lipid efflux including PGC1A and UCP3 (6).
Suppression of inflammatory cytokines
Multiple studies have looked at the effect of mice given a high fat diet with or without concurrent administration of AI. They have found remarkable results including reduction of visceral fat gain, prevention of elevated lipids, leptin, glucose and insulin as well as a reduction in several inflammatory cytokines including TNF-s and IL-6 (6,10).
AI has also been shown in mice to prevent damage from alcohol consumption (yep, they got mice drunk). The mice that weren’t lucky enough to get a dose of AI with their bourbon saw their cholesterol and triglycerides jump up and fat burning take a nose dive, while the group that received AI didn’t experience these side effects from the alcohol ingestion (11).
Mixed Capsaicinoids >90% (MC)
Capsaicinoids are a group of chemicals naturally occurring in chili peppers which possess bioactive properties with the potential to encourage fat loss through multiple angles.
Capsaicin, contained in the mixed capsaicinoids, is a well-researched TRPV1 agonist. The Transient receptor potential Vanilloid protein (TRPV1), is involved with detection and regulation of body temperature as well as sensation of pain.
A few years ago some groundbreaking research came out implicating this receptor as a major player in obesity. This is the receptor that capsaicin from chili peppers interacts with, and quite a bit of research has demonstrated that triggering TrpV1 has a significant effect on increasing energy expenditure and decreasing body fat.
Additionally, TrpV1 binding has a profound effect on the upregulation of Brown Adipose Tissue (BAT), which is the more favorably metabolically active type of fat that cranks up energy expenditure, and basically wastes calories to generate heat.
Capsaicin hits this TRPV1 angle hard, demonstrating effects such as thermogenesis, anti-inflammation, pain reduction, cardioprotection, and cholesterol support. It also acts as a digestive stimulant, and enhances permeability to micronutrients for better absorption (12).
With mixed capsaicinoids however, capsaicin is only part of the story. It gets better.
MC has been shown to augment the impact of calorie restriction on weight loss. When cutting calories, people tend to experience an increase in hunger, decrease in sense of fullness after meals, and, over time, a decrease in energy expenditure and fat oxidation. All sneaky methods the body invokes to keep us stuck where we’re at. MC has been shown to reverse all of this, allowing you to cut calories and actually see sustained weight loss without feeling miserable (13).
In a double blind crossover study using human subjects, researchers looked at the effect of MC combined with exercise, vs. a placebo and exercise. They had the subjects do 30 minutes of exercise, and then took blood samples at multiple time points after the workout. They found that the MC group had increased FFA’s and glycerol in their bloodstream at all time points compared to placebo (14). This is a marker showing that stored triglycerides in the fat cell (FFA’s with a glycerol backbone), have been liberated into the blood stream where they can then be transported and oxidized. So this tells us that MC is definitely increasing the first step of the fat burning process during exercise, known as lipolysis.
In a systematic review paper, which gathered data from 563 subjects, MC was found to increase energy expenditure, reduce energy intake and appetite, reduce abdominal fat, and increase fat oxidation (not just lipolysis) (15).
Looking closer at the appetite suppression angle, a meta-analysis showed that ingesting MC prior to meals reduced ad-libitum (meaning, “eat until you’re full”) food intake by an average of 74 calories (16). Additionally, a RCT found similar results, and although it was using a combo product including MC as opposed to MC by itself, it is still worth mentioning. They found the supplemental group noticed a significantly greater increase in satiety over the placebo group, as well as an increase in thermogenesis (17).
Carnitine Fumarate (CF)
L-Carnitine is an amino acid with a primary function of carrying fatty acids into the mitochondria so they can be oxidized. It also favorably manipulates the Acyl COA/Acetyl COA ratio in favor of fat burning, and plays a key role in energy metabolsm (18).
Fumarate is a component of the Krebs cycle and plays a key role in generating energy.
The Carnitine & Fumarate combination, as CF, will help re-supply depleted carnitine to support optimal fat oxidation while also positively modulating osteoblast function at a rate about 10-fold greater than regular L-Carnitine, which has a significant impact on whole body metabolism and energy expenditure (also previously discussed in the AI section) (19,20). If you’ve read the EvoMuse BMP write-up, you’ll know how big of a deal this osteoblast angle really is.
In rats fed a fattening diet for 16 weeks, to the point of giving them metabolic syndrome, they developed central obesity, dyslipidemia, hypertension, impaired glucose tolerance, hyperinsulinemia, and NAFLD. The rats that were given Carnitine experienced an attenuation of ALL of these issues (21). Another rat study demonstrated that Carnitine was able to counteract obesity induced muscle fiber transition, and restore a muscle oxidative metabolic phenotype (22).
Momordin is a bioactive glycoside extracted from the bitter melon fruit grown throughout Asia, Africa & The Caribbean.
This is the third ingredient in the formula to target PPAR-d, in addition to GM and AI.
As a refresher, increased expression of this nuclear receptor has been shown to increase fatty acid oxidation in skeletal muscle by shifting the body’s metabolic preference away from carbohydrate in favor of lipids (23). Momordin has been shown to upregulate human PPAR-d expression in vitro (24).
A study done in 2011 showed Bitter Melon Juice (containing momordin) was able to have a two-pronged attack on fat metabolism by inhibiting its storage as well as increasing rate of lipolysis in human fat cells (25).
In mice fed a high fat diet, the group receiving Bitter Melon bioactives lost weight, improved glucose metabolism and raised insulin sensitivity by increasing GLUT-4 density in skeletal muscle cells (26). It can also potentially slow gastric emptying, which improves glucose metabolism and insulin signaling (27).
Mangiferin is known as a xanthanoid, and it is found in mangoes as well as a few other places in nature. It represents the 2nd DCP ingredient to target PPAR-a, along with GM.
As a refresher on PPARa, its activation is directly involved with all three stages of fat burning, and is one of the most important players in lipid metabolism. It is triggered naturally during calorie deprivation and in severe carbohydrate restriction to aid in the production of ketones. Mangiferin has been shown in several studies to effectively upregulate PPAR-a (28–30).
Unlike PPAR-a, PPAR-g is responsible for increasing storage of fat in the fat cell. Mangiferin has been shown to reduce its activity thereby reducing fat storage (31).
As discussed previously in the RE section, Mangiferin also targets DGAT. As a refresher, diglyceride acetyltransferase (DGAT) is the enzyme responsible for the third and final step in producing a triglyceride from glycerol and fatty acids. Downregulate DGAT, which Mangiferin has been shown to do, and you reduce fat accumulation and increase leptin sensitivity significantly (28).
Remember CPT1 from the AI section? Mangiferin hits this angle as well, causing an upregulation of CPT1, encouraging increased fat burning. It also cranks up Lipoprotein Lipase (LPL), another necessary enzyme in the fat burning process (28).
Mangiferin has been shown to improve glucose utilization by increasing GLUT4 density on the muscle cell, while activating AMPK (31,32). Along these lines, it has also been shown to reduce the cognitive decline associated with the downstream effects of diabetes by reducing Advanced Glycation End Products, oxidative stress, and inflammation (33).
A brand new human study on Mangiferin showed some excellent results. Subjects were overweight with hyperlipidemia. After 12 weeks of either Mangiferin or placebo supplementation, the Mangiferin group had decreased triglycerides, improved insulin sensitivity, increased HDL, increased ketones, and increased LPL. Mangiferin also promoted an increased oxidation of FFA’s (34).
Lastly, Mangiferin has been shown to prevent the differentiation of adipocytes, steering satellite cells away from becoming fat cells (35).
The one side effect that comes hand in hand with Mangiferin supplementation is carnitine depletion. Thanks to the CM in this formula, this will not be an issue.
Octopamine is a naturally occurring amine found endogenously in the human brain as well as plants like bitter orange, and is structurally similar to norepinephrine.
As a selective activator of the Beta-3 adrenoreceptor, Octopamine can encourage transdifferentiation of mature white fat cells into brite/beige cells (see the EvoMuse BRITE write up for details on this process and the numerous benefits thereof) (36–38).
Octopamine has been shown to increase lipolysis in white fat, and oxidation in brown fat (37). It also stimulates FFA oxidation in the liver. This can prevent excess FFA’s from being reabsorbed by fat cells (39).
Additionally, Octopamine may provide a bit of an energy/mood boost as even though it shows a poor binding to the main stimulatory adrenergic receptors, it has still been shown to act as a CNS stimulant (40).
Quick Overview of FTO
The “Fat mass and obesity-associated protein” is an enzyme encoded by the FTO gene, which does a pretty good job of describing itself in the name. Subjects with a gene variant overexpressing FTO show higher levels of insulin and insulin resistance.
FTO predisposes individuals to fat gain and obesity, whereas FTO-negative subjects are resistant to obesity due to enhanced energy expenditure, and reduced conversion of carbohydrates to fat (de-novo lipogenesis).
Fat cells deficient in FTO exhibit 4x higher expression of UCP1 in the mitochondria, and this FTO deficiency leads to a “browning” of white adipocytes (see EvoMuse BRITE for more on why that’s awesome, which is our product directly targeting this browning effect through multiple angles) (41–43).
The next two ingredients in DCP, among other things, target FTO.
Quercetin is one of the most studied flavonoids, and has tons of extremely impressive research backing its benefits. Problem is, most of that research is either in vitro, or, in animals with dissimilar digestion/absorption framework.
The reason for the lack of good human in vivo data, is that the efficacy of this nutrient is extremely limited in humans due to low bioavailability, caused by low aqueous solubility and minimal absorption in the gut. The human liver also does a number on it through some pretty unfavorable conjugation.
One study in particular looked at human ingestion of a huge oral dose of quercetin (4g), and found no measurable increase in plasma or urine quercetin concentrations…yikes. What the researchers did find, however, was that about 53% of the quercetin dose was recovered in subject’s feces, suggesting extensive degradation by microorganisms in the gut (44).
Now comes the cool part.
Cocrystals are multi-component molecular crystals that dramatically improve bioavailability of certain nutrients (flavonoids in particular). By turning quercetin into a cocrystal with bromide, the pharmacokinetic properties become vastly superior, and this process yields a new form of quercetin which is able to completely overcome the problem of water insolubility and bioavailability (45).
This means we can finally reap all of the awesome benefits of quercetin.
For our purposes in the DCP formula, these benefits relate to multiple, potent angles to augment fat loss.
First things first, quercetin has a very high binding affinity to the aforementioned FTO gene. This means it will basically put FTO in a headlock and prevent it from carrying out its diabolical plan to keep you from losing fat. Through FTO inhibition, quercetin will favorably tip the lipolysis/adipogenesis ratio, encouraging fat loss while reducing fat storage (46,47).
Then it hits that same idea through a different pathway, just to be sure. Specifically, it does so by increasing the expression of ATGL and HSL, while downregulating FAS, LPL, and aP2 (48). Simply put, it cranks up fat burning enzymes while suppressing fat storing enzymes.
Quercetin also targets the AMPK pathway. Here’s what you need to know about AMPK in 10 seconds:
AMPK is an enzyme that regulates energy balance. When activated, it triggers fat oxidation (liver and skeletal muscle), puts the brakes on fat storage, encourages ketone production, tells the muscles to take up glucose, and as a few other cool things. Some of the benefits of exercise can be tied back to simple AMPK activation.
Quercetin has been shown to favorably regulate this AMPK pathway under several conditions, including overfeeding (49). It has also been shown to activate AMPK in both normal and insulin resistant metabolic conditions (AMPK signaling can get pretty botched in insulin resistant folks) (50).
Supplemental quercetin (given to mice) suppressed fat storage hormones, inhibited lipid accumulation in fat cells, and reduced body weight by almost 40%! (51).
Several animal studies have looked at the administration of a fattening diet, with and without quercetin, to see if any benefit from supplementation can be found. Here’s a couple of highlights:
Excess body fat tends to coincide with adipose tissue inflammation, which contributes to a dysfunctional fat cell and dysregulated adipokine secretion (54). Fat cells should be able to store fat (necessary for survival), and then also be good at releasing it to fuel the body’s energy demands. The more excess fat you pack on, the more this in/out process goes haywire, and the “in” switch gets stuck on.
It’s a complex process, so here’s what you need to know: Quercetin reduces fat cell inflammation, which should allow fat cells to respond better to dieting/calorie restriction (51,55). Through a direct effect on mitochondrial processes in the fat cell, quercetin favorably modulates multiple adipokines (54).
Lastly, quercetin can actually prevent the differentiation of stromal cells into adipocytes, which is a huge metabolic benefit (48).
Fucoxanthin, a natural xanthophyll found in brown algae and seaweed, represents our 2nd ingredient in the formula to attack FTO. It is also the 2nd ingredient to target PPAR-g suppression, and through this angle fucoxanthin has been shown to suppress fat storage (56).
A 2015 review in the Journal of Nutrition, Metabolism, and Cardiovascular Diseases called fucoxanthin a “promising option for prevention and treatment of obesity” (57).
Fucoxanthin has been shown in several studies to increase metabolic rate, increase FFA oxidation, increase heat production, induce browning of white fat, and upregulate UCP1 (58–60).
Mice fed a fattening diet with fucoxanthin showed increased expression of Beta-3 adrenergic receptor mRNA in white fat tissue (aside from the general benefits of that, it could allow Octopamine to work even better) (61).
Fucoxanthin increases FFA oxidation and reduces fat storage in a different way as well, by targeting AMPK activation (62). It has also been shown to help reduce blood glucose and improve insulin sensitivity, not only by increasing GLUT4 translocation in skeletal muscle, but also by regulating specific cytokines in fat cells (59,60).
Menthol is a naturally occurring monoterpene, and can be found in wild mint and peppermint. We’re going to revisit beta-3 AR’s here briefly to understand the benefit of Menthol. Beta-3 AR’s are found in only a few tissues in the body, the important one being brown fat. Activation of these receptors in brown fat causes an increase in energy expenditure. Things like norepinephrine release, or Octopamine can activate these receptors.
In addition to these beta-3 receptors, brown fat has temperature receptors, basically letting the body know when it senses cold, called TRPM8 receptors (also known as CMR1 receptors).
When these receptors are triggered by cold, brown fat responds by upregulating thermogenesis to warm the body (63). Menthol actually binds to these receptors, essentially tricking the body into thinking it just sensed a cold temperature, therefore carrying out the same desired effect of increased thermogenesis. White fat also contains these TRPM8 receptors, and when activated, they transdifferentiate into brite cells expressing UCP1 (64). Menthol also binds to something called the Transient Receptor Potential A1 (TRPA1), which is another cold-sensing receptor linked to brown fat activation (65,66).
In summary, DCP aims to optimize your fat loss efforts by favorably modulating DGAT, PPAR’s, inflammatory cytokines, CPT1, PDK4, Osteoblasts, TRPV1, UCP1, AMPK, LPL, FTO, lipolysis, FFA oxidation, brite cells, TRPM8, appetite suppression, and more. Fat doesn’t stand a chance!
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